Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis Inflammatory Bowel Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 170
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the clinical efficacy, safety and tolerability of apremilast (30 mg twice daily \[BID\] and 40 mg BID), compared with placebo, in participants with active Ulcerative Colitis (UC).

Detailed description:
Approximately 165 participants (55 subjects per arm) will be randomized in a 1:1:1 ratio to receive oral apremilast (30 mg BID or 40 mg BID), or identically appearing placebo BID for up to 12 weeks, followed by 40 weeks of blinded treatment with apremilast (30 mg BID or 40 mg BID).

At the end of the Blinded Active-treatment Phase (Week 52), participants who have a Mayo endoscopy score ≤ 1 will have the opportunity to participate in the Extension Phase. Participants enrolled in the Extension Phase will receive apremilast for an additional 52 weeks (Weeks 52 to 104). With the implementation of Amendment 4, participants entering the Extension Phase will receive apremilast 30 mg BID. Subjects currently in the Extension Phase who are receiving apremilast 40 mg BID will be switched to 30 mg BID at the next scheduled visit.

Arms:
arm 1: Apremilast 30 mg by mouth (PO) twice a day (BID) for 12 weeks

After 12 weeks:

* Participants who achieve at least a 20% decrease from baseline in the total Mayo score (TMS) will continue to receive apremilast 30 mg BID for an additional 40 weeks. (Wk 52)
* Participants who do not achieve at least a 20% decrease from baseline in the TMS will receive apremilast 40 mg BID for an additional 40 weeks (Wk 52)

After 52 weeks, participants who are eligible for the Extension Phase will continue to receive the same dose of apremilast assigned at Wk 12 (30 mg BID or 40 mg BID) for an additional 52 weeks (Wk 104) arm 2: Apremilast 40 mg by mouth (PO) twice a day (BID) for 12 weeks

After 12 weeks, participants assigned to the 40 mg BID dose of apremilast at baseline will continue to receive apremilast 40 mg BID for an additional 40 weeks (Wk 52)

After 52 weeks, participants who are eligible for the extension Phase will continue to receive apremilast 40 mg BID for an additional 52 weeks (Wk 104) arm 3: Identically matching placebo by mouth (PO) twice a day (BID) for 12 weeks. After 12 weeks all participants randomized to placebo at baseline will be re-randomized to receive apremilast 30 mg or 40 mg BID for an additional 40 weeks (Wk 52)

After Wk 52, participants who are eligible for the extension phase will continue to receive the same dose of apremilast assigned at Wk 12 (30 mg BID or 40 mg BID) for an additional 52 weeks (Wk 104)

Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_002.pdf: 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
1
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
TITLE PAGE
A PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) 
FOR TREATMENT OF SUBJECTS WITH ACTIVE 
ULCERATIVE COLITIS
INVESTIGATIONAL PRODUCT:
Apremilast
PROTOCOL NUMBER:
CC-10004-UC-001
DATE FINAL:
19 Feb 2014
AMENDMENT 1 FINAL:
13 Aug 2014
AMENDMENT 2 FINAL:
13 Apr 2015
AMENDMENT 3 FINAL:
20 Jul 2016
AMENDMENT 4 FINAL:
08 Aug 2018
EudraCT NUMBER:
2014-002981-64
IND NUMBER:
119696
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
2
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
6
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
PROTOCOL SUMMARY
Study Title
A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and 
safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis.
Indication
Active ulcerative colitis (UC).
Objectives
Primary Objective
To evaluate the clinical efficacy of apremilast (30 mg twice daily [BID] and 40 mg BID),
compared with placebo, in subjects with active UC.
Secondary Objectives
!
To evaluate the safety and tolerability of apremilast (30 mg BID and 40 mg BID),
compared with placebo, in subjects with active UC
!
To evaluate the long-term safety in subjects with active UC, receiving apremilast (30 
mg BID or 40 mg BID)
 
 
 
 
 
 
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
7
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
 
 
 
 
 
Study Design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
study to evaluate the efficacy and safety of 2 doses of apremilast in subjects with active UC 
(defined as a total Mayo score [TMS] of ≥ 6 to ≤11, with an endoscopic subscore ≥ 2).
Approximately 165 subjects (55 subjects per arm) will be randomized in a 1:1:1 ratio to receive 
oral apremilast (30 mg BID or 40 mg BID), or identically appearing placebo BID for up to 12 
weeks, followed by 40 weeks of blinded treatment with apremilast (30 mg BID or 40 mg BID). 
At the end of 52 weeks in the study, subjects who have a Mayo endoscopy score ≤1 will have 
the opportunity to participate in the Extension Phase and will receive apremilast for an additional 
52 weeks.
Treatment assignment will be stratified via an Interactive Voice Response System (IVRS)/or an 
Interactive Web Response System (IWRS) based on (1) concomitant use of oral corticosteroids 
and (2) previous exposure to immunosuppressants (eg, 6-mercaptopurine [6-MP], azathioprine 
[AZA], or methotrexate [MTX]). The number of subjects with previous exposure to 
immunosuppressants is targeted to comprise no more than 50% of the subjects enrolled, and no 
less than 30%. 
The study will consist of 5 phases:
!
Screening Phase – up to 4 weeks
!
Double-blind Placebo-controlled Phase – Weeks 0 to 12
!
Blinded Active-treatment Phase – Weeks 12 to 52
!
Extension Phase – Weeks 52 to 104 
o
The 52-week extension is an active-treatment phase and henceforth will be 
referred to as the Extension Phase for the remainder of the document. The 
Extension Phase was blinded prior to the implementation of Amendment 4. 
Following the implementation of Amendment 4, the Extension Phase will be 
open-label and all subjects will receive 30 mg BID as of their next visit.
!
Post-treatment Observational Follow-up Phase – The 4-week period after the last 
dose of investigational product (IP)
Double-blind Placebo-controlled Phase
Eligible subjects will enter the Double-blind, Placebo-controlled Phase at the Baseline Visit 
(Week 0/Visit 2).  Subjects will be randomly assigned to study treatment as described above.  
With the aim to mitigate potential dose-related side effects associated with apremilast, such as 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
8
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
headache and gastrointestinal (GI) disturbances, apremilast-treated subjects will be dose-titrated 
in 10-mg/day increments over the first 8 days of treatment.  All subjects will receive blister cards 
of identical appearance to maintain blinding (Table 5). Subjects will continue to receive the 
treatment assigned at baseline for 12 weeks.
Blinded Active-treatment Phase
Following 12 weeks of treatment, subjects will enter the Blinded Active-treatment Phase.  At the 
Week 12 visit, subjects will be evaluated for clinical improvement based on the TMS.  The 
endoscopy subscore assessed by the investigator will be used for the calculation of the Week 12 
TMS.
Subjects who achieve at least a 20% decrease from baseline in the TMS at Week 12 will receive 
the following IP between the Week 12 Visit and the Week 52 Visit:
!
Subjects who were randomized to apremilast (30 mg BID or 40 mg BID) at baseline will 
continue to receive the treatment assigned at baseline.  
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).
Subjects who do not achieve at least a 20% decrease from baseline in the TMS at Week 12 will 
receive the following IP until the Week 52 Visit:
!
Subjects who were randomized to apremilast 30 mg BID at baseline will be re-assigned 
apremilast 40 mg BID, with no dose titration.
!
Subjects who were randomized to apremilast 40 mg BID at baseline will continue to 
receive apremilast 40 mg BID.
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).
In order to maintain the blind for the treatment assigned at baseline, all subjects will receive 
blister cards of identical appearance during the titration period beginning at Week 12. However, 
for subjects continuing on the dosage of apremilast assigned at baseline, and for subjects who are 
not undergoing dose titration (as noted above), the IP included in the “titration” portion of the 
blister card will include the total daily dose of apremilast (30 or 40 mg BID) and will not include 
the dose titration.
Extension Phase
At the end of the Blinded Active-treatment Phase (Week 52), subjects who have a Mayo
endoscopy score ≤1 will have the opportunity to participate in the Extension Phase. Subjects 
participating in the Extension Phase will receive apremilast for an additional 52 weeks (Weeks 
52 to 104). With the implementation of Amendment 4, subjects entering the Extension Phase will 
receive apremilast 30 mg BID. Subjects currently in the Extension Phase who are receiving 
apremilast 40 mg BID will be switched to 30 mg BID at the next scheduled visit.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
9
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Post-treatment Observational Follow-up Phase
All subjects are required to spend 4 weeks in the Post-treatment Observational Follow-up Phase 
following the last dose of IP.
Study Population
The study population consists of female and male subjects 18 years and older at the time of 
signing the informed consent form (ICF).  The major eligibility criteria are:
!
Diagnosis of UC with a duration of at least 3 months, prior to the Screening Visit
!
TMS ≥ 6 to ≤ 11 prior to randomization in the study (Section 6.7)
!
Mayo endoscopic subscore ≥ 2 prior to randomization in the study
!
Subjects must have had a therapeutic failure, been intolerant to, or have a 
contraindication to at least one of the following: oral aminosalicylates (ie, 
5-aminosalicylic acid [5-ASA] compounds or sulfasalazine [SSZ]), budesonide, 
systemic corticosteroids, or immunosuppressants (eg, 6-mercaptopurine [6-MP], 
azathioprine [AZA], or methotrexate [MTX])
!
Subjects receiving oral aminosalicylates may continue their use during the study, 
provided that treatment started at least 6 weeks prior to screening, and has been at a 
stable dose for at least 14 days prior to the Screening Visit.
!
Subjects receiving oral corticosteroids may continue their use, provided that the dose 
(prednisone ≤ 20 mg/day or equivalent, budesonide ≤ 9 mg/day) has been stable for 3
weeks prior to the Screening Visit and must remain stable until the subject is eligible 
to start corticosteroids tapering, beginning at the Week 12 Visit.
Length of Study
Subjects will spend up to 112 weeks in this study: up to 4 weeks in the Screening Phase; 12 
weeks in the Double-blind Placebo-controlled Phase and 40 weeks in the Blinded Active-
treatment Phase. Subjects who participate in the Extension Phase will spend an additional 52 
weeks in the study.  All subjects are required to spend 4 weeks in the Post-treatment 
Observational Follow-up 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 
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Study Treatments
Subjects will receive one of two dose regimens of apremilast in the Double-blind Placebo-
controlled Phase (30 mg BID or 40 mg BID), or placebo BID.  During the Blinded Active-
treatment Phase, subjects will receive apremilast 30 mg BID or 40 mg BID.  With the 
implementation of Amendment 4, subjects who participate in the Extension Phase will receive 
apremilast 30 mg BID. Subjects currently receiving 40 mg BID in the Extension Phase will be 
switched to 30 mg BID at the next scheduled visit. Apremilast will be provided in blister cards as 
10-mg, 20-mg, or 30-mg tablets in the clinical image.  Matched placebo tablets will also be 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
10
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
provided.  Tablets will be taken by mouth twice daily, morning and evening, approximately 12 
hours apart, with no food restrictions.
Overview of Efficacy Assessments
!
TMS at baseline, Week 12, and Week 52, or at the Early Termination Visit if the 
Early Termination Visit occurs prior to Week 52
!
Modified Mayo score (based on stool frequency, rectal bleeding, and endoscopy) at 
baseline, Week 12, and Week 52
!
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subjects participating in the Extension Phase, through Week 104 and at the 
Observational follow-up Visit.
!
Endoscopy (flexible rectosigmoidoscopy) during the Screening Phase, Week 12, and 
Week 52 or at the Early Termination Visit if the Early Termination Visit occurs prior 
to Week 52
!
Colonoscopy, as opposed to rectosigmoidoscopy, is required at screening only if one 
was not performed within 12 months prior to the Screening Visit.
Overview of Safety Assessments
!
Adverse events (AEs)
!
Physical examinations
!
Vital signs
!
Body weight
!
Electrocardiograms (ECG)
!
Clinical laboratory safety evaluations
!
Pregnancy tests
 
 
 
 
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................19
1.1.
Apremilast..............................................................................................................19
1.2.
Ulcerative Colitis....................................................................................................20
1.3.
Nonclinical Studies.................................................................................................21
1.3.1.
In Vitro Activity .....................................................................................................21
1.3.2.
In Vivo Anti-inflammatory Activity in Animals......................................................21
1.3.2.1.
2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced Colitis Mouse Model 
of IBD ....................................................................................................................21
1.4.
Clinical Summary...................................................................................................22
1.4.1.
Clinical Pharmacology............................................................................................22
1.4.2.
Safety.....................................................................................................................23
1.4.3.
Dose Justification ...................................................................................................24
2.
STUDY OBJECTIVES...........................................................................................28
2.1.
Primary Objective...................................................................................................28
2.2.
Secondary Objectives .............................................................................................28
 
3.
STUDY ENDPOINTS............................................................................................30
3.1.
Primary Endpoint....................................................................................................30
3.2.
Secondary Endpoints ..............................................................................................30
3.2.1.
Secondary Efficacy Endpoints ................................................................................30
3.2.2.
Secondary Safety Endpoints ...................................................................................30
4.
OVERALL STUDY DESIGN ................................................................................33
4.1.
Study Design ..........................................................................................................33
4.1.1.
Internal Celgene Safety Monitoring During the Apremilast Program ......................35
4.1.2.
Internal Data Safety Monitoring Board During the Study........................................35
4.1.3.
External Safety and Efficacy Monitoring During Apremilast Program....................35
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4.2.
Study Design Rationale ..........................................................................................35
4.3.
Study Duration .......................................................................................................37
4.4.
End of Trial ............................................................................................................37
5.
TABLE OF EVENTS.............................................................................................38
6.
PROCEDURES......................................................................................................42
6.1.
Informed Consent ...................................................................................................42
6.2.
Contraception Education.........................................................................................42
6.3.
Medical and Disease History ..................................................................................42
6.4.
Inclusion/Exclusion Criteria....................................................................................42
6.5.
Prior/Concomitant Medications and Therapies........................................................43
6.6.
Safety Assessments.................................................................................................43
6.6.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ...............43
6.6.2.
Hepatitis B and C....................................................................................................43
6.6.3.
Vital Signs, Height, and Weight..............................................................................43
6.6.4.
Complete and Limited Physical Examinations ........................................................43
6.6.5.
Vasculitis Assessment ............................................................................................44
6.6.6.
Psychiatric Evaluation ............................................................................................44
6.6.7.
Stool Culture / Microbiology ..................................................................................44
6.6.8.
Twelve-lead Electrocardiogram ..............................................................................44
6.6.9.
Clinical Laboratory Evaluations..............................................................................45
6.6.10.
Adverse Events.......................................................................................................45
6.6.10.1.
Adverse Events of Special Interest..........................................................................45
6.7.
Efficacy Assessments .............................................................................................46
6.7.1.
Subject Diary for Ulcerative Colitis Disease Activity..............................................46
6.7.2.
Endoscopy..............................................................................................................46
6.7.3.
Total Mayo Score ...................................................................................................47
6.7.4.
Modified Mayo Score.............................................................................................48
6.7.5.
Partial Mayo Score .................................................................................................48
6.7.6.
Physician Global Assessment .................................................................................48
6.8.
Disease and Health-related Quality of Life Assessments.........................................48
6.8.1.
The Medical Outcome Study Short Form 12-item Health Survey V2 ......................48
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6.12.
Dosing....................................................................................................................50
6.12.1.
Investigational Product Dispensing and Counting ...................................................50
6.12.2.
Site Instructions for Dosing the Subject ..................................................................50
6.13.
Early Termination Visit ..........................................................................................50
6.13.1.
Lost to Follow-up ...................................................................................................50
6.14.
Study Completion...................................................................................................51
7.
STUDY POPULATION.........................................................................................52
7.1.
Number of Subjects and Sites .................................................................................52
7.2.
Inclusion Criteria....................................................................................................52
7.3.
Exclusion Criteria...................................................................................................53
8.
DESCRIPTION OF STUDY TREATMENTS........................................................56
8.1.
Description of Investigational Product(s)................................................................56
8.2.
Treatment Administration and Schedule .................................................................56
8.3.
Method of Treatment Assignment...........................................................................58
8.4.
Packaging and Labeling..........................................................................................59
8.5.
Investigational Product Accountability and Disposal ..............................................59
8.6.
Investigational Product Compliance........................................................................59
8.6.1.
Overdose ................................................................................................................60
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................61
9.1.
Permitted Concomitant Medications and Procedures...............................................61
9.2.
Prohibited Concomitant Medications and Procedures..............................................62
9.3.
Required Concomitant Medications and Procedures................................................62
10.
STATISTICAL ANALYSES..................................................................................63
10.1.
Overview................................................................................................................63
10.2.
Study Population Definitions ..................................................................................63
10.3.
Sample Size and Power Considerations...................................................................63
10.4.
Background and Demographic Characteristics........................................................63
10.5.
Subject Disposition.................................................................................................64
10.6.
Efficacy Analysis....................................................................................................64
10.6.1.
Primary Efficacy Endpoint......................................................................................64
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10.6.2.
Secondary Efficacy Endpoints ................................................................................64
10.7.
Safety Analysis.......................................................................................................65
11.
ADVERSE EVENTS..............................................................................................66
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................66
11.2.
Evaluation of Adverse Events.................................................................................66
11.2.1.
Seriousness.............................................................................................................66
11.2.2.
Severity/Intensity....................................................................................................67
11.2.3.
Causality ................................................................................................................68
11.2.4.
Duration .................................................................................................................68
11.2.5.
Action Taken..........................................................................................................69
11.2.6.
Outcome.................................................................................................................69
11.3.
Abnormal Laboratory Values..................................................................................69
11.4.
Pregnancy...............................................................................................................69
11.4.1.
Females of Childbearing Potential ..........................................................................69
11.4.2.
Male Subjects.........................................................................................................70
11.5.
Reporting of Serious Adverse Events......................................................................70
11.5.1.
Safety Queries ........................................................................................................70
11.6.
Expedited Reporting of Adverse Events..................................................................71
12.
DISCONTINUATIONS .........................................................................................72
13.
EMERGENCY PROCEDURES.............................................................................73
13.1.
Emergency Contact.................................................................................................73
13.2.
Emergency Identification of Investigational Products .............................................73
14.
REGULATORY CONSIDERATIONS...................................................................74
14.1.
Good Clinical Practice............................................................................................74
14.2.
Investigator Responsibilities ...................................................................................74
14.3.
Subject Information and Informed Consent.............................................................75
14.4.
Confidentiality........................................................................................................75
14.5.
Protocol Amendments.............................................................................................75
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14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................75
14.7.
Ongoing Information for Institutional Review Board/Ethics Committee .................76
14.8.
Closure of the Study ...............................................................................................76
15.
DATA HANDLING AND RECORDKEEPING.....................................................77
15.1.
Data/Documents.....................................................................................................77
15.2.
Data Management...................................................................................................77
15.3.
Record Retention....................................................................................................77
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................79
16.1.
Study Monitoring and Source Data Verification......................................................79
16.2.
Audits and Inspections............................................................................................79
17.
PUBLICATIONS ...................................................................................................80
18.
REFERENCES.......................................................................................................81
19.
APPENDICES........................................................................................................83
 
APPENDIX B.
MAYO SCORING SYSTEM.........................................................................84
APPENDIX C.
12-ITEM SHORT FORM HEALTH SURVEY, VERSION 2 ........................85
APPENDIX E.
HEPATITIS B CRITERIA INDICATING CURRENT INFECTION 
OR RISK OF CURRENT INFECTION..................................................................88
APPENDIX F.
HEPATITIS B CRITERIA INDICATING THE ABSENCE OF 
CURRENT INFECTION........................................................................................89
APPENDIX G.
BRISTOL STOOL CHART...........................................................................90
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
LIST OF TABLES
 
 
 
Table 4:
Table of Events.......................................................................................................38
Table 5:
Treatment Schema for Dose Titration .....................................................................57
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Protocol CC-10004-UC-001
Celgene Corporation
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................36
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1.
INTRODUCTION 
1.1.
Apremilast
Apremilast (CC-10004) is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) that 
works intracellularly to modulate a network of pro- and anti-inflammatory mediators.  
Phosphodiesterase 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the 
dominant PDE in inflammatory cells.  Inhibition of PDE4 elevates intracellular cAMP levels, 
which in turn downregulates the inflammatory response by modulating the expression of tumor 
necrosis factor-alpha (TNF-α), interleukin (IL)-23, IL-17, and other pro-inflammatory cytokines.  
Elevation of cAMP also increases anti-inflammatory cytokines.  These pro- and anti-
inflammatory mediators have been implicated in inflammatory bowel disease (IBD), psoriasis 
and psoriatic arthritis (PsA) (Schafer, 2010). Apremilast is currently under clinical development 
for the treatment of inflammatory autoimmune disorders, such as PsA, psoriasis, ankylosing 
spondylitis (AS), Behçet disease (BD), and atopic dermatitis. Detailed information about 
apremilast can be found in the Investigator’s Brochure (IB).
Ulcerative colitis (UC) is an intestinal inflammatory condition that is characterized by T-cell 
activation, and is associated with an atypical Type 2 helper T-cell (Th2) response mediated by 
non-classic natural killer (NK) T-cells producing IL-5 and IL-13.  Ulcerative colitis has been 
associated with the production of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and 
TNF-like ligand 1 (TL1A) (Danese, 2011).  In addition, other helper T-cell lineages have been 
recently characterized, including Th17 cells that produce the proinflammatory cytokine IL-17.  
Levels of IL-17 have been found to be increased in the mucosa of patients with IBD 
(Fujino, 2003).
TNF-α has been shown to play a role in the pathogenesis of UC and Crohn’s disease (CD).
Specifically, elevated levels of TNF-α have been found in the stool, lamina propria, and blood of 
patients with active disease and treatment with TNF-α neutralizing antibodies reduces UC and 
CD disease activity.  One pathway through which TNF-α damages the gut is through 
upregulation of matrix metalloproteinase (MMP) production by gut myofibroblasts, leading to 
extracellular matrix breakdown, tissue destruction, and ulcer formation.  In pokeweed mitogen-
stimulated gut lamina propria mononuclear cells (LPMCs) from normal subjects, apremilast 
significantly reduced TNF-α production by 63% (p < 0.001).  Additionally, apremilast 
significantly inhibited CD and UC patient LPMC-MMP-3 production in vitro (p < 0.001).  The 
reduction in LPMC-MMP-3 production by apremilast was characterized by a significant 
inhibition of LPMC-MMP-3 mRNA and protein production in a dose-dependent manner within 
the concentration range of 2 to 100 μM (Gordon, 2009).  Apremilast has also shown beneficial 
effects in the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model of IBD.  
Administration of apremilast at the dose of 2.5-mg/kg resulted in a reduction of diarrhea and the 
severity of the mucosal damage in the distal large intestine to a degree similar to the positive 
control, 5-ASA; first-line therapy in the standard of care for IBD.  Apremilast had a positive 
trophic effect on intestinal mucosal crypt morphology, particularly by increasing crypt width.  
Apremilast also reduced the loss of body weight induced by TNBS, in a dose-dependent manner.  
Together, these nonclinical results highlight the potential of apremilast in the treatment of IBD.
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As such, apremilast may act to suppress the existing inflammatory response by downregulating 
the expression of TNF-α, IL-5, IL-13 and IL-17 and other inflammatory cytokines present within 
the gastrointestinal (GI) tract, along with the inhibition of further recruitment of immune cells 
into inflamed tissue (Sandborn, 2003). 
1.2.
Ulcerative Colitis
Ulcerative colitis is a chronic, relapsing inflammatory disease of the large intestine characterized 
by inflammation and ulceration of the mucosal and submucosal intestinal layers.  It is one of the 
most common forms of IBD. 
The worldwide incidence of ulcerative colitis is 1.2 to 20.3 cases per 100,000 persons per year, 
and its prevalence is 7.6 to 246.0 cases per 100,000 per year (Danese, 2011).  The highest 
incidence and prevalence of IBD are seen in the populations of Northern Europe and North 
America, and the lowest incidence and prevalence are in continental Asia, where UC is by far the 
most common form of IBD (Danese, 2011).  Although the etiology of UC remains unknown, a 
dysregulation or overstimulation of the mucosal immune system appears to play a critical role in 
the pathophysiology of intestinal inflammation and contributes to mucosal ulceration 
(Ordás, 2012).  Clinical characteristics include rectal bleeding, diarrhea, and abdominal pain, as 
well as extraintestinal manifestations involving the skin, liver, and other sites (Danese, 2011).  
Patients with UC often have a poor quality of life and are at risk for disease flares leading to 
hospitalizations and/or surgeries. 
The main objectives of treatment in patients with UC are to induce and maintain the remission of 
symptoms and mucosal inflammation in order to improve patients’ quality of life.  Treatment of 
UC currently involves pharmacological treatment and surgery, which is indicated when 
pharmacological treatment fails or when a surgical emergency (eg, perforation of the colon) 
occurs.  Treatment takes into consideration the level of clinical activity combined with the extent 
of disease (proctitis, left-sided disease, extensive disease, or pancolitis). Pharmacological 
treatment usually involves aminosalicylates and glucocorticoids as an initial approach. Various 
immunosuppressants, as well as biologic tumor necrosis factor (TNF) blockers, are used in 
refractory or severe disease. Although these drugs can provide clinical benefit, they have 
important limitations. Aminosalicylates are only modestly effective.  Glucocorticoids can cause 
unacceptable adverse events (AEs) and do not provide a benefit as maintenance therapy.
Additionally, immunosuppressant use has been restricted to maintenance therapy and is also 
associated with significant potential toxicities. The TNF blockers, although efficacious, 
predispose patients to serious infections (including opportunistic infections) and possibly 
malignancies, (Clark, 2007; Kornbluth, 2010). Because apremilast specifically inhibits PDE4, 
which increases intracellular cyclic adenosine monophosphate (cAMP) and this modulates 
multiple pro-inflammatory and anti-inflammatory mediators, such as TNF-α, IL-12, and IL-23, it 
is believed there may be a role for this drug in the treatment of UC.
The additional burden caused by comorbidities induced by adverse effects of some of these drugs 
indicates that an unmet medical need exists for effective and well-tolerated orally active agents 
for inducing and maintaining remission in patients with active UC.
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1.3.
Nonclinical Studies
1.3.1.
In Vitro Activity
In lipopolysaccharide (LPS)-challenged peripheral blood mononuclear cells (PBMCs), 
apremilast inhibited, in order of decreasing potency interferon-γ inducible protein-10 (IP-10), 
interferon-γ (IFN-γ), monokine induced by interferon-γ (MIG), TNF-α, IL-12p70, macrophage 
inflammatory protein-1α (MIP-1α), monocyte chemotactic protein-1 (MCP-1), and granulocyte 
macrophage colony-stimulating factor (GM-CSF) production.  Reduction of TNF-α, IFN- γ, IL-
12, and IL-23 expression occurred at the messenger ribonucleic acid (mRNA) level.  It also 
inhibited IFN-γ and IL-2 production by PBMCs stimulated with staphylococcal enterotoxin B.  
In purified human Natural Killer (NK) cells, apremilast inhibited production of TNF-α and GM-
CSF.  Production of IL-8 and leukotriene B4 by polymorphonuclear neutrophils (PMN), and 
TNF-α production by human epidermal keratinocytes (HEK), were also blocked by apremilast in 
vitro.  Apremilast was tested in a model of psoriasis using normal human skin xenotransplanted 
onto beige-severe combined immunodeficient (SCID) mice and triggered with human psoriatic 
NK cells.  Orally administered apremilast (5 mg/kg/day) significantly reduced epidermal 
thickness and proliferation, and decreased the general histopathologic appearance of 
psoriasiform features.  Staining for TNF-α, human leukocyte antigen DR (HLA-DR), and 
intercellular cell adhesion molecule-1 (ICAM-1) in lesional skin was also qualitatively reduced 
by apremilast treatment (Schafer, 2010).
1.3.2.
In Vivo Anti-inflammatory Activity in Animals
1.3.2.1.
2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced Colitis Mouse Model of 
IBD
In the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model of IBD, 
apremilast reduced body weight loss in a dose-dependent manner. At the 2.5-mg/kg dose, 
apremilast reduced diarrhea and the severity of the mucosal damage in the distal large intestine 
to a degree similar to the positive control, 5-aminosalicylic acid (5-ASA; IBD treatment option).
Apremilast had a positive trophic effect on intestinal mucosal crypt morphology, particularly by 
increasing crypt width 
.  Supplemental experimentation demonstrated that, IFN-γ, IP-
10, and monokine gene expression levels did not correlate with colitis severity.  Nevertheless, 
these in vivo data highlight the beneficial effects of apremilast, ie, reducing the damage to the 
colonic mucosa, in the TNBS-induced colitis model. Also, the efficacy of apremilast was 
comparable with that of 5-ASA (anti-inflammatory agent). Together, these results highlight the 
potential of apremilast in the treatment of UC.
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Apremilast (CC-10004)
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Celgene Corporation
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1.4.
Clinical Summary
1.4.1.
Clinical Pharmacology
The pharmacokinetic (PK) disposition of apremilast has been characterized extensively in 
healthy subjects and subjects with PsA, psoriasis, asthma, and rheumatoid arthritis (RA).  In 
healthy subjects under fasting conditions, following oral administration, apremilast was rapidly 
absorbed with maximum plasma concentrations occurring approximately 2.5 hours postdose and 
with an absolute bioavailability of approximately 73%.  
 
 Coadministration with food did 
not alter the extent of absorption; therefore, apremilast can be administered with or without food. 
In vitro data indicated that human plasma protein binding of apremilast was approximately 68%.  
Apremilast was primarily eliminated as metabolites formed via multiple metabolic pathways 
including both cytochrome P450 (CYP)-mediated oxidative metabolism (and subsequent 
glucuronidation) and non-CYP-mediated hydrolysis, with less than 3% excreted unchanged in 
urine and a terminal elimination half-life of approximately 6 to 9 hours.  Apremilast did not 
inhibit CYP enzymes in vitro, suggesting that it is unlikely to inhibit the metabolism of 
coadministered CYP substrates.  There were no clinically significant interactions with 
ketoconazole, MTX, or an oral contraceptive containing ethinyl estradiol and norgestimate, when 
apremilast was coadministered with these drugs.  Pharmacokinetic studies were conducted in 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
subjects with hepatic impairment and subjects with renal impairment.  Hepatic impairment does 
not affect the PK of apremilast, while severe renal impairment increases apremilast exposure 
area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 
approximately 88%. 
Apremilast at doses higher than 30 mg BID has been evaluated previously in healthy volunteers 
in a multiple dose PK and safety study (CC-10004-PK-007), in which 9 subjects received 40 mg 
BID for 14 days; and in a thorough QT study (CC-10004-PK-008) in which 57 subjects received 
50 mg BID for 4.5 days.  Results from the thorough QT study did not show any evidence of 
prolongation of the heart rate-corrected QT interval (QTc), indicating that apremilast in this dose 
range does not pose a risk for prolongation of the QT interval.
1.4.2.
Safety
 
 
As of the cut-off date, 42 clinical studies have been completed, including:
!
24 Phase 1 studies (19 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),
!
10 Phase 2 studies (5 studies in subjects with psoriasis, 1 study in subjects with PsA, 1 
study in subjects with RA, 1 study in subjects with BD, 1 study in subjects with AD, and 
1 study in subjects with asthma),
!
7 Phase 3 studies (3 studies in subjects with psoriasis and 4 studies in subjects with PsA), 
and
!
1 Phase 4 study (in subjects with psoriasis).
A total of 7 clinical studies are currently ongoing:
!
1 Phase 1 study (in healthy subjects),
!
2 Phase 2 studies (1 in pediatric subjects with psoriasis and 1 in subjects with UC),
and
!
4 Phase 3 studies (1 study in subjects with PsA, 1 study in subjects with psoriasis of 
the scalp, 1 study in subjects with BD, and 1 study in subjects with AS).
In completed and ongoing apremilast Phase 2 or Phase 3 studies, 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 TEAEs of diarrhea, nausea, headache occurred within the first 
2 weeks of treatment and most resolved within 4 weeks.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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The majority of reported TEAEs were mild or moderate in severity and resolved while subjects 
continued apremilast treatment. 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. The overall safety profile in 
subjects with AS, BD, and RA is similar to the safety profile in the psoriasis and PsA indications.
 
 
1.4.3.
Dose Justification
Oral doses of apremilast at 30 mg BID and 40 mg BID were selected for this study after 
consideration of the nonclinical pharmacology results and clinical study results in two Phase 1 
PK studies (CC-10004-PK-007 and CC-10004-PK-008), two Phase 2 dose-ranging studies in 
PsA (CC-10004-PSA-001) and psoriasis (CC-10004-PSOR-005).  In the CC-10004-PSOR-005 
study, a clear dose response in efficacy assessments was observed between placebo, and 10, 20,
and 30 mg BID in the psoriasis population.  The CC-10004-PSOR-005 study and CC-10004-PK-
008 study demonstrated that drug exposure increased proportionally with dose (from 10 mg BID 
to 30 mg BID, and from 30 mg BID to 50 mg BID, respectively).  Additionally, apremilast has 
been tolerated with no overt safety concerns in a thorough QTc study (CC-10004-PK-008) with 
doses up to 50 mg BID.
Since the dose response had not been characterized in subjects with ulcerative colitis prior to the 
start of this study, two dose regimens were chosen (30 mg BID and 40 mg BID).  The 30 mg 
BID regimen was chosen due to its demonstrated efficacy and its acceptable safety and 
tolerability profiles in subjects with PsA and psoriasis.  The 40 mg BID regimen was chosen to 
further explore the potential therapeutic effect of apremilast and to evaluate the dose-response 
relationship in this population.  Apremilast at doses higher than 30 mg BID have been evaluated 
previously in healthy subjects in a multiple dose PK and safety study (CC-10004-PK-007), in 
which 9 subjects received 40 mg BID for 14 days; and in a thorough QT study (CC-10004-PK-
008) in which 57 subjects received 50 mg BID for 4.5 days.  In both studies, an increase in the 
incidence of AEs was noted with increasing apremilast doses.  The majority of reported AEs 
were mild to moderate in intensity.  The most frequently reported AEs were nausea, headache, 
decreased appetite, diarrhea, vomiting, and abdominal pain.  There was no evidence of dose-
related changes in vital signs, physical examinations and clinical laboratory findings.  In pooled 
data from Phase 3 PsA studies, the proportion of subjects reporting diarrhea, nausea, and 
headache increased in a treatment- and dose-dependent manner, with the highest incidence 
occurring in the first 2 weeks of treatment.  The majority of reported AEs were mild or moderate 
in severity and resolved with continued therapy.  The incidences of SAEs and other 
clinical/laboratory parameters were similar between the dose groups. 
Of note, available information from several compounds that are approved or were in 
development for IBD at the time of study start suggested that higher doses or more frequent 
dosing are required for the treatment of patients with IBD compared to patients with RA, PsA 
and/or psoriasis such as adalimumab (Humira®) (Humira, 2013), tofacitinib (Xeljanz®) 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
25
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
(Sandborn, 2012, Xeljanz, 2012), and golimumab (Simponi®) (Simponi, 2013).  Risk 
minimization measures such as ongoing safety review and Data Monitoring Committee (DMC) 
oversight were implemented to ensure that the safety of the subjects is adequately monitored.
The results from the first 12 weeks of this study indicated that subjects with active UC treated 
with apremilast 30 mg BID achieved meaningful improvements in symptoms of UC (remission), 
endoscopy, 
 compared to placebo.  Subjects 
treated with apremilast 40 mg BID achieved meaningful improvements in symptoms of UC 
(response) 
 compared to placebo. An acceptable safety profile was observed in 
both the apremilast 30 mg and 40 mg BID dose groups. Based upon the similarity of the clinical, 
endoscopic 
 endpoints in subjects treated with apremilast 30 mg and 40 mg BID 
and the plateau of dose response, as well as the extensive marketed safety experience with this 
dose, the 30 mg BID dose was determined to be the minimum dose that provides the maximum 
treatment response with an acceptable safety profile.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
26
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
27
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to evaluate the clinical efficacy of apremilast (30 mg BID 
and 40 mg BID), compared with placebo, in subjects with active ulcerative colitis (UC).
2.2.
Secondary Objectives
The secondary objectives of the study are:
!
To evaluate the safety and tolerability of apremilast (30 mg BID and 40 mg BID),
compared with placebo, in subjects with active UC
!
To evaluate the long-term safety in subjects with active UC, receiving apremilast (30 
mg BID or 40 mg BID)
 
 
 
 
 
 
 
 
 
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
29
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
The primary endpoint of this study is the proportion of subjects achieving a clinical remission in 
the TMS at Week 12, defined as a TMS of ≤ 2, with no individual subscore > 1
3.2.
Secondary Endpoints
3.2.1.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
!
The proportion of subjects achieving clinical response at Week 12, defined as a 
decrease from baseline in the TMS of at least 3 points and at least 30%, along with a 
reduction in the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS 
of ≤ 1
!
The proportion of subjects achieving endoscopic remission at Week 12, defined as a 
Mayo endoscopic subscore of 0
!
The proportion of subjects achieving endoscopic response at Week 12, defined as a 
decrease from baseline of at least 1 point in the Mayo endoscopic subscore
!
The proportion of subjects achieving a RBS ≤ 1 at Week 12
!
The proportion of subjects achieving clinical remission in the modified Mayo Score
(range: 0 to 9, based on stool frequency (SFS), RBS and endoscopy) at Week 12, 
defined as a score of 2 points or lower, with no individual subscore exceeding 1 point
!
The proportion of subjects achieving clinical response in the modified Mayo Score at 
Week 12, defined as a decrease from baseline at least 2 points and at least 25%, along 
with a reduction in the RBS of at least 1 point or an absolute RBS of ≤ 1 point
!
The proportion of subjects achieving clinical remission at Week 8, defined as a PMS 
of ≤ 2, with no individual subscore > 1
!
The proportion of subjects achieving clinical response at Week 8, defined as a 
decrease from baseline in the PMS of at least 2 points and at least 25%, along with a 
reduction in the RBS of at least 1 point or an absolute RBS of ≤ 1 point
3.2.2.
Secondary Safety Endpoints
The following safety parameters will be evaluated for the duration of the study:
!
Type, frequency, severity, and relationship of AEs to IP
!
Number of subjects who discontinue IP due to any AE
!
Frequency of clinically significant changes in physical examination, vital signs, 
and/or laboratory findings
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
32
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
 
 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
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Confidential and Proprietary
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CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
study to evaluate the efficacy and safety of 2 doses of apremilast in subjects with active UC 
(defined as a total Mayo score [TMS] of ≥ 6 to ≤ 11, with an endoscopic subscore ≥ 2).
Approximately 165 subjects (55 subjects per arm) will be randomized in a 1:1:1 ratio using an 
Interactive Voice Response system (IVRS) or an Interactive Web Response System (IWRS) to 
receive oral apremilast (30 mg BID or 40 mg BID), or identically appearing placebo BID for up 
to 12 weeks, followed by 40 weeks of blinded treatment with apremilast (30 mg BID or 40 mg 
BID).  At the end of 52 weeks in the study, subjects who have a Mayo endoscopy score ≤1 will 
have the opportunity to participate in the Extension Phase and will continue to receive apremilast
for an additional 52 weeks.
Treatment assignment will be stratified via IVRS/IWRS based on concomitant use of oral 
corticosteroids and previous exposure to immunosuppressants (eg, 6-MP, AZA, or MTX).  The 
number of subjects with previous exposure to immunosuppressants is targeted to comprise, no 
more than 50% of the subjects enrolled, and no less than 30%. 
The study will consist of 5 phases:
!
Screening Phase – up to 4 weeks
!
Double-blind Placebo-controlled Phase – Weeks 0 to 12
!
Blinded Active-treatment Phase – Weeks 12 to 52
!
Extension Phase – Weeks 52 to 104
o
The 52-week extension is an active treatment phase and henceforth will be 
referred to as the Extension Phase for the remainder of the document. The 
Extension Phase was blinded prior to the implementation of Amendment 4. 
Following the implementation of Amendment 4, the Extension Phase will be 
open-label and all subjects will receive 30 mg BID as of their next visit.
!
Post-treatment Observational Follow-up Phase – The 4-week period after the last 
dose of investigational product (IP).
Double-blind Placebo-controlled Phase
Eligible subjects will enter the Double-blind Placebo-controlled Phase for 12 weeks, at the 
Baseline Visit (Week 0, Visit 2).  Subjects will be randomly assigned to study treatment as 
described above. With the aim to mitigate potential dose-related side effects associated with 
apremilast, such as headache and gastrointestinal (GI) disturbances, apremilast-treated subjects 
will be dose-titrated in 10-mg/day increments over the first 8 days of treatment (Table 5).  All 
subjects will receive blister cards of identical appearance to maintain blinding. Subjects will 
continue to receive the treatment assigned at baseline for 12 weeks.
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Apremilast (CC-10004)
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Blinded Active-treatment Phase
Following 12 weeks of treatment, subjects will enter the Blinded Active-treatment Phase for 40 
weeks.  At the Week 12 visit, subjects will be evaluated for clinical improvement based on the 
TMS.  The endoscopy subscore assessed by the investigator will be used for the calculation of 
the Week 12 TMS. 
Subjects who achieve at least a 20% decrease from baseline in the TMS at Week 12 will receive 
the following IP between the Week 12 Visit and the Week 52 Visit:
!
Subjects who were randomized to apremilast (30 mg BID or 40 mg BID) at baseline will 
continue to receive the treatment assigned at baseline.  
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).  
Subjects who do not achieve at least a 20% decrease from baseline in the TMS at Week 12 will 
receive the following IP until the Week 52 Visit:
!
Subjects who were randomized to apremilast 30 mg BID at baseline will be re-assigned 
apremilast 40 mg BID, with no dose titration.
!
Subjects who were randomized to apremilast 40 mg BID at baseline will continue to 
receive apremilast 40 mg BID.
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).
In order to maintain the blind for the treatment assigned at baseline, all subjects will receive 
blister cards of identical appearance during the titration period beginning at Week 12. However, 
for subjects continuing on the dosage of apremilast assigned at baseline, and for subjects who are 
not undergoing dose titration (as noted above), the IP included in the “titration” portion of the 
blister card will include the total daily dose of apremilast (30 or 40 mg BID) and will not include 
the dose titration.
Extension Phase
At the end of the Blinded Active-treatment Phase (Week 52), subjects who have a Mayo
endoscopy score ≤1 will have the opportunity to participate in the Extension Phase. Subjects 
participating in the Extension Phase will receive apremilast for an additional 52 weeks (ie, 
Weeks 52 to 104). Subjects entering the Extension Phase will receive apremilast 30 mg BID as 
of their next visit. Subjects currently in the Extension Phase who are receiving apremilast 40 mg 
BID will be switched to 30 mg BID at the next scheduled visit.
Post-treatment Observational Follow-up Phase
All subjects are required to spend 4 weeks in the Post-treatment Observational Follow-up Phase 
following the last dose of IP.
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Apremilast (CC-10004)
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4.1.1.
Internal Celgene Safety Monitoring During the Apremilast Program
In addition to ongoing safety monitoring conducted by investigators and individual study 
personnel, cumulative and interval blinded AEs, SAEs, discontinuations due to AEs, and 
abnormal laboratory findings will be reviewed internally by the Safety Management Team 
(SMT) on a regular basis.  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.  
4.1.2.
Internal Data Safety Monitoring Board During the Study
Unblinded safety data has been reviewed regularly by an internal data safety monitoring board 
(iDSMB) at Celgene that is independent of the study team.  With the implementation of 
Amendment 4, all subjects will be in the Extension Phase and will receive open-label apremilast 
30 mg BID at their next visit. Therefore, the iDSMB is no longer necessary to support
CC-10004-UC-001. 
4.1.3.
External Safety and Efficacy Monitoring During Apremilast Program
Monitoring has been performed by an independent, external DMC assessing both safety and 
efficacy as outlined in the DMC charter.  The DMC was comprised of 3 independent external 
trialists and an independent, external statistician, for whom there was no identified conflict of 
interest.  The DMC was convened approximately every 6 months. Following the meeting with 
the DMC on 27 Oct 2017 the DMC continued to recommend that the study could continue as 
planned.
After all subjects completed the 12-week Placebo-controlled Phase, Celgene determined that the 
DMC was no longer necessary to support the CC-10004-UC-001 study since the safety profile of 
apremilast in UC is similar to that observed in the approved indications and no new safety signal 
emerged in CC-10004-UC-001.
4.2.
Study Design Rationale
This study represents the first investigation of apremilast in subjects with UC.  This study will 
provide information on the safety and clinical efficacy in the UC population prior to advancing 
to larger clinical trials, as well as provide critical information for the design of future studies in 
this population. 
The purpose of this study is to determine whether apremilast is effective and safe in the treatment 
of subjects with active UC.  The primary measure of efficacy will be clinical remission 
determined by the TMS during the Double-blind Placebo-controlled Phase at Week 12.  Clinical 
remission is defined as a TMS ≤ 2, with no individual subscore > 1, at Week 12.  The TMS is a 
widely accepted standard for the evaluation of patients with UC and is commonly used as an 
endpoint in clinical trials (Rutgeerts, 2005).  The laboratory results, AEs, vital signs, 
electrocardiograms (ECGs), pregnancy tests and physical examinations will be monitored to 
evaluate safety.
A schematic diagram illustrating the study design is shown in Figure 1.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
36
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Figure 1:
Overall Study Design
Subjects who achieve at least 20% decrease from baseline in the total Mayo score (TMS) at Week 12 will receive the following study treatment until the Week 52 Visit:
Subjects assigned apremilast (30 mg BID or 40 mg BID) at baseline will continue to receive the treatment assigned at baseline; Subjects assigned placebo at baseline will be re-
randomized to receive apremilast (30 mg or 40 mg BID). 
Subjects who do not achieve at least 20% decrease from baseline in the TMS at Week 12 will receive the following IP until the Week 52 Visit: 
!
Subjects assigned apremilast 30 mg BID at baseline will be re-assigned to receive apremilast 40 mg BID
!
Subjects assigned apremilast 40 mg BID at baseline will continue to receive apremilast 40 mg BID. Subjects assigned placebo at baseline will be re-randomized to 
receive apremilast (30 mg or 40 mg BID)
At the end of 52 weeks in the study, subjects who have a Mayo endoscopy score ≤1 will have the opportunity to participate in the Extension Phase and receive apremilast 30 mg 
BID. Subjects currently in the Extension Phase who are receiving apremilast 40 mg BID will be switched to 30 mg BID at the next scheduled visit.
All subjects are required to spend 4 weeks in the Post-treatment Observational Follow-up Phase following the last dose of IP. 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
37
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
4.3.
Study Duration
Subjects will spend up to 112 weeks in this study: up to 4 weeks in the Screening Phase; 12 
weeks in the Double-blind Placebo-controlled Phase and 40 weeks in the Blinded Active-
treatment Phase. Subjects who participate in the Extension Phase will spend an additional 52 
weeks in the study.  Subjects are required to spend 4 weeks in the Post-treatment Observational 
Follow-up Phase following the last dose of IP.
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 prespecified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
38
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
5.
TABLE OF EVENTS
Table 4:
Table of Events
Screen-
ing 
Phase
Double-blind Placebo-controlled Phase
Blinded Active-treatment Phase
Extension Phase
ET
Post-treatment
Observational 
Follow-up
Phase
Visit Number
1
2
Baseline 
Visit
3
4
5
6a
7
8
9
10
11b
12
13
14
ETc
15d
Week
-4 to -1
0
(Day 1)
2
(± 3 
days)
4
(± 3 
days)
8
(± 3 
days)
12
(± 3 
days)
16
(± 3 
days)
24
(±3
days)
36
(±3
days)
48
(± 3 
days)
52
(±3 
days)
68
(±7
days)
86
(±7
days)
104
(±7
days)
ET
(±3 
days)
Obs. Follow-up 
(± 7 
days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
--
Inclusion / Exclusion 
Criteria
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior / Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test and 
Contraception Educatione
X
X
-
-
-
X
-
-
-
-
X
X
X
X
X
-
Hepatitis B and C Tests
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Clinical Lab Evaluations
X
X
-
-
-
X
-
-
X
-
X
X
X
X
X
-
Stool Culture / 
Microbiology
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Height
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Vital Signs / Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam
X
-
-
-
-
X
-
-
-
-
X
-
-
X
X
-
Limited Physical Exam
-
X
-
-
-
-
-
X
-
-
-
Xf
Xf
-
X
Adverse Eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
39
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Table 4:
Table of Events (Continued)
Screen-
ing 
Phase
Double-blind Placebo-controlled Phase
Blinded Active-treatment Phase
Extension Phase
ET
Post-treatment
Observational 
Follow-up
Phase
Visit Number
1
2
Baseline 
Visit
3
4
5
6a
7
8
9
10
11b
12
13
14
ETc
15 d
Week
-4 to -1
0
(Day 1)
2
(± 3 
days)
4
(± 3 
days)
8
(± 3 
days)
12
(± 3 
days)
16
(± 3 
days)
24
(±3
days)
36
(±3
days)
48
(± 3 
days)
52
(±3 
days)
68
(±7
days)
86
(±7
days)
104
(±7
days)
ET
(±3 
days)
Obs. Follow-up 
(± 7 
days)
Psychiatric Evaluationh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
-
-
-
-
X
-
-
-
-
X
-
-
X
X
-
Subject Diary for UC 
Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Contact: 
Remind subjects who are 
participating in the 
Extension Phase to 
complete diaries 1 week 
before each visit.
-
-
-
-
-
-
-
-
-
-
-
X
X
X
X
X
PGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Partial Mayo Score 
(PMS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopy (Flexible 
Rectosigmoidoscopy/
colonoscopyj
X
-
-
-
-
X
-
-
-
-
X
-
-
-
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
40
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Table 4:
Table of Events (Continued)
Screen-
ing 
Phase
Double-blind Placebo-controlled Phase
Blinded Active-treatment Phase
Extension Phase
ET
Post-treatment
Observational 
Follow-up
Phase
Visit Number
1
2
Baseline 
Visit
3
4
5
6a
7
8
9
10
11b
12
13
14
ETc
15d
Week
-4 to -1
0
(Day 1)
2
(± 3 
days)
4
(± 3 
days)
8
(± 3 
days)
12
(± 3 
days)
16
(± 3 
days)
24
(±3
days)
36
(±3
days)
48
(± 3 
days)
52
(±3 
days)
68
(±7
days)
86
(±7
days)
104
(±7
days)
ET
(±3 
days)
Obs. Follow-up 
(± 7 
days)
Total Mayo Score 
(TMS)
-
X
-
-
-
X
-
-
-
-
X
-
-
-
Xk
-
SF-12v2 (Short Form 
12-item Health Survey, 
version 2)
-
X
-
-
-
X
-
-
-
-
X
-
-
X
-
-
Dispense IP
-
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
Return and Count IP
-
-
X
X
X
X
X
X
X
X
X
X
X
X
X
-
ECG=Electrocardiogram; ET= Early Termination Visit; 
; IP = Investigational Product; Obs. Follow-up=Post-treatment Observational 
Follow-up Phase; 
; PGA= Physicians Global Assessment; PMS= Partial Mayo Score; TMS= Total Mayo Score; UC= ulcerative colitis.
a Subjects will be evaluated based on the TMS at the Week 12 Visit and will receive blinded active IP for an additional 40 weeks (Section 4.1).
b At the Week 52 Visit, subjects who have a Mayo endoscopy score ≤1 will have the opportunity to participate in an Extension Phase and will receive apremilast 30 mg BID. With 
the implementation of Amendment 4, subjects currently in the Extension Phase who are receiving apremilast 40 mg BID will be switched to 30 mg BID at the next scheduled 
visit.
c Subjects who discontinue from the study prior to the Week 52 Visit, or prior to the Week 104 Visit for subjects participating in the Extension Phase, will have the Early 
Termination Visit.  Subjects who complete the Week 52 Visit and do not participate in the Extension Phase will not have the Early Termination Visit. 
d The Post-treatment Follow-up Visit will be conducted approximately 4 weeks after the last dose of IP for all subjects.
e The female subject's chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be 
initiated at least 28 days before randomization). Contraception education is for males and Females of Child Bearing Potential (FCBP).  Pregnancy testing will be performed 7 
times during the study for FCBP.  Serum pregnancy tests will be performed at Screening and urine pregnancy testing will be done at the Baseline Visit, Week 12, Week 52 (or at 
the Early Termination Visit if prior to the Week 52 Visit) and all visits during the Extension Phase.  In addition, urine pregnancy testing will be done at the Early Termination 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
41
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Visit.  Urine pregnancy test kits will be provided to the site.  The investigator will educate all FCBP about the different options of contraceptive methods and their correct use at 
Screening and Baseline Visits.  The subject will be re-educated every time their contraceptive measures/methods or their ability to become pregnant changes.  A pregnancy 
test(s) should be administered if the FCBP subject misses a menstrual period. 
f During the Extension Phase, a limited physical exam may be performed to evaluate an adverse event, or for any reason, at the discretion of the investigator.
g When reviewing adverse events, evaluation of vasculitis (Section 6.6.5) and/or psychiatric evaluation (Section 6.6.6) are to be assessed as appropriate.
h Evaluate the need for referral to a Psychiatrist and other actions, including discontinuation, as required per protocol Section 6.6.6.
j The screening endoscopy will consist of a colonoscopy or flexible rectosigmoidoscopy. Colonoscopy is required at screening only for those subjects who have not had a 
colonoscopy within 12 months prior to the Screening Visit. Rectosigmoidoscopies will be repeated at Week 12 and Week 52 (or at the Early Termination Visit if prior to the 
Week 52 Visit). Rectosigmoidoscopy will not be repeated if within 4 weeks of the previous endoscopy.  Rectosigmoidoscopy is not required during the Extension Phase. 
k The following procedures and assessments are not required at the Early Termination Visit for subjects who discontinue the study during the Extension Phase: 
rectosigmoidoscopy,
; calculation of the TMS,
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
42
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
6.
PROCEDURES
The following procedures/assessments will be conducted according to the schedule indicated in 
the Table of Events (Table 4).
6.1.
Informed Consent
An Informed Consent Form (ICF) must be signed by the subject before any study-related 
assessments are performed.  
 
Details of the informed consent process may be 
found in Section 14.3.
6.2.
Contraception Education
The risks to a fetus or to a nursing child from apremilast are not known at this time.  In animal 
studies, there were more miscarriages in female mice and monkeys who were given high doses 
of apremilast than in those who were not given apremilast.  In addition, baby mice from the 
apremilast-treated mothers weighed less than normal baby mice. Results of the animal and in 
vitro studies can be found in the IB.
All females of childbearing potential (FCBP1) must use one of the approved contraceptive 
options as described in Section 7.2 while on investigational product and for at least 28 days after 
administration of the last dose of the IP.
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 correct and consistent use of effective contraceptive 
methods in order to successfully prevent pregnancy. 
6.3.
Medical and Disease History
Relevant medical history should be recorded, including caffeine consumption, smoking and 
alcohol history, as well as previous relevant surgeries.  Disease history includes history of UC 
(ie, the disease under study).
6.4.
Inclusion/Exclusion Criteria
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations are expected to be completed during the 28-day Screening Phase, prior to the date of 
the first dose of IP (study randomization). 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) to 
qualify for participation in the study. Subjects may be allowed to re-screen upon discussion with 
the Sponsor. The subject’s source documents must support his/her qualifications for the study 
                                               
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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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
43
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
(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/Concomitant Medications and Therapies
All medications (prescription and nonprescription, including vitamins) taken by the subject up to 
30 days prior to the Screening Visit (Visit 1) should be recorded, including the stop dates for 
medications prohibited in the study.  All medications taken by the subject at any time during the 
study must also be recorded.  Other key medications and therapies, such as previous treatment 
for tuberculosis or relevant diseases, should also be recorded.
6.6.
Safety Assessments
6.6.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP at 
screening.  A urine pregnancy test will be performed on all FCBP at the Baseline Visit, Week 12, 
Week 52 and at all visits during the Extension Phase. In addition, a urine pregnancy test will be 
done at the Early Termination Visit. A urine pregnancy test kit will be provided by the central 
laboratory.  Pregnancy tests should be performed if the FCBP has missed a menstrual period or 
the contraception method has changed.
6.6.2.
Hepatitis B and C
The hepatitis screen includes testing for hepatitis B surface antigen and antibody, hepatitis B 
core antibodies (IgG/IgM), and antibodies to hepatitis C. Blood will also be drawn at screening 
for confirmatory hepatitis C testing to be completed for subjects who test positive for hepatitis C 
antibodies.
6.6.3.
Vital Signs, Height, and Weight
Vital signs, including temperature, pulse, and seated blood pressure, will be taken during the 
visits indicated in Table 4. Height will be measured and recorded at screening; weight will also 
be measured and recorded at screening and then as indicated in Table 4. Body mass index (BMI) 
will be calculated at screening.
6.6.4.
Complete and Limited Physical Examinations
Complete physical examinations will include evaluation of the skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, abdominal, neurological, lymphatic, and musculoskeletal systems.  
Limited physical examinations will include evaluation of the skin, respiratory, cardiovascular, 
lymphatic, and musculoskeletal systems.  Results of the complete and limited physical 
examinations will be recorded only in the source documents. 
Clinically significant abnormal findings (with the exception of the disease under study [UC]) 
identified prior to first dose of IP will be recorded on the electronic case report form (eCRF) as 
medical history; clinically significant findings after the first dose of IP will be recorded as AEs.
Note:  Gynecological and urogenital examinations will not be performed unless for cause.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
44
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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 patient 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.
6.6.6.
Psychiatric Evaluation
Depression has been reported with the use of apremilast. Details are provided in the IB
(Section 4.3.7.2.2).
The investigator should advise subjects, their caregivers, and families of the need to be alert for 
the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such 
changes occur, to contact the investigator. 
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 Post-
treatment Observational Follow-up Visit after the Early Termination Visit.
At any time during the study (post randomization), the investigator (and/or appropriate site staff) 
should evaluate any subject who has thoughts of suicide to determine if the subject truly has 
suicide ideation. In such 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 Post-treatment Observational Follow-up Visit.
A copy of the psychiatric evaluation report must reside in the subject’s source document.
6.6.7.
Stool Culture / Microbiology
Stool culture analysis and assessment of Clostridium difficile toxin will be performed at the 
Screening Visit. A portion of the sample collected at screening will be retained for confirmatory 
testing to be completed for subjects who test positive for Clostridium difficile antigen. Subjects 
who are positive for C. difficile toxin may rescreen for the study after they have successfully 
completed therapy and had 2 months of consecutive negative tests for C. difficile.
6.6.8.
Twelve-lead Electrocardiogram
The 12-lead ECG will be performed after the subject has been supine for approximately 3
minutes. Sites are to utilize their own local ECG machines for the study and the automated ECG 
readings will be further interpreted by the investigator by clinically correlating them with the 
subject’s condition.  The investigator’s clinical interpretation will be recorded in the eCRF as: 
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normal; abnormal, not clinically significant; or abnormal, clinically significant. “Abnormal, 
clinically significant” results should be recorded in the Medical History eCRF if found prior to 
first dose of IP or in the AE eCRF if found after the first dose of IP. 
6.6.9.
Clinical Laboratory Evaluations
A central laboratory will be used for this study.  Clinical laboratory evaluations will include:
!
Hematology: complete blood count (red blood cell [RBC] count, hemoglobin, 
hematocrit, white blood cell [WBC] count and differential, absolute WBC counts, 
platelet count)
!
Serum chemistries: total protein, albumin, calcium, phosphorous, glucose, total 
cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein 
cholesterol (LDL), triglycerides, uric acid, total bilirubin, alkaline phosphatase, 
aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), 
sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, 
lactic dehydrogenase (LDH), magnesium 
!
Urinalysis: dipstick urinalysis (specific gravity, pH, glucose, ketones, protein, blood, 
bilirubin, leukocyte esterase, nitrite, and urobilinogen) 
∀
Microscopic urinalysis (epithelial cells, RBC, WBC, and casts) will be performed 
only if the dipstick urinalysis is abnormal
Note:  Clinical laboratory evaluations are not required to be fasting.  However, the site will 
record whether a clinical laboratory evaluation was fasting or nonfasting on the lab requisition 
form.
6.6.10.
Adverse Events
Adverse events (Section 11.1) will be recorded by the investigator from the time the subject 
signs informed consent to 28 days after the last dose of IP.  The AEs, including SAEs, will be 
recorded on the AE page of the eCRF and in the subject’s source documents.  All SAEs must be 
reported to Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by 
facsimile, or other appropriate method, using the SAE Report Form, or approved equivalent 
form.  Worsening of a subject’s UC, including UC flare, should be considered as worsening of 
disease under study, and should not be captured as an AE.  Worsening or exacerbation of UC, 
including UC flare, meeting the definition of an SAE should be reported as an SAE.
6.6.10.1.
Adverse Events of Special Interest
6.6.10.1.1. Diarrhea
Diarrhea and loose stools have been reported as AEs in subjects receiving PDE4 inhibitors, 
including apremilast. Since diarrhea is a cardinal symptom of UC, it may be difficult to evaluate 
the potential effect of apremilast in the frequency and consistency of stools in this subject
population.  In order to help characterize diarrhea as an adverse reaction, and differentiate from 
symptoms of intestinal inflammation, ongoing review of the Subject Diary for Ulcerative Colitis 
(Section 6.7.1) and the Bristol Stool Chart (Appendix G) for the frequency and consistency of 
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the stools, respectively, will be conducted and analyzed 
 
.  Diarrhea will only be documented as an AE when reported 
by the subject and assessed by the investigator as a new event or worsening of pre-existing 
diarrhea.
6.6.10.1.2. Weight Loss
Subjects with UC may experience weight loss as part of the disease process.  In addition weight 
loss has been observed with apremilast.  Therefore, as part of the ongoing safety surveillance for 
this study, the decrease in subject weight as compared to baseline will be evaluated throughout 
the study. Subjects with an unexplained weight loss ≥ 7.5% from baseline will be discontinued 
from the study.
6.7.
Efficacy Assessments
6.7.1.
Subject Diary for Ulcerative Colitis Disease Activity
Subjects will be provided with the Subject Diary for UC Disease Activity 
 at study 
visits in order to record the following information:
!
Normal number of stools per day (when not having a flare)
!
Number of toilet visits for defecation (per day)
!
Presence of blood in the stools (if any)
!
Description of blood in the stools (if any)
!
Abdominal pain/cramps
!
General well-being
Diaries will be completed from screening until the Week 52 Visit or Early Termination Visit, and 
the Observational Follow-up Visit. Subjects who participate in the Extension Phase will 
complete diaries for 7 days prior to each scheduled visit, or Early Termination Visit, and the 
Observational Follow-up Visit.  
The information extracted will be used for calculation of the Mayo score. In order to encourage 
consistent diary recording, subjects are required to enter diary data continuously throughout the 
study.  The method of diary data collection will be electronic data capture.
6.7.2.
Endoscopy
The screening endoscopy may consist of either a flexible rectosigmoidoscopy or a colonoscopy.  
A colonoscopy is required during the Screening Phase only for those subjects who have not had a 
colonoscopy within 12 months prior to the Screening Visit.  Subsequent endoscopies 
(rectosigmoidoscopies) will be performed on Week 12 and Week 52, or at the Early Termination 
Visit if the Early Termination Visit occurs prior to Week 52. The flexible rectosigmoidoscopy 
will not be repeated within 4 weeks of the previous rectosigmoidoscopy.  Rectosigmoidoscopy is 
not required during the Extension Phase or at the Early Termination Visit for subjects who 
discontinue the study during the Extension Phase. 
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Images of all endoscopic procedures (flexible rectosigmoidoscopy/colonoscopy) will be captured 
and sent to a centralized reader for their assessment, which will be used for the calculation of the 
TMS. 
The screening endoscopy that is assessed by the central reader will be used to calculate the TMS 
to determine study eligibility. The Week 12 endoscopy assessment performed by the 
investigator will be used to calculate the TMS for the determination of subjects who do not 
achieve at least a 20% decrease from baseline in the TMS, at the Week 12 Visit. The Week 52 
endoscopy assessment performed by the investigator will be used to determine eligibility for 
entry into the Extension Phase (Mayo endoscopy score ≤1). 
 
 
  
 
 
 
 
6.7.3.
Total Mayo Score
The TMS is an instrument designed to measure disease activity of UC.  The Mayo score ranges 
from 0 to 12 points (Rutgeerts, 2005).  It consists of 4 subscores, each graded from 0 to 3 with 
higher scores indicating more severe disease (Appendix B):
!
Stool Frequency Subscore (SFS)
!
Rectal Bleeding Subscore (RBS) 
!
Endoscopy Subscore 
!
Physician’s Global Assessment (PGA)
The frequency of the TMS assessment is described in the Table of Events (Table 4).  During the 
Screening Phase, if the subject’s Mayo score, excluding the endoscopy subscore (PMS), is ≥ 4 
points, appropriate endoscopy examination (flexible rectosigmoidoscopy or colonoscopy) will be 
performed to assess the TMS.  Diary data used to calculate the TMS is described in 
Section 6.7.1.
If the subject scores ≥ 2 on the endoscopic subscore at screening, and meets all other 
inclusion/exclusion criteria, the subject will be randomized.  The endoscopy should be performed 
within the Visit window. Documented results from the screening endoscopy must be available 
for the investigator’s interpretation prior to randomization.
Clinical response is defined as a decrease from baseline in TMS of at least 3 points, and at least a 
30% decrease in the TMS, with an accompanying decrease in the RBS of at least 1 point or 
absolute RBS of 0 or 1.  Clinical remission is defined as TMS ≤ 2 points, with no individual 
subscore exceeding 1 point.  Endoscopic response is defined as a 1-point or greater decrease 
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from baseline in the endoscopy subscore.  Endoscopic remission is defined as endoscopy 
subscore of 0.
6.7.4.
Modified Mayo Score
A modification to the total Mayo score will be implemented in this study. This modified Mayo 
score will be based on the stool frequency, rectal bleeding and endoscopy subscores of the total 
mayo score, and will exclude the PGA subscore, since this is a global measure that is subjective 
in nature. The modified Mayo Score ranges from 0 to 9 points. Clinical response is defined as a 
decrease from baseline in modified Mayo Score of at least 2 points and at least 25%, with an 
accompanying decrease in the RBS of at least 1 point or an absolute RBS of 0 or 1.  Clinical 
remission is defined as a modified Mayo Score of 2 points or lower, with no individual subscore 
exceeding 1 point.
6.7.5.
Partial Mayo Score
The PMS is the sum of the RBS, SFS, and PGA, and ranges from 0 to 9 points.  Clinical 
response is defined as a decrease from baseline in PMS of at least 2 points and at least 25%, with 
an accompanying decrease in the RBS of at least 1 point or an absolute RBS of 0 or 1.  Clinical 
remission is defined as a PMS of 2 points or lower, with no individual subscore exceeding 
1 point.  The PMS will be assessed as described in Table 4, Table of Events.
6.7.6.
Physician Global Assessment
The PGA is done as part of the Mayo score.  It acknowledges three other criteria: the subject’s 
daily recollection of abdominal discomfort and general sense of wellbeing, and other 
observations, such as physical findings and the subject’s performance status. 
6.8.
Disease and Health-related Quality of Life Assessments
6.8.1.
The Medical Outcome Study Short Form 12-item Health Survey V2
The Medical Outcome Study Short Form 12-item Health Survey, version 2 (SF-12v2)
(Appendix C) is a self-administered instrument consisting of 12 items from the original Short 
Form Health Survey SF-36, across all dimensions.  The 12 items include the self assessment of 
health, physical functioning, physical role limitation, mental role limitation, social functioning,
mental health, and pain (Ware, 1996).  The instrument was designed to reduce respondent burden 
while achieving minimum standards of precision.  Version 2 of the Survey allows for the 
calculation of an 8-scale profile in addition to the two summary scores.
 
 
 
 
 
 
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6.12.
Dosing
6.12.1.
Investigational Product Dispensing and Counting
After the subject has satisfied all inclusion and exclusion criteria, IP will be dispensed as 
specified by the IWRS/IVRS. The tear-off label from each blister card should be pasted into the 
drug accountability document in each subject’s record. Subjects must be instructed to return all 
previously issued empty blister cards and/or unused IP at the time that new IP is issued. A 
detailed record of tablets issued and returned at each visit must be maintained in the subject’s 
record.
6.12.2.
Site Instructions for Dosing the Subject
At each visit, 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.
6.13.
Early Termination Visit
The Early Termination Visit is based on the subject’s withdrawal from the study prior to Week
52.  For subjects participating in the Extension Phase, the Early Termination Visit is based on the 
subject’s withdrawal from the study after Week 52 and prior to Week 104. Participation in the 
study is completely voluntary. Subjects are also free to withdraw from the study at any time if 
they feel they are not benefiting from the study in order to receive rescue therapy and/or receive 
treatment with standard medical care.  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. Refer to Table 4 for the assessments to be performed at the Early 
Termination Visit.
6.13.1.
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.
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6.14.
Study Completion
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.  
For the purpose of analysis, study completion for an individual subject is defined as reaching the 
Week 52 Visit.  For subjects participating in the Extension Phase, completion of the Extension 
Phase for an individual subject is defined as completing the Week 104 Visit. Subjects not 
meeting this definition will be considered early termination subjects. All subjects are required to 
return for the Post-treatment Observational Follow-up Visit approximately 4 weeks after the last 
dose of IP.
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7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
Approximately 165 subjects will be enrolled in this study at approximately 80 sites.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female aged 18 and over at the time of signing the informed consent. 
2. Must understand and voluntarily sign an informed consent form prior to any study related 
assessments/procedures being conducted.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Diagnosis of UC with duration of at least 3 months prior to the Screening Visit.
5. TMS ≥ 6 to ≤ 11 (range: 0-12) prior to randomization in the study.
6. Endoscopic subscore ≥ 2 (range: 0-3) on the Mayo score prior to randomization in the 
study.
7. Subjects are required to have a colonoscopy if not performed within 12 months of the 
Screening Visit.
8. Subjects must have had a therapeutic failure, been intolerant to, or have a 
contraindication to, at least one of the following: oral aminosalicylates (ie, 5-
aminosalicylic acid [5-ASA] compounds or sulfasalazine [SSZ]), budesonide, systemic 
corticosteroids, or immunosuppressants (eg, 6-mercaptopurine [6-MP], azathioprine 
[AZA], or methotrexate [MTX]).
9. Subjects receiving oral corticosteroids may continue their use during the study, provided 
that the dose (prednisone ≤ 20 mg/day or equivalent, budesonide ≤ 9 mg/day) has been 
stable for 3 weeks prior to the Screening Visit. If oral corticosteroids were recently 
discontinued, discontinuation must have been completed at least 3 weeks prior to the 
Screening Visit. Corticosteroid doses should remain stable until the subject is eligible to 
start corticosteroids tapering, beginning at the Week 12 Visit. 
10. Oral aminosalicylates are permitted during the study, provided that treatment started at 
least 6 weeks prior to screening with a stable dose of at least 14 days prior to the 
Screening Visit.  The dose of oral aminosalicylates must remain stable through Week 52 
or until Week 104 for subjects who participate in the Extension Phase.
11. Must meet the following laboratory criteria:
!
White blood cell count ≥ 3000/mm3 (≥3.0 X 109/L) and < 14,000/mm3
(< 14 X 109/L)
!
Platelet count ≥100,000/mm3 (≥100 X 109/L)
!
Serum creatinine ≤1.5 mg/dL (≤132.6 μmol/L)
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!
AST (SGOT) and ALT (SGPT) % 2 X upper limit of normal (ULN).  If initial test 
shows ALT or AST > 2 times the ULN, one repeat test is allowed during the 
screening period
!
Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L) or albumin > lower limit of normal (LLN).  
If initial test result is > 2 g/dL, one repeat test is allowed during the screening period
!
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
12. Females of childbearing potential (FCBP) must have a negative pregnancy test at 
Screening and the Baseline Visit.  While on IP and for at least 28 days after taking the 
last dose of IP, FCBP who engage in activity in which conception is possible must use 
one of the approved contraceptive options2 described below: 
Option 1:  Any one of the following highly effective methods:  hormonal 
contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine 
device (IUD); tubal ligation; or partner’s vasectomy
OR
Option 2:  Male or female condom (latex condom or nonlatex condom NOT made 
out of natural [animal] membrane [for example, polyurethane]; PLUS one additional 
barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or 
(c) contraceptive sponge with spermicide
13. Male subjects (including those who have had a vasectomy) who engage in activity in 
which conception is possible must use barrier contraception (male latex condom or 
nonlatex condom NOT made out of natural [animal] membrane [for example, 
polyurethane]) while on investigational product and for at least 28 days after the last dose 
of investigational product.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Diagnosis of Crohn's disease, indeterminate colitis, ischemic colitis, microscopic colitis, 
radiation colitis or diverticular disease-associated colitis.
2. Ulcerative colitis restricted to the distal 15 cm or less (eg, ulcerative proctitis).
3. Subjects who have had surgery as a treatment for UC or who, in the opinion of the 
Investigator, are likely to require surgery for UC during the study.
4. Clinical signs suggestive of fulminant colitis or toxic megacolon.
5. Evidence of pathogenic enteric infection.
6. History of colorectal cancer or colorectal dysplasia (with the exception of adenomatous 
colonic polyps that have been completely resected).
7. Prior use of any TNF inhibitor (or any biologic agent).
                                               
2 The female subject’s chosen form of contraception must be effective by the time the female subject is randomized 
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8. Prior use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine or thalidomide.
9. Use of IV corticosteroids within 2 weeks of the Screening Visit.
10. Use of immunosuppressants (AZA, 6-MP or MTX) within 8 weeks the Screening Visit.
11. Use of topical treatment with 5-ASA or corticosteroid enemas or suppositories within 2 
weeks of the Screening Visit.
12. History of any clinically significant neurological, renal, hepatic, gastrointestinal, 
pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or 
disease, or any other medical condition that, in the investigator's opinion, would preclude 
participation in the study.
13. Prior history of suicide attempt at any time in the subject’s lifetime prior to 
randomization in the study or major psychiatric illness requiring hospitalization within 3 
years of study randomization.
14. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she was to participate in the study or confounds the 
ability to interpret data from the study.
15. Pregnant or breast feeding. 
16. History of any of the following cardiac conditions within 6 months of screening:  
myocardial infarction, acute coronary syndrome, unstable angina, new onset atrial 
fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, 
ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, 
interventional cardiac catheterization (with or without a stent placement), interventional 
electrophysiology procedure, or presence of implanted defibrillator.
17. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections (including but not limited to tuberculosis and atypical mycobacterial 
disease and herpes zoster), human immunodeficiency virus (HIV), or any major episode 
of infection requiring hospitalization or treatment with intravenous (IV) or oral 
antibiotics within 4 weeks of screening.
18. Subjects with active hepatitis B infection, as described in Appendix E, are ineligible for 
the study.  Subjects without current hepatitis B infection, as described in Appendix F,
may participate in the study.
19. Subjects who are confirmed positive for hepatitis C are not eligible for the study.
20. History of congenital or acquired immunodeficiency (eg, Common Variable 
Immunodeficiency Disease).
21. History of malignancy, except for:
a.
Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas
b. Treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of 
the cervix with no evidence of recurrence within the previous 5 years
22. Any condition that could affect oral drug absorption, including gastric resections, 
gastroparesis or bariatric surgery, such as gastric bypass.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
55
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
23. Subject has received any investigational drug or device within 1 month or 5 elimination 
half-lives, whichever is longer, prior to the Screening Visit.
24. History of alcohol, drug, or chemical abuse within the 6 months prior to screening.
25. Known hypersensitivity to apremilast or any excipients in the formulation.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
56
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
The chemical name of apremilast (CC-10004) is acetamide, N-[2-[(1S)-1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl) ethyl]-2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl].
Apremilast will be provided as 10-mg, 20-mg, or 30-mg tablets.  Placebo will be provided as 
identically appearing 10-mg, 20-mg or 30-mg tablets.  In addition, tablets (both, apremilast and 
placebo) required for dose titration cards will also be provided.
8.2.
Treatment Administration and Schedule
Tablets will be taken by mouth twice daily, in the morning (AM) and in the evening (PM), 
approximately 12 hours apart, with no food restrictions.  With the aim to mitigate potential dose-
related side effects associated with apremilast such as headache and GI disturbances, apremilast-
treated subjects will be dose-titrated in 10-mg/day increments over the first 8 days of treatment 
in the Double-blind Placebo-controlled Phase.  
After 12 weeks of treatment, apremilast-treated subjects who do not achieve at least a 20% 
decrease from baseline in the TMS, will receive apremilast 40 mg BID.  Placebo subjects, will be 
re-randomized to receive apremilast 30 mg BID or 40 mg BID, and will be dose-titrated prior to 
receiving active treatment (Table 5).  However, in order to maintain the blind for the treatment 
assigned at baseline, all subjects will receive blister cards of identical appearance during both 
titration periods. In the absence of a 40-mg tablet, two 20-mg tablets or identically appearing 
placebo will be taken by those subjects randomized to the 40-mg BID apremilast dose group.
Subjects who complete 52 weeks of treatment and have a Mayo endoscopy score ≤ 1 will be 
eligible to participate in the 52-week Extension Phase and receive apremilast treatment. With the 
implementation of Amendment 4, subjects entering the Extension Phase from the Week 52 Visit 
will receive apremilast 30 mg BID. Subjects currently in the Extension Phase who are receiving 
apremilast 40 mg BID will be switched to 30 mg BID at the next scheduled visit.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
57
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
Table 5:
Treatment Schema for Dose Titration
Treatment Schema for Dose Titrationa
Treat-
ment
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8 + 
Thereafter
Group
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
30 mg 
BID
10 mg A 10 mg P 10 mg A10 mg A 10 mg A 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg A 20 mg A 20 mg A 20 mg A 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P
30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg A 30 mg A 30 mg A 30 mg A 30 mg A 30 mg A 30 mg A
40 mg 
BID
10 mg A 10 mg P 10 mg A10 mg A 10 mg A 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg A 20 mg A 20 mg A 20 mg A 20 mg P 20 mg P 20 mg P 20 mg P 20 mg A 20 mg A 20 mg A
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg A 20 mg A 20 mg A
30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg A 30 mg A 30 mg A 30 mg A 30 mg P 30 mg P 30 mg P
Placebo 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P 10 mg P
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P
20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P 20 mg P
30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P 30 mg P
A = Apremilast; BID = twice daily; P = Placebo.
Note:  In the absence of a 40 mg tablet, subjects will take 2 x 20 mg apremilast tablets or placebo BID.
a Active apremilast subjects will be dose titrated during the first 8 days of the study (Week 0, Day 1); At the week 12 Visit, placebo subjects will be re-randomized to apremilast 
30 mg or 40 mg BID and will be dose titrated for the first 8 days of treatment.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
58
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
8.3.
Method of Treatment Assignment
After the informed consent is signed, subjects will be assigned a subject identification number 
using a centralized IVRS/IWRS.  At the Baseline Visit, a centralized schema will be applied to 
assign subjects who meet the inclusion/exclusion criteria in a 1:1:1 ratio to receive either 
apremilast 30 mg PO BID or 40 mg PO BID, or placebo.
Subjects will be randomized by following two stratification parameters:
!
Concomitant use of oral corticosteroids
!
Previous exposure to immunosuppressants (eg, 6-MP, AZA, or MTX)
The number of subjects with previous exposure to immunosuppressants is targeted to comprise 
no more than 50% of the subjects enrolled, and no less than 30%. 
Following 12 weeks of treatment, subjects will enter the Blinded Active-treatment Phase.  At the 
Week 12 visit, subjects will be evaluated for clinical improvement based on the TMS.  The 
endoscopy subscore assessed by the investigator will be used for the calculation of the Week 12 
TMS. 
Subjects who achieve at least a 20% decrease from baseline in the TMS at Week 12 will receive 
the following IP between the Week 12 Visit and the Week 52 Visit:
!
Subjects who were randomized to apremilast (30 mg BID or 40 mg BID) at baseline will 
continue to receive the treatment assigned at baseline.  
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).
Subjects who do not achieve at least a 20% decrease from baseline in the TMS at Week 12 will 
receive the following IP until the Week 52 Visit:
!
Subjects who were randomized to apremilast 30 mg BID at baseline will be re-assigned 
apremilast 40 mg BID, with no dose titration.
!
Subjects who were randomized to apremilast 40 mg BID at baseline will continue to 
receive apremilast 40 mg BID.
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment (Table 5).
Subjects who participate in the Extension Phase will receive apremilast 30 mg BID. With the 
implementation of Amendment 4, subjects currently in the Extension Phase who are receiving 40 
mg BID will be switched to 30 mg BD at the next scheduled visit. 
Designated study personnel at the investigational sites will be assigned password-protected, 
coded identification numbers that give them authorization to call into the IVRS/IWRS to 
randomize subjects.  The system will present a menu of questions by which the study personnel 
will identify the subject and confirm eligibility.  When all questions have been answered, the 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
59
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
IVRS/IWRS will assign a randomization identification number.  Confirmation of the 
randomization will be sent via fax 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 
interactive IVRS/IWRS.
8.4.
Packaging and Labeling
All IP, including placebo and apremilast tablets, will be supplied by Celgene to the principal 
investigator as blister cards for the duration of the study. 
Apremilast will be provided in blister cards as 10-mg, 20-mg, or 30-mg tablets in the clinical 
image.  Tablets will be taken by mouth twice daily, morning and evening, approximately 12
hours apart, with no food restrictions.
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.
8.5.
Investigational Product Accountability and Disposal
The investigator, or designee, is responsible for taking an inventory of each shipment of IP 
received, and comparing it with the accompanying IP shipping order/packing list.
The investigator, or designee, will verify the accuracy of the information on the form, sign and 
date it, retain a copy in the study file, and return a copy to Celgene.
The IP will be stored according to the storage conditions identified on the drug label.  At the 
study site, all IP will be stored in a locked, safe area to prevent unauthorized access.
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.
Investigational Product Compliance
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP.  Investigational Product will be dispensed as noted in Table 4, Table of 
Events. The subjects will be instructed to return the IP containers, including any unused 
medication, to the study site at each visit for tablet counts and reconciliation.  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.  If a subject misses 4 or more consecutive days of 
dosing, Celgene must be contacted to decide whether dosing should resume or whether the
subject should be terminated from the study, and enter into the Post-treatment Observational 
Follow-up Phase.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
60
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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.
8.6.1.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP (apremilast), 
and on a per dose basis, is defined as ingestion of greater than 100 mg of apremilast (greater than 
two AM or PM sections in the blister card) in any 24-hour dosing period whether by accident or 
intentionally. Adverse Events associated with an overdose must be collected on the AE page of 
the eCRF (see Section 11.1) for all overdosed subjects, but the overdose itself is not considered 
an AE. Other required or optional nonstudy drugs intended for prophylaxis of certain side 
effects, etc, are excluded from this definition.
For subjects receiving open-label apremilast 30 mg BID in the Extension Phase, overdose on a 
per dose basis is defined as ingestion of 4 or more 30-mg apremilast tablets in any 24-hour 
period whether by accident or intentional. On a schedule or frequency basis, overdose is defined 
as dosing more than 4 times in any 24-hour period.
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.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
61
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
All medications (prescription and non-prescription), treatments, and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated 
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the eCRF.  The dose, unit, frequency, route, indication, date the medication 
was started, and date the medication was stopped (if not ongoing) must be recorded. 
9.1.
Permitted Concomitant Medications and Procedures
The following medications are allowed during the study:
!
Oral aminosalicylates (sulfasalazine [SSZ] or 5-ASA compounds) are allowed during 
the study, provided that treatment was initiated at least 6 weeks prior to screening, 
and has been given at a stable dose for at least 14 days prior to the Screening Visit. 
The dose of oral aminosalicylates must remain stable through the duration of the 
study or early termination from the study. 
!
Oral corticosteroids are allowed during the study, provided that the subject has been 
receiving therapy at a stable dose (prednisone ≤20 mg/day or equivalent mg/day) for 
at least 3 weeks prior to the Screening Visit. The subject must remain on a stable 
dose until the Week 12 Visit, after which time the dose may be tapered according to 
the following tapering schedule:
∀
For prednisone doses > 10 mg (or equivalent) daily dose, each week the daily 
dose is to be tapered by 5 mg until a dose of 10 mg/day is reached, after that each 
week the daily dose is to be tapered by 2.5 mg until discontinuation.
∀
For prednisone doses ≤ 10 mg (or equivalent), each week the daily dose is to be 
tapered by 2.5 mg until discontinuation. 
∀
Subjects receiving budesonide should have their daily dose tapered by 3 mg every 
3 weeks.
∀
Subjects who experience UC-related symptoms after the tapering regimen is 
completed are permitted to receive the same corticosteroid treatment taken prior 
to the initiation of the tapering schedule, provided that the dosage is the same as 
the dose taken prior to tapering.
If oral corticosteroids were recently discontinued, discontinuation must have been 
completed at least 3 weeks prior to the Screening Visit.
!
Acetaminophen and low-dose aspirin for cardiovascular prophylaxis are allowed.
Note:  The dose of concomitant oral aminosalicylates cannot be increased above the baseline 
dose during the study.  No new UC therapy can be prescribed once the subject has been 
randomized to the study. 
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
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62
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
9.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are prohibited during all treatment portions of the study 
including the Double-blind Placebo-controlled Phase (Week 0 to Week 12), the Blinded Active-
treatment Phase (Week 12 to Week 52); and for subjects who participate in the Extension Phase, 
from Week 52 to Week 104, or to the Early Termination Visit for subjects who discontinue 
prematurely from the study:
!
Use of the CYP3A4 inducers, rifampin and carbamazepine, bosentan, efavirenz, 
etravirine, modafinil, nafcillin, St. John’s wort
!
Uses of any biologic agents, including TNF blockers
!
Use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine or thalidomide
!
Use of topical treatment with 5-ASA or corticosteroid enemas or suppositories is 
prohibited during the study and must be discontinued 2 weeks prior to the Screening 
Visit
!
Use of intravenous corticosteroids is prohibited during the study and must be 
discontinued 2 weeks prior to the Screening Visit
!
Use of AZA, 6-MP, or MTX is prohibited during the study and must be discontinued 
8 weeks prior to the Screening Visit
!
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).
9.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications.
Required procedures include endoscopy (rectosigmoidoscopy or colonoscopy)
 
as noted in Table 4.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
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63
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10.
STATISTICAL ANALYSES
10.1.
Overview
Key elements of the statistical analysis plan are outlined in this section. The comprehensive plan 
will be documented in a separate Statistical Analysis Plan (SAP).
Planned data analyses include: 1) an analysis at the completion of the 12-week Placebo-
controlled Phase for all subjects (referred to as the Double-blind Placebo-controlled Phase 
analysis hereafter); 2) an analysis at the completion of the Active-treatment Phase for all subjects
after 52 weeks of treatment; and 3) the final analysis at the completion of the entire study.
10.2.
Study Population Definitions
Safety analyses will be based on the safety population, which will include all subjects who are 
randomized and receive at least one dose of IP.  Subjects will be included in the treatment group 
corresponding to the IP they actually received for the analyses using the safety population.
The intent-to-treat (ITT) population will be the primary population for efficacy analyses.  The 
ITT population will consist of all subjects who are randomized as specified in the protocol and 
receive at least one dose of IP.  Subjects will be included in the treatment group to which they 
were randomized, irrespective of the treatment actually received, for the analyses using the ITT 
population.
The per-protocol (PP) population will consist of all subjects included in the ITT population who 
have at least one post-baseline efficacy evaluation and no protocol violations that may 
substantially affect the efficacy results. The final determination on these protocol violations, and 
thereby the composition of the PP population, will be made prior to the Placebo-controlled Phase 
analysis, and will be separately documented.  Subjects will be included in the treatment group to 
which they were randomized, irrespective of the treatment actually received, for the analyses 
using the PP population.
10.3.
Sample Size and Power Considerations
A 2-group chi-square test with a 0.1 two-sided significance level will have approximately 80% 
power to detect a true 20% absolute difference (30% versus 10%) between a dose of apremilast 
and placebo, for the proportion of subjects achieving a clinical remission at Week 12 when the 
sample size in each group is 49. Assuming a dropout rate of 10% prior to Week 12, 
approximately 165 subjects (approximately 55 subjects per group) are planned to be randomized 
in this study.
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and other continuous demographic 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.
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10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued along with primary 
reason for discontinuation, completed) will be summarized using frequency and percent for both 
treatment and follow-up phases.  A summary of subjects enrolled by site will be provided. 
Protocol violations/deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
The ITT population (Section 10.2) will be the primary population for efficacy analyses.  A 
supportive analysis using the PP population will also be performed for the primary efficacy 
endpoint.
The comparisons for the primary efficacy endpoint will be based on two-sided statistical tests at 
a significance level of 0.1. A hierarchical approach will be used to adjust for multiplicity. For the 
primary endpoint, the first test in the hierarchy will be the apremilast 40 mg BID treatment group 
compared to placebo, followed by the apremilast 30 mg BID treatment group compared to 
placebo.  If any of the active treatment groups (apremilast 30 mg or 40 mg BID) is discontinued 
prior to the end of the study, the treatment comparison will be conducted for the retained 
treatment group vs. placebo based on a two-sided statistical test at the 0.1 level.  Additional 
endpoints subsequent to the primary endpoint comparisons may be added to the hierarchy and 
specified in the SAP.
Summary of all efficacy endpoints over time will be provided using frequency and percent for 
categorical endpoints and descriptive statistics for continuous endpoints.
10.6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical remission, as defined as a TMS of ≤ 2 with no 
individual subscore > 1 at Week 12.  The proportion of subjects who achieve a clinical remission 
at Week 12 between any apremilast (30 mg BID or 40 mg BID) group and the placebo group will 
be compared using the Cochran-Mantel-Haenszel (CMH) test controlling for the randomization 
stratification factors specified.  Subjects who prematurely discontinue the study before Week 12
will be considered as nonresponders. 
10.6.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints defined in Section 3.2.1 will be analyzed using the CMH test 
controlling for the randomization stratification factors as will be done for the primary efficacy 
endpoint.
 
 
 
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10.7.
Safety Analysis
The safety analyses will be performed using the safety population (Section 10.2).
Treatment-emergent adverse events will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) classification system.  All AEs will be summarized by system 
organ class, preferred term, severity and relationship to IP.  Adverse events leading to death or to 
discontinuation from treatment and 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 descriptively by visit.  In addition, shift tables showing the 
number of subjects with values low, normal, and high compared to the normal ranges 
pretreatment versus post-treatment will be provided. 
Vital sign measurements, including weight, will be summarized descriptively by visit.
 
 
 
 
 
 
 
 
 
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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. 
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 drug exposure eCRF page. (See Section 8.6.1 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 eCRF but should 
not be reported as an SAE itself.
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; weight loss; diarrhea;
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. Adverse events 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.  
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all AEs as to: 
11.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
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AE report fo
AE report f
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!
Results in persistent or significant incapacity / disability (a substantial disruption of 
the subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect; and/or
!
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 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.
If an AE is considered serious, both the AE page/screen of the CRF 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. 
Mild
!
Asymptomatic or mild symptoms; clinical or diagnostic observations only
!
Intervention not indicated
!
Activities of Daily Life (ADLs) minimally or not affected
!
No or minimal intervention/therapy may be required 
Moderate 
!
Symptom(s) cause moderate discomfort
!
Local or noninvasive intervention indicated
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!
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!
More than minimal interference with ADLs but able to carry out daily social and 
functional activities.
!
Drug therapy may be required
Severe (could be nonserious or serious)
!
Symptoms causing severe discomfort/pain
!
Symptoms requiring medical/surgical attention/intervention
!
Interference with ADLs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)
!
Drug therapy is required.
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious,” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not Suspected:
Means a causal relationship of the AE to 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 AE. ‘Reasonable possibility’ means there is 
evidence to suggest a causal relationship between the IP and the 
AE.
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, the name of the manufacturer when 
reporting the event will be provided.
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
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1.2.4.


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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, recovered with sequelae, not recovered, 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.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a SAE.  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the 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.  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.
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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.  
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 anytime thereafter that are suspected of being related to 
IP. SAEs occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the 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.
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11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to apremilast based on the IB.
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, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
Celgene or its authorized representative shall notify the investigator of the following 
information:
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, refer to the Serious Adverse Event Report Form 
Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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n
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Pregnancy


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12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the IP 
and/or from the study:
!
Adverse event(s)
!
Lack of efficacy
!
Withdrawal by subject
!
Death
!
Lost to follow up
!
Protocol violation
!
Study terminated by sponsor
!
Pregnancy
!
Unexplained weight loss ≥ 7.5% from baseline
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. The reason for discontinuation should be recorded in the eCRF and in the 
source documents.
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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).  This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on call Celgene/CRO 
Medical Monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless, in the opinion of the 
investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the investigator, continuing IP can negatively affect the outcome of the subject’s treatment. 
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, the investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The investigator should ensure that the code is broken only in accordance with the protocol. The 
investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the investigator thorough the IVRS/IWRS 
by using an emergency unblinding personal identification number (PIN), and the investigator 
should call IVRS/IWRS for unblinded dose information.
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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 Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
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 form 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 form, the 
informed consent form 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 form.  The revised informed consent form 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 form 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 form, 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.
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 
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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 form
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;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
15.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of 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 form 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;
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!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. The 
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, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring will 
include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the 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 CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, 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
Clark M, Colombel JF, Feagan BC, Fedorak RN, Hanauer SB, Kamm MA, et al.  American 
gastroenterological association consensus development conference on the use of biologics in the 
treatment of inflammatory bowel disease, June 21-23, 2006. Gastroenterology 2007;133(1):312-
39.
Danese S, Fiocchi C.  Ulcerative colitis. N Engl J Med 2011;365(18):1713-25.
Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al.  Increased expression of 
interleukin 17 in inflammatory bowel disease. Gut 2003;52(1):65-70.
Gordon JN, Prothero JD, Thornton CA, Pickard KM, Di Sabatino A, Goggin PM, et al.  
CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α 
and MMP-3 production in patients with inflammatory bowel disease. J Crohns Colitis 
2009;3(3):175-82.
Humira [package insert]. North Chicago, IL: AbbVie; 2013.
Kornbluth A, Sachar DB.  Ulcerative colitis practice guidelines in adults: American College Of 
Gastroenterology, Practice Parameters Committee.  Am J Gastroenterol 2010;105(3):501-23.
Lewis SJ, Heaton KW.  Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997;32(9):920–4.
Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, et al.  A comprehensive 
immunization strategy to eliminate transmission of hepatitis B virus infection in the United 
States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: 
immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-
16):1-31.
Ordás I, Eckmann L, Talamini, Baumgart DC, Sandborn WJ. Ulcerative colitis.  Lancet 
2012;380(9853):1606-19.
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al.  Infliximab for 
induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353(23):2462-76.
Sandborn WJ, Yednock TA.  Novel approaches to treating inflammatory bowel disease: targeting 
alpha-4 integrin. Am J Gastroenterol 2003;98(11):2372-82.
Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al.  Tofacitinib, an oral Janus 
kinase inhibitor, in active ulcerative colitis.  N Engl J Med 2012;367(7):616-24.
Sands BE, Abreu MT, Ferry GD, Griffiths AM, Hanauer SB, Isaacs KL, et al.  Design issues and 
outcomes in IBD clinical trials. Inflamm Bowel Dis 2005;11(Suppl 1):S22–8.
Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al.  Apremilast, a cAMP 
phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of 
psoriasis. Br J Pharmacol 2010;159(4):842–55.
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-aminosalicylic acid therapy for mildly 
to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317(26):1625-9.
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eagan BG, R
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Simponi [package insert], Horsham, PA:  Janssen Biotech, Inc.; 2013.
Xeljanz [package insert], New York, NY: Pfizer: 2012.
Ware JE, Kosinski MA, Keller SD.  A 12-Item Short-Form Health Survey: construction of scales 
and preliminary tests of reliability and validity. Med Care 1996;34(3):220-33.
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19.
APPENDICES
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APPENDIX B. MAYO SCORING SYSTEM
Stool frequency subscore (SFS)*
0 = Normal number of stools for this patient
1 = 1 – 2 stools more than normal
2 = 3 – 4 stools more than normal
3 = 5 or more stools more than normal
* Each patient serves as his or her own control to establish normal stool frequency and the 
degree of abnormal stool frequency.
Rectal bleeding subscore (RBS)**
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passed
** The daily bleeding score represents the most severe bleeding of the day.
Endoscopy subscore: Findings of flexible sigmoidoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Physician's Global Assessment subscore (PGA)
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Source:  Schroeder, 1987.
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APPENDIX C. 12-ITEM SHORT FORM HEALTH SURVEY, VERSION 2
Source: Ware, 1996.
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APPENDIX E. HEPATITIS B CRITERIA INDICATING CURRENT 
INFECTION OR RISK OF CURRENT INFECTION
Result
Interpretation
HBsAg
anti-HBc
IgM anti-HBC
anti-HBs
Positive
Positive
Positive
Negative
Acutely infected
HBsAg
anti-HBc
IgM anti-HBC
anti-HBs
Positive
Positive
Negative
Negative
Chronically infected
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Negative
Interpretation unclear; four possibilities:
!
Resolved infection (most common)
!
False-positive anti-HBc, thus susceptible
!
“Low level” chronic infection
!
Resolving acute infection
Abbreviations: HBsAg= hepatitis B surface antigen; anti- HBc= antibody to the hepatitis B core antigen; anti- HBs= 
antibody to hepatitis B surface antigen; IgM anti-HBC= IgM antibody to hepatitis B core antigen 
(Source:  Mast, 2005).
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APPENDIX F.
HEPATITIS B CRITERIA INDICATING THE ABSENCE 
OF CURRENT INFECTION
Result
Interpretation
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Negative
Susceptible to hepatitis B infection
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Positive
Immune due to natural infection
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Positive
Immune due to hepatitis B vaccination
Abbreviations: HBsAg= hepatitis B surface antigen; anti-HBc= antibody to the hepatitis B core antigen; 
anti-HBs= antibody to the hepatitis B surface antigen (Source: Mast, 2005).
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
90
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
APPENDIX G. BRISTOL STOOL CHART
Source: Lewis, 1997.
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
91
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
92
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
CCI
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
93
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
CCI
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
94
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
CCI
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Apremilast (CC-10004)
Protocol CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
95
CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
CCI
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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Apremilast (CC-10004)
Summary of Changes CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Subject
Revised Section(s) 
Change / Justification
Dose for 
Extension Phase
Protocol Summary, Dose 
Justification (Section 1.4.3), 
Study Design (Sections 4.1, 
4.2 [Figure 1]), Table of 
Events [footnote b], 
Description of Study 
Treatments (Sections 8.2, 
8.3, 8.4)
The primary purpose of this protocol amendment is to adjust the dose in the 
Extension Phase such that all patients receive apremilast 30 mg twice daily 
(BID). Based upon the similarity of the clinical, endoscopic 
 
endpoints and the plateau of dose response observed in subjects treated with 
apremilast 30 mg and 40 mg BID after the first 12 weeks, as well as the 
extensive marketed safety experience with this dose, the 30 mg BID dose was 
determined to be the minimum dose that provides the maximum treatment 
response with an acceptable safety profile.
Overdose 
definition for 
Extension Phase
Overdose (Section 8.6.1)
For subjects receiving apremilast 30 mg BID in the Extension Phase, overdose 
for this period is now defined as 4 or more 30 mg tablets in any 24-hour period, 
or dosing more than 4 times in 24 hours. This is consistent with the overdose 
definition for other apremilast protocols using 30 mg BID.
Data Monitoring 
Committee 
(DMC) and 
Internal Data 
Safety 
Monitoring Board
(iDSMB)
Decommissioning
Internal Data Safety 
Monitoring Board During the 
Study (Section 4.1.2), 
External Safety and Efficacy 
Monitoring During 
Apremilast Program (Section 
4.1.3)
With the implementation of Amendment 4, all subjects will be in the Extension 
Phase and will receive open-label apremilast 30 mg BID as of their next visit. 
Therefore, the iDSMB is no longer necessary to support CC-10004-UC-001. 
After all subjects completed the 12-week Placebo-controlled Phase, Celgene 
determined that the DMC was no longer necessary to support CC-10004-UC-
001, as the safety profile of apremilast in ulcerative colitis (UC) is similar to 
that observed in the approved indications and no new safety signal emerged in 
CC-10004-UC-001.
Celgene’s Safety Management Team (SMT) will continue to review safety data 
for CC-10004-UC-001 on a regular basis.
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Apremilast (CC-10004)
Summary of Changes CC-10004-UC-001
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-10004-UC-001 Amendment 4 Final: 08 Aug 2018
The amendment also includes several other minor clarifications and corrections:
Subject
Revised Section(s) 
Change / Justification
Safety Update
Safety (Section 1.4.2)
Section was updated to reflect the most current information in Investigator 
Brochure (IB).
 
 
 
Footnotes in 
Table of Events
Table of Events (Section 5, 
Table 4)
Minor clarifications were made to footnotes d and e.
Subject Diary
Subject Diary for Ulcerative 
Colitis Disease Activity 
(Section 6.7.1)
The reference to paper diaries was removed as diaries are completed via an 
electronic device. In addition, abdominal pain/cramps and general well-being 
were added to the bulleted list of items that are collected in the subject diary.
Corticosteroid 
Treatment and 
Tapering
Permitted Concomitant 
Medications and Procedures
(Section 9.1)
This section now clarifies that subjects who experience UC-related symptoms 
after completing the corticosteroid tapering regimen are permitted to receive the 
same treatment taken prior to tapering, provided that the dose is the same.
Endoscopy time 
points
Required Concomitant 
Medications and Procedures 
(Section 9.3)
This section now references Table 4 (Table of Events) for the time points at 
which endoscopy is required.
Reasons for 
Discontinuation
Discontinuations (Section 
12)
The reasons for discontinuation were updated to align with the Clinical Data 
Interchange Standard Consortium (CDISC).
ICH definition
Good Clinical Practice 
(Section 14.1)
ICH acronym was updated to reflect current name (International Council for 
Harmonisation).
Medical Monitor 
Contact 
Medical Monitor/ 
Emergency Contact
Medical monitor title was updated to 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
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&&8&
DATE FINAL:
29 Sep 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 (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
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
 
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................15
4.2.1.
Primary Endpoint....................................................................................................15
4.2.2.
Secondary Efficacy Endpoints ................................................................................15
4.2.3.
Secondary Safety Endpoints ...................................................................................16
4.3.
Stratification, Randomization, and Blinding............................................................17
4.4.
Sample Size Determination.....................................................................................17
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
5.1.
Reporting Conventions ...........................................................................................18
5.2.
Safety Analysis Periods ..........................................................................................18
5.3.
Time Points ............................................................................................................20
5.3.1.
Analysis Time Point Assignments...........................................................................20
5.3.2.
Screening and Baseline Definitions.........................................................................21
5.4.
Analysis Populations ..............................................................................................21
5.4.1.
Intent-to-treat Population........................................................................................21
5.4.2.
Per-protocol Population ..........................................................................................21
5.4.3.
Safety Population....................................................................................................22
5.4.4.
Apremilast Subjects as Randomized Population......................................................22
5.4.5.
Apremilast Subjects as Treated Population .............................................................22
6.
SUBJECT DISPOSITION......................................................................................23
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
3
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................24
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................25
8.1.
Demographics and Baseline Characteristics ............................................................25
8.2.
Baseline Disease Characteristics.............................................................................25
8.3.
Medical History......................................................................................................27
8.4.
Prior Medications/Procedures .................................................................................27
9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT.........................28
9.1.
Treatment Duration.................................................................................................28
9.2.
Treatment Compliance............................................................................................28
10.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................30
10.1.
Concomitant Medications .......................................................................................30
10.2.
Concomitant Procedures.........................................................................................30
11.
EFFICACY ANALYSIS ........................................................................................31
11.1.
Multiplicity.............................................................................................................31
11.2.
Missing Data Handling ...........................................................................................31
11.2.1.
Treatment Failures..................................................................................................31
11.2.2.
Binary Efficacy Endpoints......................................................................................31
11.2.2.1.
Primary Approach for Analysis...............................................................................31
11.2.2.2.
Sensitivity Analyses ...............................................................................................32
11.2.2.3.
Approach for Descriptive Summary........................................................................32
11.2.3.
Continuous Efficacy Endpoints...............................................................................32
11.2.3.1.
Primary Approach for Analysis...............................................................................32
11.2.3.2.
Approach for Descriptive Summary........................................................................32
11.3.
Analysis of Primary Endpoint.................................................................................32
11.3.1.
Primary Analysis of Primary Endpoint....................................................................32
11.3.2.
Sensitivity Analyses of Primary Endpoint...............................................................33
11.4.
Analyses of Secondary Efficacy Endpoints.............................................................33
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
4
11.7.
Assessing Study Center Effect and Treatment-by-center Interaction .......................36
12.
SAFETY ANALYSIS ............................................................................................37
12.1.
Adverse Events.......................................................................................................37
12.1.1.
Overall Summary of TEAEs ...................................................................................37
12.1.2.
All TEAEs..............................................................................................................38
12.1.3.
Common TEAEs ....................................................................................................38
12.1.4.
Drug-related TEAEs...............................................................................................39
12.1.5.
TEAEs by Maximum Severity................................................................................39
12.1.6.
Serious TEAEs.......................................................................................................39
12.1.7.
TEAEs Leading to Drug Interruption and Leading to Drug Withdrawal..................39
12.1.8.
Deaths ....................................................................................................................39
12.2.
Clinical Laboratory Evaluations..............................................................................40
12.3.
Vital Signs and Body Weight..................................................................................40
12.4.
Electrocardiogram ..................................................................................................41
15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................46
16.
REFERENCES.......................................................................................................47
17.
APPENDICES........................................................................................................48
17.1.
Laboratory Marked Abnormalities Criteria .............................................................48
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Definitions of Entry and Completion in Disposition Summaries..............................23
 
Table 5:
Laboratory Marked Abnormalities Criteria .............................................................48
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................15
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Meaning
AE
Adverse event
ANCOVA
Analysis of covariance
APR 30 BID, 
APR 40 BID
Apremilast 30 mg twice daily,
Apremilast 40 mg twice daily
BID
Twice daily
BMI
Body mass index
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
ECG
Electrocardiograms
GI
Gastrointestinal
HRQoL
Health-related quality of life
IP
Investigational product
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
MMS
Modified Mayo score
 
PGA
Physician’s global assessment
PMS
Partial Mayo score
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
9
Abbreviation
Meaning
PP
Per-protocol
PT
Preferred term
RBS
Rectal bleeding subscore
SAE
Serious adverse event
SAP
Statistical analysis plan
SF-12v2
The Medical Outcomes Study Short Form 12-item Health Survey, version 2 (SF-
12v2)
SFS
Stool frequency subscore
SOC
System organ class
SD
Standard deviation
TEAE
Treatment-emergent adverse event
TMS
Total Mayo score
UC
Ulcerative colitis
WHO 
World Health Organization 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-10004-UC-001 “A Phase 2, Randomized, Placebo-Controlled, Multicenter Study to 
Investigate the Efficacy and Safety of Apremilast (CC-10004) for Treatment of Subjects with 
Active Ulcerative Colitis” as amended on 20 Jul 2016. It contains definitions of analysis
populations, derived variables and statistical methods for the analysis of efficacy and safety.
 
 
Planned data analyses include 1) an analysis at the completion of the 12-week Placebo-controlled 
Phase for all subjects (referred to as the Double-blind Placebo-controlled Phase analysis 
hereafter), 2) an analysis at the completion of the Active-treatment Phase (through Week 52) for 
all subjects, and 3) the final analysis at the completion of the entire study.
In this SAP, apremilast 30 mg twice daily (BID) and apremilast 40 mg BID are referred to as 
APR 30 BID and APR 40 BID, respectively. Investigational product (IP) refers to placebo, APR 
30 BID, or APR 40 BID.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to evaluate the clinical efficacy of apremilast (30 mg BID
and 40 mg BID), compared with placebo, in subjects with active ulcerative colitis (UC).
3.2.
Secondary Objectives
The secondary objectives of the study are:
!
To evaluate the safety and tolerability of apremilast (30 mg BID and 40 mg BID), 
compared with placebo, in subjects with active UC
!
To evaluate the long-term safety in subjects with active UC, receiving apremilast (30 mg 
BID or 40 mg BID)
 
 
 
 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
12
 
 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
study to evaluate the efficacy and safety of 2 doses of apremilast in subjects with active UC 
(defined as a total Mayo score [TMS] of ≥ 6 to ≤ 11, with an endoscopic subscore ≥ 2).
Approximately 165 subjects (55 subjects per arm) will be randomized in a 1:1:1 ratio using an 
Interactive Voice Response system (IVRS) or an Interactive Web Response System (IWRS) to 
receive oral apremilast (30 mg BID or 40 mg BID), or identically appearing placebo BID for up 
to 12 weeks, followed by 40 weeks of blinded treatment with apremilast (30 mg BID or 40 mg 
BID). At the end of 52 weeks in the study, subjects who have a Mayo endoscopy score ≤ 1 will 
have the opportunity to participate in the Extension Phase and will continue to receive the same 
treatment assigned during the Blinded Active-treatment Phase for an additional 52 weeks.
Treatment assignment will be stratified via IVRS/IWRS based on concomitant use of oral 
corticosteroids and previous exposure to immunosuppressants (eg, 6-MP, AZA, or MTX). The 
number of subjects with previous exposure to immunosuppressants is targeted to comprise, no 
more than 50% of the subjects enrolled, and no less than 30%. 
The study will consist of 5 phases:
!
Screening Phase – up to 4 weeks
!
Double-blind Placebo-controlled Phase – Weeks 0 to 12
!
Blinded Active-treatment Phase – Weeks 12 to 52
!
Extension Phase – Weeks 52 to 104
o
The 52-week extension is a blinded, active treatment phase and henceforth will be 
referred to as the Extension Phase for the remainder of the document.
!
Post-treatment Observational Follow-up Phase – The 4-week period after the last dose of 
investigational product (IP).
Double-blind Placebo-controlled Phase
Eligible subjects will enter the Double-blind Placebo-controlled Phase for 12 weeks, at the 
Baseline Visit (Week 0, Visit 2). Subjects will be randomly assigned to study treatment as 
described above. With the aim to mitigate potential dose-related side effects associated with 
apremilast, such as headache and gastrointestinal (GI) disturbances, apremilast-treated subjects 
will be dose-titrated in 10-mg/day increments over the first 8 days of treatment. All subjects will 
receive blister cards of identical appearance to maintain blinding. Subjects will continue to 
receive the treatment assigned at baseline for 12 weeks.
Blinded Active-treatment Phase
Following 12 weeks of treatment, subjects will enter the Blinded Active-treatment Phase for 40 
weeks. At the Week 12 visit, subjects will be evaluated for clinical improvement based on the 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
14
TMS. The endoscopy subscore assessed by the investigator will be used for the calculation of the 
Week 12 TMS. 
Subjects who achieve at least a 20% decrease from baseline in the TMS at Week 12 will receive 
the following IP between the Week 12 Visit and the Week 52 Visit:
!
Subjects who were randomized to apremilast (30 mg BID or 40 mg BID) at baseline will 
continue to receive the treatment assigned at baseline.  
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment.  
Subjects who do not achieve at least a 20% decrease from baseline in the TMS at Week 12 will 
receive the following IP until the Week 52 Visit:
!
Subjects who were randomized to apremilast 30 mg BID at baseline will be re-assigned 
apremilast 40 mg BID, with no dose titration.
!
Subjects who were randomized to apremilast 40 mg BID at baseline will continue to 
receive apremilast 40 mg BID.
!
Subjects who were randomized to placebo at baseline will be re-randomized to receive 
apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in 10-mg/day increments 
over the first 8 days of treatment.
In order to maintain the blind for the treatment assigned at baseline, all subjects will receive 
blister cards of identical appearance during the titration period beginning at Week 12. However, 
for subjects continuing on the dosage of apremilast assigned at baseline, and for subjects who are 
not undergoing dose titration (as noted above), the IP included in the “titration” portion of the 
blister card will include the total daily dose of apremilast (30 or 40 mg BID) and will not include 
the dose titration.
Extension Phase
At the end of the Blinded Active-treatment Phase (Week 52), subjects who have a Mayo 
endoscopy score ≤ 1 will have the opportunity to participate in the Extension Phase. Subjects 
participating in the Extension Phase will continue to receive the same treatment assigned during 
the Blinded Active-treatment Phase for an additional 52 weeks (ie, Weeks 52 to 104).
Post-treatment Observational Follow-up Phase
All subjects are required to spend 4 weeks in the Post-treatment Observational Follow-up Phase 
following the last dose of IP.
The study schematic is presented in Figure 1 below.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
15
Figure 1:
Overall Study Design
4.2.
Study Endpoints
4.2.1.
Primary Endpoint
The primary endpoint of this study is the proportion of subjects achieving a clinical remission in
the TMS at Week 12, defined as a TMS of ≤ 2, with no individual subscore > 1.
4.2.2.
Secondary Efficacy Endpoints
!
The proportion of subjects achieving clinical response at Week 12, defined as a decrease 
from baseline in the TMS of at least 3 points and at least 30%, along with a reduction in 
the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS of ≤ 1
!
The proportion of subjects achieving endoscopic remission at Week 12, defined as a 
Mayo endoscopic subscore of 0
!
The proportion of subjects achieving endoscopic response at Week 12, defined as a 
decrease from baseline of at least 1 point in the Mayo endoscopic subscore
!
The proportion of subjects achieving a RBS ≤ 1 at Week 12
!
The proportion of subjects achieving clinical remission in the modified Mayo Score 
(MMS) (range: 0 to 9, based on stool frequency (SFS), RBS and endoscopy) at Week 12, 
defined as a score of 2 points or lower, with no individual subscore exceeding 1 point
!
The proportion of subjects achieving clinical response in the MMS at Week 12, defined 
as a decrease from baseline at least 2 points and at least 25%, along with a reduction in 
the RBS of at least 1 point or an absolute RBS of ≤ 1 point
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
16
!
The proportion of subjects achieving clinical remission at Week 8, defined as a partial 
Mayo score (PMS) of ≤ 2, with no individual subscore > 1
!
The proportion of subjects achieving clinical response at Week 8, defined as a decrease 
from baseline in the PMS of at least 2 points and at least 25%, along with a reduction in 
the RBS of at least 1 point or an absolute RBS of ≤ 1 point
4.2.3.
Secondary Safety Endpoints
!
Type, frequency, severity, and relationship of AEs to IP
!
Number of subjects who discontinue IP due to any AE
!
Frequency of clinically significant changes in physical examination, vital signs, and/or 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
17
 
 
 
4.3.
Stratification, Randomization, and Blinding
Approximately 165 subjects (55 subjects per arm) will be randomized in a 1:1:1 ratio using an 
IVRS/IWRS to receive oral apremilast (30 mg BID or 40 mg BID), or identically appearing 
placebo BID for up to 12 weeks, followed by 40 weeks of blinded treatment with apremilast (30 
mg BID or 40 mg BID).  At the end of 52 weeks in the study, subjects who have a Mayo 
endoscopy score ≤ 1 will have the opportunity to participate in the Extension Phase and will 
continue to receive the same treatment assigned during the Blinded Active-treatment Phase for 
an additional 52 weeks.
Treatment assignment will be stratified via IVRS/IWRS based on concomitant use of oral 
corticosteroids and previous exposure to immunosuppressants (eg, 6-MP, AZA, or MTX).  The 
number of subjects with previous exposure to immunosuppressants is targeted to comprise, no 
more than 50% of the subjects enrolled, and no less than 30%.
4.4.
Sample Size Determination
A 2-group chi-square test with a 0.1 two-sided significance level will have approximately 80%
power to detect a true 20% absolute difference (30% versus 10%) between a dose of apremilast
and placebo, for the proportion of subjects achieving a clinical remission at Week 12 when the
sample size in each group is 49. Assuming a dropout rate of 10% prior to Week 12, 
approximately 165 subjects (approximately 55 subjects per group) are planned to be randomized
in this study.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
18
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
The following reporting conventions apply generally to tables, listings, and figures:
!
Treatment comparisons between each apremilast group and the placebo group will be 
made for the efficacy 
 analyses.
!
Stratified analyses will use the 2 randomization stratification factors (concomitant use of 
oral corticosteroids [yes/no] and previous exposure to immunosuppressants [yes/no]), 
unless otherwise specified.
!
Stratified analyses and subgroup analyses with respect to the 2 randomization 
stratification factors will be based on each subject’s actual strata according to the clinical 
database of prior/concomitant medications, rather than the strata as randomized in the 
IVRS/IWRS.
!
P-values will be 2-sided and presented with 4 decimal places. P-values that are rounded 
to 0.0000 will be presented as “< 0.0001” and p-values that are rounded to 1 “> 0.9999”.
!
Confidence intervals (CIs) will be presented as 2-sided 95% CIs.
!
Summary statistics will consist of the number and percentage of subjects in each category 
for discrete variables, and the sample size, mean, standard deviation (SD), median, 
minimum, 25th percentile (Q1), 75th percentile (Q3), and maximum for continuous 
variables.
!
All mean, median, Q1, Q3, and CI values will be formatted to one more decimal place 
than the measured value. Standard deviation values will be formatted to two more 
decimal places than the measured value. Minimum and maximum will be formatted to the 
same number of decimal places as the measured value.
!
All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form XX (XX.X), where the percentage is in the 
parentheses.
!
Change from baseline is calculated as the post-baseline value minus the baseline value.
!
All laboratory data will be reported using standard international units.
!
All analysis and summary tables will include the analysis population sample size (ie, 
number of subjects) in the column headings.
!
Listings will include both the randomized treatment and actual treatment.
5.2.
Safety Analysis Periods
For the safety analysis, the following analysis periods for post-baseline data are defined. Safety 
data in these periods are considered treatment-emergent.
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Apremilast (CC-10004)
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Celgene 
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!
Weeks 0-12 placebo-controlled phase: This period encompasses data through Week 12. It 
starts on the date of the first dose of IP in the study, and ends on the date before IP 
dispensing at Week 12 for subjects who receive at least 1 dose of IP after Week 12
(defined as the date of the last dose of IP in the study no earlier than the date of IP 
dispensing at Week 12), or 28 days after the last dose of IP in the study or on the date of 
the actual last follow-up in the study, whichever comes first, for subjects who discontinue 
at or prior to Week 12.
Of note, this period is exclusive of the date of the first dose of IP in the study and 
inclusive of the date of IP dispensing at Week 12 for the analyses of the lab, vital signs, 
weight, and ECG data.
The safety analysis tables for the placebo-controlled phase will be presented by the 
following 4 groups: placebo, APR 30 BID, APR 40 BID, and APR total. 
!
Weeks 0-52 apremilast-exposure period: This period encompasses all apremilast-
exposure data through Week 52, irrespective of when the apremilast exposure starts (at 
Week 0 or 12) in the study. It starts on the date of the first dose of apremilast in the study, 
and ends on the date before IP dispensing at Week 52 for subjects who receive at least 1 
dose of apremilast after Week 52 (defined as the date of the last dose of apremilast in the 
study no earlier than the date of IP dispensing at Week 52), or 28 days after the last dose 
of apremilast in the study or on the date of the actual last follow-up in the study, 
whichever comes first, for subjects who discontinue at or prior to Week 52.
Of note, this period is exclusive of the date of the first dose of apremilast in the study and 
inclusive of the date of IP dispensing at Week 52 for the analyses of the lab, vital signs, 
weight, and ECG data.
The safety analysis tables, with an exception for the summaries of labs, vital signs, and 
body weight by time point, for the apremilast-exposure period during Weeks 0-52 will be 
presented by the following 4 groups: APR 30 BID, APR 40 BID, APR 30 BID/APR 40 
BID, and APR total, as follows:
o
The APR 30 BID group includes the data during the APR 30 BID treatment for 
subjects who receive APR 30 BID only in the study, subjects who initially receive 
APR 30 BID and switch to APR 40 BID at Week 12, and subjects who initially 
receive placebo and switch to APR 30 BID at Week 12.
o
The APR 40 BID group includes the data during the APR 40 BID treatment for 
subject who receive APR 40 BID only in the study and subjects who initially 
receive placebo and switch to APR 40 BID at Week 12.
o
The APR 30 BID/APR 40 BID group includes the data during the APR 40 BID 
treatment for subjects who initially receive APR 30 BID and switch to APR 40 
BID at Week 12.
o
The APR total group combines all the data of all the groups.
For the summaries of labs, vital signs, and body weight by time point, the data during the 
APR 30 BID and APR 40 BID treatments after Week 12 for subjects who initially receive 
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
20
placebo and switch to APR 30 BID and APR 40 BID, respectively, at Week 12 will be 
summarized in the placebo/APR 30 BID and placebo/APR 40 BID groups, respectively.
!
Weeks 0-104 apremilast-exposure period: This period encompasses all apremilast-
exposure data through Week 104, irrespective of when the apremilast exposure starts (at 
Week 0 or 12) in the study. It starts on the date of the first dose of apremilast in the study, 
and ends 28 days after the last dose of apremilast in the study or on the date of the actual 
last follow-up in the study, whichever comes first.
Of note, this period is exclusive of the date of the first dose of apremilast in the study for 
the analyses of the lab, vital signs, weight, and ECG data.
The treatment groups presented in the safety analysis tables for the apremilast-exposure 
period during Weeks 0-104 will be the same as those for the apremilast-exposure period 
during Weeks 0-52.
!
Weeks 52-104 apremilast-exposure period: This period encompasses the apremilast-
exposure data during Weeks 52-104 and is to be summarized for subjects who receive at 
least 1 dose of apremilast after Week 52 (defined as the date of the last dose of apremilast
in the study no earlier than the date of IP dispensing at Week 52). It starts on the date of 
IP dispensing at Week 52, and ends 28 days after the last dose of apremilast in the study 
or on the date of the actual last follow-up in the study, whichever comes first.
Of note, this period is exclusive of the date of IP dispensing at Week 52 for the analyses 
of the lab, vital signs, weight, and ECG data.
The safety analysis tables for the apremilast-exposure period during Weeks 52-104 will 
be presented by the following 3 groups: APR 30 BID, APR 40 BID, and APR total.
In the analyses of the lab, vital signs, weight, and ECG data, the value at the end of an analysis 
period is determined as the last post-baseline value among scheduled, unscheduled, and ET visits 
(excluding the follow-up visit) in the analysis period, whereas the worst value of an analysis 
period is determined among all visits (including the follow-up visit) in the analysis period.
5.3.
Time Points
5.3.1.
Analysis Time Point Assignments
The designation of time points used for analysis (analysis time points) will be based on the actual 
day of assessment relative to the date of the first dose of IP in the study (relative day, ie, date of 
assessment – date of the first dose of IP in the study + 1), rather than the nominal visit recorded.
Visits to be assigned with this method include the screening, Week 0 through Week 104, 
unscheduled, and early termination visits. The only exception is the assessments recorded at the 
post-treatment observational follow-up visit, which will be assigned to the follow-up visit.
All assessments performed prior to the date of the first dose of IP in the study will be assigned to 
the screening analysis time point. All assessments performed on the date of the first dose of IP in 
the study will be assigned to the Week 0 analysis time point.
The analysis time point assignments for the post-baseline visits (excluding the post-treatment 
observational follow-up visit) will be based on the relative day windows. These relative day 
windows are continuous, mutually exclusive, stretch from the date after the first dose of IP in the 
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Apremilast (CC-10004)
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Celgene 
Confidential and Proprietary
21
study to the midpoint between the first 2 scheduled visits, from midpoint to midpoint between 
each successive pair of scheduled visits, and from the last midpoint onward for the last scheduled 
visit. If data are available on multiple days within a relative day window, then the assessment 
closest to the visit’s target day (ie, study week × 7 + 1) will be used for that analysis time point. 
If the relative days from 2 assessments are equally close to, but on different sides of the target 
day, then the latter assessment will be used for that analysis time point. If multiple assessments 
are available on the same relative day, then the average of these assessments will be used for that 
relative day, except for the lab and ECG data for which the assessment at a later time of the same 
day will be used.
For efficacy 
 analyses, the data after the date of treatment failure (Section 11.2) 
will be set to missing prior to the assignments of analysis time points.
5.3.2.
Screening and Baseline Definitions
The screening SFS and RBS (involving the subject diary data) will be derived from the 3 earliest 
days with a non-missing value within a 7-day window that is allowed to be rolling within the 14 
days of the screening visit, whereas the screening PGA is defined as the first assessment on or 
before the date of the first dose of IP in the study.
Unless otherwise specified, the baseline value is defined as the last assessment on or before the 
date of the first dose of IP in the study. The baseline SFS and RBS will be derived from the 3 
most recent days (or as few as 2 days) with a non-missing value within the 7 days prior to the 
day before the screening endoscopy. In case of insufficient diary data during this period, the 
baseline value will be set to the screening value. The baseline TMS is calculated using the 
baseline SFS, RBS, PGA, and endoscopy subscores that are identified separately. The baseline 
PMS and MMS are calculated similarly.
For the safety analysis, the baseline value is defined as the last assessment on or before the date 
of the first dose of IP in the study for the analysis of the placebo-controlled phase, and the last 
assessment on or before the date of the first dose of apremilast for the analysis of an apremilast-
exposure period.
5.4.
Analysis Populations
5.4.1.
Intent-to-treat Population
The intent-to-treat (ITT) population will be the primary population for the efficacy analysis. The 
ITT population will consist of all subjects who are randomized as specified in the protocol and 
receive at least 1 dose of IP. To assess change from baseline, a baseline value and at least 1 post-
baseline value are also required. Subjects will be included in the treatment group to which they 
were randomized, irrespective of the treatments actually received.
5.4.2.
Per-protocol Population
A supportive analysis using the per-protocol (PP) population will be performed for the primary 
efficacy endpoint (clinical remission defined in the TMS) and the first secondary efficacy 
endpoint (clinical response defined in the TMS). The PP population will consist of all subjects 
included in the ITT population who have no protocol violations that may substantially affect the
efficacy results. These protocol violations could include, but are not limited to, not meeting key 
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inclusion/exclusion criteria, gross IP non-compliance, receiving incorrect IP, treatment 
unblinding by the investigator, concomitant use of protocol-prohibited medications that are 
potentially effective for UC for an unrelated comorbid condition, not having the required 
assessment at the designated time point for reasons other than experiencing a treatment failure, 
or discontinuing due to lack of efficacy or a drug-related AE prior to the time point. The final 
determination on protocol violations, and thereby the composition of the PP population, will be 
made prior to the unblinding of the database for the Double-blind Placebo-controlled Phase 
analysis and will be separately documented. Subjects will be included in the treatment group to 
which they were randomized, irrespective of the treatments actually received.
5.4.3.
Safety Population
The safety analysis for the placebo-controlled phase will be based on the safety population, 
which will consist of all subjects who are randomized and receive at least 1 dose of IP. At least 1
post-baseline assessment is required for inclusion in the analysis of each specific laboratory, vital 
sign, weight, or ECG parameter. To assess change from baseline, a baseline measurement is also 
required. Subjects will be included in the treatment group corresponding to the IP they actually 
received.
5.4.4.
Apremilast Subjects as Randomized Population
The efficacy analysis during Weeks 12-104 will be based on the apremilast subjects as 
randomized population, which will include all subjects who are randomized (at Week 0) or re-
randomized (at Week 12) to an apremilast dose group and receive at least 1 dose of apremilast.
To assess change from baseline, a baseline value and at least 1 post-baseline value are also 
required. Subjects will be included in the apremilast dose group to which they were randomized 
or re-randomized.
5.4.5.
Apremilast Subjects as Treated Population
The safety analysis for an apremilast-exposure period will be based on the apremilast subjects as 
treated population, which will include all subjects who are randomized (at Week 0) or assigned 
(at Week 12) to an apremilast dose group, and receive at least 1 dose of apremilast. At least 1 
post-baseline assessment is required for inclusion in the analysis of each specific laboratory, vital 
sign, weight, or ECG parameter. To assess change from baseline, a baseline measurement is also 
required. Subjects will be included in the apremilast dose group corresponding to the apremilast 
dose they actually received.
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6.
SUBJECT DISPOSITION
The number of subjects screened, the numbers and percentages of subjects randomized and not 
randomized, and of the eligibility criteria failed will be summarized based on all subjects 
screened.
The number and percentage of subjects included in the analysis populations will be summarized 
based on all subjects randomized.
Subject disposition (entered, completed, discontinued, along with primary reason for 
discontinuation) will be summarized based on all subjects randomized, unless otherwise 
specified below, for
!
Weeks 0-12
!
Weeks 0-52
!
Weeks 12-52 (based on subjects who complete Week 12)
!
Weeks 52-104 (based on subjects who enter the Extension Phase)
!
Post-treatment observational follow-up phase (entered and completed only) within each 
of the above periods (based on subjects who enter the respective period)
The definitions of entry and completion in the above disposition summaries are given in Table 2.
Table 2:
Definitions of Entry and Completion in Disposition Summaries
Disposition 
Category
Weeks 0-12
Weeks 0-52
Weeks 12-52
Weeks 52-104
Follow-up Phase
Entered
Randomized
Randomized
Completed 
Week 12/Visit 
6
Completed 
Week 52/Visit 
11 and 
indicated 
continuation 
into Extension 
Phase in eCRF 
Indicated continuation into 
Follow-up Phase in eCRF 
and had data after the last 
non-follow-up visit (Week 
104/Visit 14 or ET visit, 
excluding any unscheduled 
visits associated with Week 
104/Visit 14 and ET visit)
Completed
Completed 
Week 12/Visit 
6
Completed 
Week 52/Visit 
11
Completed 
Week 52/Visit 
11
Completed 
Week
104/Visit 14
Completed the follow-up 
visit
A listing of discontinued subjects with reason for discontinuation will be provided.
The number and percentage of subjects by region, country, and site will be provided based on all 
subjects randomized.
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7.
PROTOCOL DEVIATIONS/VIOLATIONS
Protocol violations and deviations will be summarized for the Screening Phase and Weeks 0-12
using the ITT population, for Weeks 12-52 for subjects who complete Week 12, and for Weeks 
52-104 for subjects who enter the Extension Phase.
A listing of all protocol violations and deviations in the study will be provided.
&(/*(1(35235,(7$5<,1)250$7,21


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized descriptively using the ITT 
population. The comparability of the treatment groups for each relevant characteristic will be 
assessed descriptively in table format; no statistical hypothesis tests will be performed on these 
characteristics. Subject data listings will be provided.
8.1.
Demographics and Baseline Characteristics
The following characteristics will be summarized as continuous variables:
!
Age (years)
!
Baseline body weight (kg)
!
Baseline body mass index (BMI; kg/m2)
The following characteristics will be summarized as categorical variables:
!
Age (< 65, ≥ 65 years; < 40, 40 – < 65, 65 – < 75, 75 – < 85, ≥ 85 years)
!
Sex (male, female)
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, other, not collected or reported)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino, unknown)
!
Region (North America, Western Europe, Eastern Europe/Russia, Australia/New 
Zealand)
!
Baseline body weight (< 55, 55 – < 70, 70 – < 85, 85 – < 100, ≥ 100 kg)
!
Baseline BMI (< 18.5, 18.5 – < 25, 25 – < 30, 30 – < 35, 35 – < 40, and ∀40 kg/m2)
!
Alcoholic beverages (yes [< 1 drink per week, 1 – 14 drinks per week, > 14 drinks per 
week], no)
!
Tobacco history (never smoked, past smoker, current smoker) 
Age will be calculated as (date of informed consent – date of birth + 1) / 365.25 when the full 
date of birth is collected; otherwise, the age recorded will be used.
8.2.
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized as continuous variables:
!
Duration of UC (years)
!
Screening TMS
!
Baseline TMS
!
Baseline PMS
!
Baseline MMS
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!


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!
Baseline SFS
!
Baseline RBS
!
Baseline PGA subscore
!
Baseline endoscopy subscore
!
Baseline SF-12v2 Physical Component Summary (PCS) score
!
Baseline SF-12v2 Mental Component Summary (MCS) score
The following baseline disease characteristics will be summarized as categorical variables:
!
Duration of UC (< 2, 2 – < 5, 5 – < 10, ≥ 10 years)
!
Disease localization (Rectum and sigmoid colon only, left side of colon)
!
Baseline extraintestinal manifestations (yes [peripheral arthropathy, axial arthropathies, 
pyoderma gangrenosum, erythema nodosum, episcleritis, uveitis, primary sclerosing 
cholangitis, other], no)
!
Therapeutic failure with or intolerance to UC medications (yes [never responded, loss of 
response, partial response, intolerance], no)
!
Therapeutic failure with or intolerance to oral aminosalicylates (yes [never responded, 
loss of response, partial response, intolerance], no)
!
Therapeutic failure with or intolerance to budesonide (yes [never responded, loss of 
response, partial response, intolerance], no)
!
Therapeutic failure with or intolerance to systemic corticosteroids (yes [never responded, 
loss of response, partial response, intolerance], no)
!
Therapeutic failure with or intolerance to immunosuppressants (yes [never responded, 
loss of response, partial response, intolerance], no)
!
Contraindication to UC medications (yes [oral aminosalicylates, budesonide, systemic 
corticosteroids, immunosuppressants], no)
!
Concomitant use of oral corticosteroids (as randomized) (yes, no)
!
Concomitant use of oral corticosteroids (per clinical database) (yes, no)
!
Previous exposure to immunosuppressants (as randomized) (yes, no)
!
Previous exposure to immunosuppressants (per clinical database) (yes, no)
!
Screening TMS (< 6, 6 – 8, 9 – 11, 12)
!
Baseline TMS (< 6, 6 – 8, 9 – 11, 12)
!
Baseline endoscopy subscore (0 – 1, 2, 3)
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Duration of UC will be calculated as (date of informed consent – date of diagnosis + 1) / 365.25.
8.3.
Medical History
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA), and summarized based on the ITT population by system organ class (SOC) and 
preferred term (PT), with SOCs sorted in the standard international order and PTs within each 
SOC in descending order of frequency, and by PT only in descending order of frequency.
8.4.
Prior Medications/Procedures
Prior medications are defined as medications with a start date before the date of the first dose of 
IP in the study (whether or not the end date is before the date of the first dose of IP). Prior 
medications that continue on or after the date of the first dose of IP will be also reported as 
concomitant medications. The Anatomical Therapeutical Chemical (ATC) coding scheme of the 
World Health Organization Drug Dictionary (WHODD) will be used to group medications into 
relevant categories. Prior medications will be summarized based on the ITT population by ATC2
level and standardized medication name, with ATC2 levels and standardized medication names 
within each ATC2 level sorted in descending order of frequency.
Prior procedures are similarly defined. Prior procedures will be coded according to the 
MedDRA, and summarized based on the ITT population by SOC and PT, with SOCs sorted in 
the standard international order and PTs within each SOC in descending order of frequency.
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9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT
9.1.
Treatment Duration
Treatment duration will be summarized for the Weeks 0-12 placebo-controlled phase using the 
safety population, for the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods using the 
apremilast subjects as treated population, and for the Weeks 52-104 apremilast-exposure period 
for subjects who receive at least 1 dose of apremilast after Week 52. 
Treatment duration (in weeks) is calculated as (the date of the last dose of IP in the period – the 
date of the first dose of IP in the period + 1) / 7 and rounded to one decimal place. The date of 
the last dose of IP in the Weeks 0-12 placebo-controlled phase is defined as the date before IP 
dispensing at Week 12. The date of the last dose of IP in the Weeks 0-52 apremilast-exposure 
period and the date of the first dose of IP in the Weeks 52-104 apremilast-exposure period are 
defined as the date before and the date of, respectively, IP dispensing at Week 52.
Treatment duration will be summarized as a continuous variable, and as a categorical variable 
with the following exposure intervals: 
!
Weeks 0-12 placebo-controlled phase: ≤ 4, > 4 – 8, > 8 – 12, > 12 weeks
!
Weeks 0-52 apremilast-exposure period: ≤ 4, > 4 – 8, > 8 – 12, > 12 – 20, > 20 – 28, > 28 
– 36, > 36 – 44, > 44 – 52, and > 52 weeks
!
Weeks 0-104 apremilast-exposure period: ≤ 4, > 4 – 8, > 8 – 12, > 12 – 20, > 20 – 28, 
> 28 – 36, > 36 – 44, > 44 – 52, > 52 – 68, > 68 – 86, > 86 – 104, > 104 weeks
!
Weeks 52-104 apremilast-exposure period (intervals denote the number of weeks relative 
to the date of the first dose of IP in the Weeks 52-104 apremilast-exposure period as 
defined above): ≤ 16, > 16 – 34, > 34 – 52, > 52 weeks
A subject data listing of study drug records will be provided. 
9.2.
Treatment Compliance
As part of the routine recording of the amount of IP taken by each subject, the numbers of tablets 
dispensed and returned will be recorded at each visit. These records will be used to calculate 
treatment compliance. Treatment compliance will be summarized for the Weeks 0-12 placebo-
controlled phase using the ITT population, for Weeks 12-52 for subjects who receive at least 1 
dose of apremilast after Week 12 (defined as the date of the last dose of apremilast in the study
no earlier than the date of IP dispensing at Week 12), and for Weeks 52-104 for subjects who 
receive at least 1 dose of apremilast after Week 52.
The compliance rate (%) for each subject will be computed as 100 times the total number of 
tablets taken (the total number of tablets dispensed minus the total number of tablets returned) 
over the period divided by the intended total number of tablets that should have been taken over 
the same period (defined by the first and last IP dose dates in the period). The date of the last 
dose of IP in the Weeks 0-12 placebo-controlled phase and the date of the first dose of IP in 
Weeks 12-52 are defined as the date before and the date of, respectively, IP dispensing at Week 
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12. The date of the last dose of IP in Weeks 12-52 and the date of the first dose of IP in Weeks 
52-104 are defined as the date before and the date of, respectively, IP dispensing at Week 52.
Treatment compliance rate will be summarized as a continuous variable, and as a categorical 
variable with the following categories:  < 75%, 75% – 120%, and > 120%.
A subject data listing of drug accountability records will be provided.


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10.
CONCOMITANT MEDICATIONS AND PROCEDURES
Concomitant medications and procedures will be summarized for the Weeks 0-12 placebo-
controlled phase using the safety population, for the Weeks 0-52 and Weeks 0-104 apremilast-
exposure periods using the apremilast subjects as treated population, and for the Weeks 52-104 
apremilast-exposure period for subjects who receive at least 1 dose of apremilast after Week 52.
10.1.
Concomitant Medications
A concomitant medication in each of the above periods is defined as a non-study medication 
with any amount taken during the period as defined in Section 5.2.
The ATC coding scheme of the WHODD will be used to group medications into relevant 
categories. Concomitant medications will be summarized by ATC2 level and standardized 
medication name, with ATC2 levels and standardized medication names within each ATC2 level 
sorted in descending order of frequency.
10.2.
Concomitant Procedures
Concomitant procedures are defined similarly to concomitant medications. Concomitant 
procedures will be coded according to the MedDRA, and summarized by SOC and PT, with 
SOCs sorted in the standard international order and PTs within each SOC in descending order of 
frequency.
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11.
EFFICACY ANALYSIS
11.1.
Multiplicity
Formal statistical tests, conducted at a 2-sided significance level of 0.1, are planned between 
APR 40 BID and placebo and between APR 30 BID and placebo for the primary efficacy 
endpoint. To control the family-wise Type 1 error rate at the 0.1 level, these 2 formal statistical 
tests will be carried out by using a fixed sequence testing procedure, with the comparison 
between APR 40 BID and placebo tested first. The comparison between APR 30 BID and 
placebo will be tested only if the comparison between APR 40 BID and placebo is statistically 
significant. If any of the 2 apremilast dose groups is discontinued prior to the end of the study, 
the treatment comparison will be conducted for the comparison between the retained apremilast 
dose and placebo at a 2-sided significance level of 0.1.
 
For formal statistical tests that are planned but not performed as a result of the aforementioned 
multiplicity adjustment strategy, as well as for any other comparisons that are not subjected to 
multiplicity adjustment, nominal 2-sided p-values (without adjustment for multiplicity) will be 
provided as a measure of the strength of association between the endpoint and the treatment 
effect rather than formal tests of hypotheses.
11.2.
Missing Data Handling
11.2.1.
Treatment Failures
Subjects who have (1) protocol-prohibited initiation or dose increase of concomitant UC 
medications, or (2) a colectomy (partial or total) or an ostomy will be considered treatment 
failures after the date of the event. Use of antidiarrheals or dose increase of oral corticosteroids 
back to the baseline dose for subjects undergoing corticosteroid tapering will not be considered a 
treatment failure.
Efficacy data after the date of treatment failure will be considered missing. Of note, for efficacy 
 analyses, the data after the date of treatment failure will be set to missing prior to 
the assignments of analysis time points as described in Section 5.3.1.
11.2.2.
Binary Efficacy Endpoints
11.2.2.1.
Primary Approach for Analysis
For binary efficacy endpoints, the primary approach to handling missing data will be 
nonresponder imputation (NRI), where subjects who have insufficient data for response 
determination for the time point under consideration will be considered nonresponders for that 
time point. Insufficient data, including missing data at baseline (if the binary endpoint assesses 
change from baseline) or a post-baseline time point, will be determined after the handling of time 
points as described in Sections 5.3.
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11.2.2.2.
Sensitivity Analyses
Sensitivity analyses using different missing data handling approaches (data as observed [DAO] 
and last observation carried forward [LOCF]) will be performed for the primary efficacy 
endpoint (clinical remission defined in the TMS) and the first secondary efficacy endpoint 
(clinical response defined in the TMS).
In the DAO analyses, only subjects with sufficient data for response determination at the time 
point under consideration will be included.
In the LOCF analyses, missing data at the time point under consideration will be imputed by the 
last post-baseline observation. For the TMS which consists of 4 individual subscores, the LOCF 
method will be applied to the individual subscores rather than directly to the TMS, and then the 
TMS will be calculated based on the observed or imputed subscores. Subjects who still have 
insufficient data for response determination at the time point under consideration despite the 
application of LOCF (eg, no post-baseline data) will be considered nonresponders for that time 
point.
11.2.2.3.
Approach for Descriptive Summary
Binary endpoints by time point will also be summarized based on DAO, where only subjects 
with sufficient data for response determination at the time point under consideration will be 
included in the summary of that time point.
11.2.3.
Continuous Efficacy Endpoints
11.2.3.1.
Primary Approach for Analysis
For continuous efficacy endpoints, the primary missing data handling approach will be last 
observation carried forwarded (LOCF). For subjects who initially receive placebo and switch to 
an apremilast dose at Week 12 and subjects who initially receive APR 30 BID and switch to 
APR 40 BID at Week 12, the values on or before the date of IP dispensing at Week 12 will not 
be carried over beyond Week 12. For the TMS, PMS, and MMS, which are composite scores 
derived from individual subscores, the LOCF method will be applied to the individual subscores
rather than to the composite score.
11.2.3.2.
Approach for Descriptive Summary
Continuous endpoints by time point will also be summarized based on DAO, where only subjects 
with sufficient data at the time point under consideration will be included in the summary of that 
time point.
11.3.
Analysis of Primary Endpoint
11.3.1.
Primary Analysis of Primary Endpoint
The primary objective of the study will be evaluated by testing the superiority of each of the 2 
apremilast doses over placebo with respect to the proportion of subjects achieving a clinical 
remission in the TMS, defined as a TMS of ≤ 2, with no individual subscore > 1, at Week 12 
based on the ITT population and the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors. Within-group proportions, 2-sided 95% CIs (based on the 
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1.3.1.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
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33
Wilson score method) for the within-group proportions, unstratified treatment differences in 
proportions, stratified treatment differences in proportions using the weighted average of the 
treatment differences across the strata with the CMH weights, stratified 2-sided 95% CIs (based 
on the stratified Newcombe method [Yan, 2010]) for the treatment differences in proportions, 
and the 2-sided p-values from the CMH tests, will be provided. Missing data will be handled by 
the NRI approach.
11.3.2.
Sensitivity Analyses of Primary Endpoint
The following sensitivity analyses will be performed for the primary endpoint: 1) using the PP 
population and the NRI method for missing data; 2) using DAO (Section 11.2.2.2); 3) using the 
ITT population and the LOCF method for missing data (Section 11.2.2.2). The statistical 
methods adopted for the primary analysis will also be used for these sensitivity analyses.
11.4.
Analyses of Secondary Efficacy Endpoints
The analyses of secondary efficacy endpoints will be performed identically to the primary 
analysis of the primary endpoint. In addition, the sensitivity analyses of the primary endpoint
will also be performed for the first secondary efficacy endpoint (clinical response defined in the 
TMS).
 
 
 
 
 
 
 
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Statistical Analysis Plan. Protocol CC-10004-UC-001
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36
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.7.
Assessing Study Center Effect and Treatment-by-center Interaction
This study is a multicenter study. The limited sample size of the study relative to the number of 
study sites does not allow for a meaningful assessment of study center effect.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
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37
12.
SAFETY ANALYSIS
Safety will be evaluated via descriptive statistics and point estimates. No inferential testing for 
statistical significance will be performed.
The safety analyses will be based on the safety population for the Weeks 0-12 placebo-controlled 
phase, the apremilast subjects as treated population for the Weeks 0-52 and Weeks 0-104 
apremilast-exposure periods, and subjects who receive at least 1 dose of apremilast after Week 
52 for the Weeks 52-104 apremilast-exposure period. The treatment groups presented for these 
analysis periods are described in Section 5.2.
12.1.
Adverse Events
AEs will be coded according to the MedDRA. Unless otherwise specified, AEs will be 
summarized by SOC and PT, with SOCs sorted in the standard international order and PTs 
within each SOC in descending order of subject incidence.
For the analyses of AEs, the following point estimates are provided, unless otherwise specified:
!
Subject incidence: Subject incidence (i.e., percentage [%] used in a frequency summary) 
is defined as the number of subjects with the specific event divided by the number of 
subjects included in the analysis. Subjects with multiple occurrences of the specific event 
in the specific analysis period will be counted only once in the numerator.
!
Exposure-adjusted incidence rate (EAIR) per 100 person-years: The EAIR per 100 
person-years is defined as 100 times the number of subjects with the specific event 
divided by the total exposure time (in years) to the event 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 duration of the specific analysis period as described in 
Section 5.2, whereas the exposure time for a subject with the specific event is the 
duration of the specific analysis period 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 person-years is interpreted as the expected number of subjects 
with at least 1 occurrence of the specific event per 100 person-years of exposure to the 
event.
A subject data listing of all AEs (including treatment-emergent AEs [TEAEs] and non-TEAEs) 
will be provided.
12.1.1.
Overall Summary of TEAEs
An overall summary of the following TEAE categories will be provided for the Weeks 0-12 
placebo-controlled phase, the Weeks 0-52, Weeks 0-104, and Weeks 52-104 apremilast-exposure 
periods:
!
Any TEAE
!
Any drug-related TEAE
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Confidential and Proprietary
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!
Any severe TEAE 
!
Any serious TEAE
!
Any serious drug-related TEAE
!
Any TEAE leading to drug interruption
!
Any TEAE leading to drug withdrawal
!
Any TEAE leading to death
In addition, the overall summary of TEAE categories will be provided by age category (< 65, ≥ 
65), race (white, non-white), and region (North America, Western Europe, Eastern 
Europe/Russia, Australia/New Zealand) for the Weeks 0-12 placebo-controlled phase and the 
Weeks 0-104 apremilast-exposure period.
12.1.2.
All TEAEs
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence) for the Weeks 0-12 placebo-controlled phase, the Weeks 0-52, Weeks 0-104, 
and Weeks 52-104 apremilast-exposure periods.
All TEAEs by exposure interval will be summarized for the Weeks 0-12 placebo-controlled 
phase and the Weeks 0-104 apremilast-exposure period. The exposure intervals are ≤ 2, > 2 – 4, 
> 4 – 8, > 8 weeks for the Weeks 0-12 placebo-controlled phase, and ≤ 2, > 2 – 4, > 4 – 12, > 12 
– 20, > 20 – 28, > 28 – 36, > 36 – 44, > 44 – 52, > 52 – 68, > 68 – 86, > 86 weeks for the Weeks 
0-104 apremilast-exposure period. 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 
starts. The denominator of a subject incidence is the number of subjects with the exposure time
reaching the lower bound of the particular exposure interval, and the denominator of an EAIR is 
the sum of the exposure time during the exposure interval (up to the start date [inclusive] of the 
first occurrence of the specific event for each subject reporting the event in the interval) among
the same number of subjects as in the denominator of the corresponding subject incidence.
All TEAEs will be summarized by sex and concomitant use of oral corticosteroids for the Weeks 
0-12 placebo-controlled phase and the Weeks 0-104 apremilast-exposure period.
All TEAEs starting after the date of the last dose of IP and up to 28 days after the last dose of IP 
will be summarized for subjects who enter the observational follow-up phase during the Weeks 
0-12 placebo-controlled phase and the Weeks 0-104 apremilast-exposure period. The EAIR will 
not be provided in this summary.
12.1.3.
Common TEAEs
Any TEAEs with subject incidence ≥ 5% (or another cutoff if justified) in any treatment group
and any non-serious TEAEs with subject incidence ≥ 5% (or another cutoff if justified) in any 
treatment group will be summarized for the Weeks 0-12 placebo-controlled phase and the Weeks 
0-104 apremilast-exposure period.
Onset day and duration will be summarized for any TEAEs with subject incidence ≥ 5% (or 
another cutoff if justified) in any treatment group for the Weeks 0-12 placebo-controlled phase 
and the Weeks 0-104 apremilast-exposure period. Multiple occurrences of a specific event for 
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65, ≥
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e exposure
exposure
d phase
phase, an
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– 68, > 68 
68, > 68
counted on
counted on
TEAE in ea
TEAE in 
e is the num
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exposure i
exposure i
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exposure
fo
for each su
each
n the denom
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ed by sex 
hase and 
se an th
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04


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Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
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39
the same subject will all be counted in the summaries of onset day and duration. For subjects 
who initially receive placebo and switch to an apremilast dose at Week 12, AEs with start dates 
in the placebo-controlled phase and end dates in the apremilast-exposure period will be
summarized as ongoing for the summary of duration in the placebo-controlled phase, whereas for 
all other subjects, the actual AE end dates regardless of being in the placebo-controlled phase or 
apremilast-exposure period will be used for calculating duration. Duration will not be calculated 
for AEs reported as ongoing.
12.1.4.
Drug-related TEAEs
Drug-related TEAEs will be summarized for the Weeks 0-12 placebo-controlled phase, the 
Weeks 0-52, Weeks 0-104, and Weeks 52-104 apremilast-exposure periods.
12.1.5.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if needed, 
missing) for the Weeks 0-12 placebo-controlled phase, the Weeks 0-52, Weeks 0-104, and 
Weeks 52-104 apremilast-exposure periods. 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. If the severity is missing for one or more of the occurrences, the maximum 
severity of the remaining occurrences will be used. If the severity is missing for all of the 
occurrences, the subject will be counted only once in the “missing” category of severity.
12.1.6.
Serious TEAEs
Serious TEAEs will be summarized for the Weeks 0-12 placebo-controlled phase, the Weeks 0-
52, Weeks 0-104, and Weeks 52-104 apremilast-exposure periods.
Serious TEAEs will also be summarized by sex and concomitant use of oral corticosteroids for 
the Weeks 0-12 placebo-controlled phase and the Weeks 0-104 apremilast-exposure period.
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided.
12.1.7.
TEAEs Leading to Drug Interruption and Leading to Drug Withdrawal
TEAEs leading to drug interruption will be summarized for the Weeks 0-12 placebo-controlled 
phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods.
TEAEs leading to drug withdrawal will be summarized for the Weeks 0-12 placebo-controlled 
phase, the Weeks 0-52, Weeks 0-104, and Weeks 52-104 apremilast-exposure periods.
TEAEs leading to drug withdrawal will also be summarized by sex and concomitant use of oral 
corticosteroids for the Weeks 0-12 placebo-controlled phase and the Weeks 0-104 apremilast-
exposure period.
A subject data listing of TEAEs leading to drug withdrawal will be provided.
12.1.8.
Deaths
TEAEs leading to death will be summarized for the Weeks 0-12 placebo-controlled phase, the 
Weeks 0-52 and Weeks 0-104 apremilast-exposure periods. A subject data listing of all deaths 
will be provided.
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104
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2.1.8.
2.1.8.


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12.2.
Clinical Laboratory Evaluations
The following protocol-specified hematologic and serum chemistry parameters from the central 
laboratory will be summarized:
!
Hematology: complete blood count (red blood cell [RBC] count, hemoglobin, hematocrit, 
white blood cell [WBC] count and differential, absolute WBC counts, platelet count)
!
Serum chemistries: total protein, albumin, calcium, phosphorous, glucose, total 
cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein 
cholesterol (LDL), triglycerides, uric acid, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), sodium, 
potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, lactate 
dehydrogenase (LDH), magnesium
For the above hematologic and serum chemistry parameters, summary statistics of observed 
values and changes from baseline will be provided by time point (including the end of period and 
the post-treatment observational follow-up visit) for the Weeks 0-12 placebo-controlled phase, 
the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods.  Frequency summaries (shift 
tables) of shifts from baseline to post-baseline time points (including shifts to the end of period 
value and to the worst value) by category of low/normal/high/both low and high (the last 
category for the shift to the worst value only) will be provided for the Weeks 0-12 placebo-
controlled phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods.
Frequency summaries of the shift from baseline to the worst value by folds of ULN (<= 1xULN, 
> 1 to 2xULN, > 2 to 3xULN, > 3 to 5xULN, > 5 to 8xULN, > 8xULN) will be provided for 
ALT, AST, total bilirubin, and alkaline phosphatase for the Weeks 0-12 placebo-controlled 
phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods.
Summaries of laboratory marked abnormalities as defined in Section 17.1 will be provided for 
the Weeks 0-12 placebo-controlled phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure 
periods. Subject incidence for each abnormality will be calculated based on subjects with a 
baseline value and at least 1 post-baseline value in the period under consideration for criteria 
requiring baseline, or subjects with at least 1 post-baseline value in the period under 
consideration for criteria not requiring baseline. Separate summaries of laboratory marked 
abnormalities will also be presented by normal baseline and abnormal baseline. For the purpose 
of these summaries, abnormal (normal) baseline is defined as a baseline value that is low (normal 
or high) for criteria concerning low values and as a baseline value that is high (normal or low) 
for criteria concerning high values; both low and high are relative to the laboratory normal range.
A subject data listing including all values of a subject’s laboratory parameter(s) that have any 
marked abnormality will be provided. A subject data listing of all laboratory data (including 
urinalysis) will be provided.
12.3.
Vital Signs and Body Weight
For vital signs and body weight, summary statistics of observed values and changes from 
baseline (also percent change from baseline for body weight) will be provided by time point 
(including the end of period and the post-treatment observational follow-up visit) for the Weeks 
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2.3.
2.3.


Apremilast (CC-10004)
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0-12 placebo-controlled phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods.
Frequency summaries (shift tables) of shifts from baseline to post-baseline time points (including 
shifts to the end of period value and to the worst value) by category of low/normal/high/both low 
and high (the last category for the shift to the worst value only) will be provided for pulse, 
systolic and diastolic blood pressures (SBP and DBP) for the Weeks 0-12 placebo-controlled 
phase, the Weeks 0-52 and Weeks 0-104 apremilast-exposure periods. The normal ranges are 
defined as: 60 – 100 beats/minute for pulse, 90 – 140 mmHg for systolic blood pressure, and 60 
– 90 mmHg for diastolic blood pressure.
Frequency summaries of change and percent change in body weight from baseline to the end of 
the respective analysis period for all subjects with a baseline value and at least 1 post-baseline 
value, as well as by baseline BMI category (< 18.5, 18.5 to < 25, 25 to < 30, 30 to < 35, 35 to 
< 40, and ∀40 kg/m2) and by baseline weight category (< 70, ∀70 to < 85, ∀85 to < 100, and ∀
100 kg) will be provided for the Weeks 0-12 placebo-controlled phase, the Weeks 0-52 and 
Weeks 0-104 apremilast-exposure periods. 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 respective analysis period 
(excluding the value obtained at the post-treatment observational follow-up visit, if applicable).
A subject data listing of all vital signs and body weight will be provided, with subjects with body 
weight loss of ∀7.5% from baseline flagged.
12.4.
Electrocardiogram
Frequency summaries (shift tables) of the shift from baseline to the end of period in investigator 
clinical interpretation of ECG (normal; abnormal, not clinically significant; and abnormal, 
clinically significant) will be provided for the Weeks 0-12 placebo-controlled phase, the Weeks 
0-52 and Weeks 0-104 apremilast-exposure periods.
A subject data listing including all of a subject’s ECG interpretations will be provided for 
subjects who have any clinically significant abnormal interpretation by the investigator.
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Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
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42
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
Not applicable.
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16.
REFERENCES
Yan X, Su XG. Stratified Wilson and Newcombe confidence intervals for multiple binomial 
proportions. Statistics in Biopharmaceutical Research 2010;2:329-335.
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17.
APPENDICES
17.1.
Laboratory Marked Abnormalities Criteria
Table 5:
Laboratory 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
   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
   Triglycerides
mmol/L
> 3.4
   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
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8
> 13.9
13.9
<
$5
$
> 3 x
> 3 x
$5
7$
/L
/L
>
7$
7$
7$
7$
mmol/L
mol/L
(7
mmol/
mm
5,
3
23
52
35
3
( 3
1
cytes
cytes
(1
rophils
phils
*(
Platelets
Platele
/*
(/


Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
49
$7,21
&(/*(1(35235,(7$5<,1)250$7


Apremilast (CC-10004)
Statistical Analysis Plan. Protocol CC-10004-UC-001
Celgene 
Confidential and Proprietary
50