Conditions: Crohn's Disease
Keywords: Crohn's Disease GED 0301 Mongersen Safety Irritable Bowel Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 310
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess long-term safety data of GED-0301 for a period of up to 208 weeks in adult subjects (i.e., ≥ 18 years of age) who participated in the core Phase 3 GED-0301-CD-002 and GED-0301-CD-003 studies and adolescent subjects (i.e., 12 to 17 years of age) who participated in the core Phase 3 GED-0301-CD-003 study. Although all subjects will receive active treatment, this study is double-blinded for the entire 208 weeks for the purpose of preserving the blind of the subject's treatment allocation in the initial, core Phase 3 GED-0301 study.

The GED-0301-CD-003 trial was not initiated; see detailed description.

Detailed description:
This is a long-term active treatment study in patients with Crohn's disease (CD). Subjects who met the early escape criteria in Study GED-0301-CD-002, or subjects who completed Study GED-0301-002 or GED-0301-003, may be eligible for this study. Primary objective is to assess long-term safety of GED 0301. Additional efficacy and patient reported outcomes will be explored.

There are 5 possible treatment groups for GED-0301-CD-002 Subjects (Groups 1-5). There are 3 possible treatment groups for GED-0301-CD-003 subjects (Groups 1-3). Treatment is assigned based on clinical improvement achieved or not achieved from the core GED-0301 study.

1. continuous GED-0301 160 mg once daily for 12 weeks, followed by alternating placebo once daily for 4 weeks with GED-0301 160 mg once daily for 4 weeks, through Week 208;
2. alternating GED-0301 160 mg once daily for 4 weeks with placebo once daily for 4 weeks, through Week 208;
3. alternating placebo once daily for 4 weeks with GED-0301 160 mg once daily for 4 weeks, through Week 208;
4. continuous GED-0301 40 mg once daily through Week 208;
5. alternating placebo once daily for 4 weeks, followed by GED-0301 40 mg once daily for 4 weeks, through Week 208.

The GED-0301-CD-003 trial was not initiated; the GED-0301 program was terminated; no safety findings were noted.

Arms:
arm 1: GED-0301 160 mg once daily (QD) for 12 weeks, followed by alternating Placebo (PBO) QD for 4 weeks with GED 0301 160 mg QD for 4 weeks, up to 208 weeks, if the subject previously received Placebo in the prior GED-0301 Study arm 2: Alternating GED-0301 160 mg once daily (QD) for 4 weeks with placebo (PBO) QD for 4 weeks, up to 208 weeks, depending on previous response in the prior GED-0301 study arm 3: Alternating PBO once daily (QD) for 4 weeks with GED-0301 40 mg QD for 4 weeks with, up to 208 weeks, depending on previous response in the prior GED-0301 study arm 4: GED-0301 40 mg once daily (QD) for up to 208 weeks arm 5: Alternating PBO QD for 4 weeks with GED-0301 160 mg QD for 4 weeks, through Week 208

Interventions: intervention 1: GED-0301 intervention 2: Placebo
Intervention descriptions: intervention 1: Mongersen intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
1
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
TITLE PAGE
A PHASE 3, LONG-TERM ACTIVE TREATMENT 
EXTENSION STUDY OF MONGERSEN (GED-0301) IN 
SUBJECTS WITH CROHN’S DISEASE
PROTOCOL NUMBER:
GED-0301-CD-004
DATE FINAL:
11 Sep 2015
DATE AMENDMENT 1 FINAL:
06 Jan 2017
EudraCT NUMBER:
2015-001963-37
IND NUMBER:
123278
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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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
2
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone:
 (Office)
 (Cell)
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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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
3
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
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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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
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)/Independent Ethics Committee (IEC) procedures, 
instructions from Celgene representatives, the Declaration of Helsinki, International 
Council for Harmonisation (ICH) Good Clinical Practices Guidelines, and local 
regulations governing the conduct of clinical studies.
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
5
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
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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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
6
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, long-term active treatment extension study of mongersen (GED-0301) in subjects 
with Crohn’s disease
Indication
Mongersen (GED-0301) is being studied for the treatment of subjects with active Crohn’s 
disease (CD) and ulcerative colitis (UC). Although the etiology of CD has not been completely 
elucidated, there has been significant advancement in the understanding of the disease 
pathogenesis.  There is evidence that the chronic intestinal inflammation is caused by an 
excessive immune response to mucosal antigens that is not appropriately controlled by the 
normal counter-regulatory mechanisms.  One of the counter-regulatory mechanisms involves 
transforming growth factor-beta 1 (TGF-β1).  TGF-β1 is a multifunctional factor that has been 
shown to be involved in regulating growth, differentiation, and function of immune and 
nonimmune cells (Monteleone, 2001).  TGF-β1 has been shown to play an important role in the 
control of immune homeostasis and acts as a potent negative regulator of mucosal inflammation.  
TGF-β1 knockout mice developed a severe multiple-organ inflammatory disease, in which the 
lymphocytic infiltration of the affected organs was associated with increased production of tumor 
necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ).  Studies have shown that 
abrogation of TGF-β1 signaling in T cells alone is sufficient to disrupt T and B cell homeostasis 
and induce T cell-mediated inflammatory lesions in various organs, including the intestine.  It 
has been widely demonstrated that neutralization of TGF-β1 results in the induction and/or 
amplification of pathogenic responses responsible for the development of experimental colitis 
resembling either CD or UC (Monteleone, 2012).
TGF-β1 signaling is regulated by Smads, a family of proteins that serve as substrates for TGF-β1 
type I and type II receptors.  The TGF-β type I receptor recognizes Smad2 and Smad3 which, 
upon phosphorylation of Smad3, en route to the nucleus, associate with Smad4, forming 
complexes that participate in transcriptional control of target genes.  In addition to the activating 
Smads, an inhibiting Smad also exists.  Smad7 interacts with activated receptors and prevents 
phosphorylation of Smad2 and Smad3.  The advance in the understanding of the involvement of 
the TGF-β signaling pathway in the pathogenesis of CD and the identification of the role of 
Smad7 in inflammatory bowel disease (IBD) has provided the rationale for the development of a 
new drug that, through the inhibition of Smad7 expression, could restore TGF-β1 signaling, thus 
inhibiting the production of pro-inflammatory molecules such as TNF-α and IFN-γ.
GED-0301 is an investigational medicinal product in clinical development for the treatment of 
CD and UC.  GED-0301 is an antisense oligodeoxynucleotide that is complementary to the 
sequence of the messenger ribonucleic acid (mRNA) transcript of Smad7. Orally administered 
GED-0301 is formulated as a gastro-resistant, delayed release, pH-dependent tablet designed to 
deliver the active substance in the distal gastrointestinal (GI) tract with negligible systemic 
exposure.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
the investigational product (IP).
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
7
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Objectives
Primary Objective
!
To evaluate the long-term safety of oral GED-0301 in subjects with CD
Secondary Objectives (Adult Subjects)
!
There are no secondary objectives for adult subjects included in this study.
Secondary Objectives (Adolescent Subjects)
!
To evaluate the efficacy of GED-0301 on clinical activity in subjects with CD
!
To evaluate long-term endoscopic outcomes of GED-0301 in subjects with CD
!
To evaluate the long-term changes in linear growth in response to GED-0301 in subjects 
with CD
 
 
 
 
 
 
 
Study Design
This is a Phase 3, double-blind, long-term active treatment extension study to evaluate the 
long-term safety 
 of GED-0301 for 208 weeks in adult and adolescent 
subjects with CD who previously participated in either of the following two Phase 3 GED-0301 
studies:
!
Study GED-0301-CD-002 (Adult Subjects)
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
8
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
Study GED-0301-CD-003 (Adult and Adolescent Subjects)
The purpose of this study is to assess long-term safety data of GED-0301 for a period of up to 
208 weeks in adult subjects (ie, ≥ 18 years of age) who participated in the core Phase 3 
GED-0301-CD-002 and GED-0301-CD-003 studies and adolescent subjects (ie, 12 to 17 years 
of age) who participated in the core Phase 3 GED-0301-CD-003 study.  
 
Although all subjects will receive active treatment, this study is double-blinded for the entire 208 
weeks for the purpose of preserving the blind of the subject’s treatment allocation in the initial, 
core Phase 3 GED-0301 study.
Subjects from Study GED-0301-CD-002 who completed the study at Week 52, or who met the 
early escape criteria (Appendix H) and were discontinued during the time period beginning at
Week 12 through Week 52, may be eligible to enter this study.  
Subjects from Study GED-0301-CD-003 who completed the study at Week 12 may also be 
eligible to enter this long-term active treatment study.
Subjects who discontinued Studies GED-0301-CD-002 or GED-0301-CD-003 prior to the 
Week 12 Visit are not eligible for this study.
The study will consist of 3 periods:
!
Screening Period – up to 4 weeks (ie, 1 day to 28 days depending on when long-term 
active treatment is available for the subject at the study center)
!
Long-term Active Treatment Period – 208 Weeks (Week 0 to Week 208)
!
Follow-up Period – 4 weeks (ie, no investigational product [IP] taken)
At Week 12, subjects will be evaluated to determine if they should be discontinued from the 
study based on clinical criteria.  Subjects, who meet the following criteria, will be discontinued
from the study at Week 12:
 
Subjects who complete this study through Week 208 will have a 4-week Follow-up Visit.  
Subjects who prematurely discontinue treatment from the study at any time prior to Week 208
will have an Early Termination (ET) Visit and a 4-week Follow-up Visit. The ET Visit should 
be scheduled as soon as possible after the last dose of IP.  If the ET Visit occurs 28 days after the 
last dose of IP, then the Follow-up Visit is not required.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
9
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Study Population
The study population will consist of subjects with CD who previously participated in either of 
the following two Phase 3 GED-0301 studies (ie, GED-0301-CD-002 or GED-0301-CD-003) 
and have completed at least through the Week 12 Visit in each of those studies.
Length of Study
Subjects may participate for a maximum of 216 weeks with 3 different study periods: up to 
4 weeks in the Screening Period; 208 weeks in the Long-term Active Treatment Period; and 
4 weeks in the Follow-up Period.
The long-term active-treatment period of 208 weeks may be shortened in regions where 
GED-0301 becomes commercially available prior to study completion.
The End of Study is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary
 analysis, as prespecified in the protocol, 
whichever is the later date.  There are no secondary objectives or endpoints for the adult subjects 
in this study.
Study Treatments
Subjects will receive blinded-active GED-0301 treatment during the 208-week Long-term Active
Treatment Period. GED-0301 will be provided as 40-mg gastro-resistant, delayed release,
pH-dependent tablets or matching placebo tablets in blister cards. All 160 mg once daily 
treatments are taken as four 40 mg tablets once daily in this study.  See Appendix G for a full 
description of Study GED-0301-CD-004 treatment assignments.  Subjects will be instructed to 
take 4 tablets in the morning, 30 minutes before breakfast with a glass of water.
This study is currently designed as a double-blind, active treatment extension study.  
Nevertheless, it should be noted that the dose regimens of GED-0301 could be adjusted or 
changed during this long-term active treatment study or this study could be changed to an open-
label study, based on new information learned from any of the ongoing GED-0301 clinical 
studies.  Any modifications to the dose regimens would be changed through a protocol 
amendment, which would require regulatory health authority and ethics committee approvals 
prior to implementation.
Overview of Key Safety Assessments
!
Adverse events (AEs)
!
Vital signs
!
Physical examination
!
Body weight
!
Height (adolescent subjects)
!
Electrocardiograms (ECGs)
!
Clinical laboratory safety evaluations 
!
Pregnancy tests
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
10
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
Overview of Key Efficacy Assessments (Adolescent Subjects)
!
Simple Endoscopic Score for Crohn’s Disease (SES-CD) for previous 
GED-0301-CD-003 subjects
!
Crohn’s Disease Activity Index (CDAI) 
 
!
Pediatric Crohn’s Disease Activity Index (PCDAI)
 
 
 
Statistical Methods
The safety and efficacy analyses will be based on the long-term active treatment population, 
which will consist of all subjects who enter the long-term active treatment study and receive at 
least 1 dose of IP during the long-term active treatment study.
Treatment-emergent adverse events (TEAEs) will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) classification system.  All TEAEs will be summarized by 
system organ class, preferred term, severity, and relationship to IP.  The TEAEs leading to death 
or to discontinuation from treatment and serious TEAEs 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, vital signs, weight, and ECG data will be summarized descriptively by time point.  
In addition, shift tables showing the number of subjects with values low, normal, and high 
compared to the normal ranges at baseline versus post-baseline will be provided for laboratory 
tests.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
11
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
12
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................19
1.1.
Disease Background ...............................................................................................19
1.2.
Compound Background ..........................................................................................20
1.2.1.
Nonclinical Experience...........................................................................................21
1.2.2.
Clinical Summary...................................................................................................22
1.2.2.1.
Clinical Pharmacology............................................................................................22
1.2.2.2.
Clinical Safety........................................................................................................22
1.3.
Rationale ................................................................................................................22
1.3.1.
Study Rationale and Purpose ..................................................................................22
1.3.2.
Rationale for the Study Design ...............................................................................23
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................23
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................25
3.
OVERALL STUDY DESIGN ................................................................................31
3.1.
Study Design ..........................................................................................................31
3.2.
Study Duration for Subjects....................................................................................35
3.3.
End of Study...........................................................................................................35
4.
STUDY POPULATION.........................................................................................36
4.1.
Number of Subjects ................................................................................................36
4.2.
Inclusion Criteria....................................................................................................36
4.2.1.
Inclusion Criteria for Adult Subjects.......................................................................36
4.2.2.
Inclusion Criteria for Adolescent Subjects ..............................................................37
4.3.
Exclusion Criteria (Adult and Adolescent Subjects)................................................38
5.
TABLE OF EVENTS.............................................................................................39
6.
PROCEDURES......................................................................................................57
6.1.
Screening Period.....................................................................................................57
6.1.1.
Screening Visit .......................................................................................................57
6.2.
Treatment Period ....................................................................................................59
6.2.1.
Unscheduled Visits.................................................................................................62
6.3.
Early Termination Visit ..........................................................................................62
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EDMS Doc. Number:
GED-0301
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6.4.
Follow-up Period....................................................................................................64
6.4.1.
Study Completion...................................................................................................65
6.4.2.
Lost to Follow-up ...................................................................................................65
6.5.
Safety Assessments.................................................................................................65
6.5.1.
Physical Examination .............................................................................................65
6.5.2.
Electrocardiogram ..................................................................................................65
6.5.3.
Clinical Laboratory Assessments ............................................................................66
6.5.4.
Clinically Significant Abnormal Findings...............................................................66
6.5.5.
Contraception Education.........................................................................................66
6.5.6.
Cancer Surveillance................................................................................................67
6.6.
Efficacy Assessments .............................................................................................67
6.6.1.
Subject Daily Diary ................................................................................................67
6.6.2.
Crohn’s Disease Activity Index ..............................................................................68
6.6.4.
Pediatric Crohn’s Disease Activity Index (Adolescent Subjects).............................69
6.6.4.1.
Erythrocyte Sedimentation Rate..............................................................................70
6.6.6.
Ileocolonoscopy......................................................................................................71
6.6.8.
Simple Endoscopic Score for CD............................................................................72
6.6.9.
Weight, Height, BMI, and Height Velocity (Adolescent Subjects) ..........................72
 
7.
DESCRIPTION OF STUDY TREATMENTS........................................................75
7.1.
Description of Investigational Product(s)................................................................75
7.2.
Treatment Administration and Schedule .................................................................75
7.2.1.
Dose Modification or Interruption...........................................................................80
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
14
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
7.2.2.
Overdose ................................................................................................................80
7.3.
Method of Treatment Assignment...........................................................................80
7.4.
Packaging and Labeling..........................................................................................80
7.5.
Investigational Product Accountability and Disposal ..............................................81
7.6.
Investigational Product Compliance........................................................................81
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................82
8.1.
Permitted Concomitant Medications for CD and Procedures...................................82
8.1.1.
Corticosteroid Tapering Procedure..........................................................................82
8.2.
Prohibited Concomitant Medications and Procedures..............................................82
8.3.
Required Concomitant Medications and Procedures................................................82
9.
STATISTICAL CONSIDERATIONS ....................................................................83
9.1.
Overview................................................................................................................83
9.2.
Study Population Definitions ..................................................................................83
9.3.
Sample Size and Power Considerations...................................................................83
9.4.
Background and Demographic Characteristics........................................................83
9.5.
Subject Disposition.................................................................................................83
9.6.
Efficacy Analysis....................................................................................................83
9.7.
Safety Analysis.......................................................................................................83
9.8.
Interim Analysis .....................................................................................................84
9.9.
Other Topics...........................................................................................................84
9.9.1.
Internal Celgene Safety Monitoring During the GED-0301 Program: Role of 
the Safety Management Team.................................................................................84
9.9.2.
External Safety Monitoring: Role of the Independent DMC....................................84
10.
ADVERSE EVENTS..............................................................................................85
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................85
10.2.
Evaluation of Adverse Events.................................................................................85
10.2.1.
Seriousness.............................................................................................................85
10.2.2.
Severity/Intensity....................................................................................................86
10.2.3.
Causality ................................................................................................................87
10.2.4.
Duration .................................................................................................................88
10.2.5.
Action Taken..........................................................................................................88
10.2.6.
Outcome.................................................................................................................88
10.3.
Abnormal Laboratory Values..................................................................................88
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2


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
10.4.
Pregnancy...............................................................................................................88
10.4.1.
Females of Childbearing Potential ..........................................................................89
10.5.
Reporting of Serious Adverse Events......................................................................89
10.5.1.
Safety Queries ........................................................................................................90
10.6.
Expedited Reporting of Adverse Events..................................................................90
11.
DISCONTINUATIONS .........................................................................................91
11.1.
Treatment Discontinuation......................................................................................91
11.2.
Study Discontinuation ............................................................................................91
12.
EMERGENCY PROCEDURES.............................................................................92
12.1.
Emergency Contact.................................................................................................92
12.2.
Emergency Identification of Investigational Products .............................................92
13.
REGULATORY CONSIDERATIONS...................................................................93
13.1.
Good Clinical Practice............................................................................................93
13.2.
Investigator Responsibilities ...................................................................................93
13.3.
Subject Information and Informed Consent.............................................................94
13.4.
Confidentiality........................................................................................................94
13.5.
Protocol Amendments.............................................................................................94
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................94
13.7.
Ongoing Information for Institutional Review Board/Independent Ethics 
Committee..............................................................................................................95
13.8.
Termination of the Study ........................................................................................95
14.
DATA HANDLING AND RECORDKEEPING.....................................................96
14.1.
Data/Documents.....................................................................................................96
14.2.
Data Management...................................................................................................96
14.3.
Record Retention....................................................................................................96
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................98
15.1.
Study Monitoring and Source Data Verification......................................................98
15.2.
Audits and Inspections............................................................................................98
16.
PUBLICATIONS ...................................................................................................99
17.
REFERENCES.....................................................................................................100
18.
APPENDICES......................................................................................................103
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................103
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16.6.


EDMS Doc. Number:
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Protocol GED-0301-CD-004
Celgene Corporation
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APPENDIX B.
SUBJECT DAILY DIARY ..........................................................................106
APPENDIX C.
CROHN’S DISEASE ACTIVITY INDEX (CDAI) SCORE ........................107
APPENDIX E.
PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX..............................109
APPENDIX F.
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE (SES-
CD) .....................................................................................................................111
APPENDIX G.
THE STUDY GED-0301-CD-004 TREATMENT TABLE..........................112
APPENDIX H.
THE STUDY GED-0301-CD-002 EARLY ESCAPE CRITERIA................115
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
LIST OF TABLES
Table 1:
Study Objectives – Adult Subjects (≥ 18 years of age at screening of core 
study) from GED-0301-CD-002 and GED-0301-CD-003 .......................................25
Table 2:
Study Endpoints – Adult Subjects from GED-0301-CD-002 and 
GED-0301-CD-003 ................................................................................................25
Table 3:
Study Objectives – Adolescent Subjects (12-17 years of age, inclusive) from 
GED-0301-CD-003 ................................................................................................27
Table 4:
Study Endpoints – Adolescent Subjects from GED-0301-CD-003 ..........................28
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) ...................................................39
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4)...........................................48
Table 7:
Investigational Product Dispensing Schedule for the Treatment Period at 
Year 1.....................................................................................................................76
Table 8:
Investigational Product Dispensing Schedule for the Treatment Period at 
Year 2.....................................................................................................................77
Table 9:
Investigational Product Dispensing Schedule for the Treatment Period at 
Year 3.....................................................................................................................78
Table 10:
Investigational Product Dispensing Schedule for the Treatment Period at 
Year 4.....................................................................................................................79
Table 11:
Abbreviations and Specialist Terms......................................................................103
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
18
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................34
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
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19
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
1.
INTRODUCTION 
1.1.
Disease Background 
Crohn’s disease (CD) is a chronic, disabling, relapsing, systemic inflammatory disease that 
mainly affects the ileum and the colon, although it may involve any segment of the 
gastrointestinal (GI) tract.  Crohn’s disease may also present with extraintestinal manifestations 
and associated immune disorders (Baumgart, 2012).  It is one of the most common forms of 
inflammatory bowel disease (IBD).  The precise cause of CD is unknown, but it is considered to 
be an autoimmune disease due to a combination of genetic, environmental and immunologic 
factors (MacDonald, 2005).  The peak age of disease onset is between 15 and 25 years of age.  
While the onset of CD is most commonly in the third decade of life, CD presents in up to 30% of 
cases before the age of 20 years (Kelsen, 2008) and around 10% of cases develop before the age 
of 17 years.
In North America, the incidence of the disease is estimated to be between 3.1 and 14.6 cases per 
100,000 person-years, with 10,000 to 47,000 new cases of CD diagnosed annually 
(Loftus, 2004). The overall incidence of CD in Europe is about 5.6 per 100,000 inhabitants, and 
is about 7.0 per 100,000 person-years in northern centers versus 3.9 in southern centers 
(Loftus, 2004).
Patients with CD may present with symptoms that include abdominal pain, diarrhea, and weight 
loss, and the course of the disease can be associated with systemic symptoms such as malaise, 
anorexia, or fever.  Childhood-onset CD is more severe and complicated and typically exhibits a 
higher disease activity index score compared to late-onset or adult CD (Mamula, 2003; Van 
Limbergen, 2008; Pigneur, 2010).  The GI presentation of CD both in adults and in children is 
dependent mainly on the location and extent of disease involvement.  The anatomic location of 
CD is similar in older children (> 8 years) and adults, most commonly involving the terminal 
ileum or any small bowel (Van Limbergen, 2008; Markowitz, 2009).
Crohn’s disease has a chronic relapsing course, with approximately half of the patients having 
been in remission at any given time (Loftus, 2002).  Common complications are intestinal 
strictures and fistulas, with an increased frequency over time, occurring in more than half of the 
patients by 20 years after diagnosis, and often requiring surgery (Baumgart, 2012).  
Extraintestinal manifestations have been reported in 6% to 47% of the patients with CD, 
including manifestations that are associated with intestinal activity (eg, peripheral arthritis, 
erythema nodosum, aphthous ulcers) and manifestations not associated with intestinal activity
(eg, pyoderma gangrenosum, uveitis, spondylarthropathy, primary sclerosing cholangitis); non 
CD-specific autoimmune diseases which represent only a major susceptibility to autoimmunity 
(eg, hemolytic anemia, vitiligo, diabetes mellitus, psoriasis); and CD-related complications due 
to metabolic or anatomical abnormalities (eg, thromboembolic events, osteopathy, 
nephrolithiasis) (Vavricka, 2011; Bernstein, 2005). Adolescent patients with CD commonly 
present with growth and pubertal delay. In addition, extraintestinal manifestations of CD such as 
erythema nodosum, mouth ulceration, and large-joint lesions that may occur years before any GI 
symptoms develop have been observed in children with CD (Mamula, 2003).  Additionally, 
patients with a history of prolonged CD are at increased risk of developing small bowel and 
colorectal cancer (Baumgart, 2012).
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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Treatment of patients with CD represents a difficult challenge.  The natural history of CD is 
characterized by a remitting and relapsing course that progresses to complications and surgery in 
the majority of patients. A stepwise approach according to disease location and severity at 
presentation has been advocated, with the primary aim of inducing and maintaining clinical 
remission, improving quality of life (QoL), and minimizing short- and long-term toxicity and 
complications (Lichtenstein, 2009; Dignass, 2010).  Treatment of CD currently involves 
pharmacological treatment and surgery, the latter of which is indicated for medically refractory 
disease, strictures, abscesses and neoplastic lesions.  Pharmacological treatment may involve 
aminosalicylates, antibiotics, glucocorticoids, immunomodulators (azathioprine [AZA], 
6-mercaptopurine [6-MP], and methotrexate [MTX]), and biologic compounds, such as tumor 
necrosis factor-alpha (TNF-α) blockers and integrin antagonists. Patients with mild to moderate 
disease usually receive aminosalicylates, antibiotics, or budesonide; systemic steroids and 
immunosuppressants, which are used when the initial approach fails or in cases of moderate to 
severe disease, and biologics are usually reserved for refractory cases or severe disease 
(Lichtenstein, 2009).
Although these drugs can provide clinical benefit, they have important limitations. 
Aminosalicylates are minimally effective in patients with CD, antibiotics have not consistently 
demonstrated efficacy in controlled trials, and glucocorticoids, although effective in the short 
term, can cause unacceptable adverse events (AEs) and do not provide a benefit as maintenance 
therapy (Lichtenstein, 2009). For pediatric patients, consensus guidelines recommend that 
corticosteroids should not be administered as maintenance therapy mainly due to the 
corticosteroid-induced adrenal suppression that can occur as early as one week after starting 
therapy.  In children, where growth retardation can ensue, exclusive enteral nutrition (EEN) is 
employed as first-line therapy in some centers before using steroids with 5-aminosalicylates 
(Kansal, 2013; Ruemmele, 2014).  However, compliance with long-term EEN treatment is 
challenging.
Additionally, immunosuppressant use has been restricted to maintenance therapy and is also 
associated with significant potential toxicities, such as malignancies and infections. Biologics, 
such as TNF-α blockers, have improved the care of patients with CD by providing induction and 
maintenance of remission and decreasing the need for hospitalizations and surgeries, but roughly 
two-thirds of patients do not achieve remission after 1 year of treatment. Additionally, after 
failing to respond to a TNF-α blocker, the response to a second TNF-α blocker is significantly 
lower. The TNF-α blockers may predispose patients to serious safety concerns, including 
opportunistic infections and malignancies (Clark, 2007).
There is a clear need for new therapeutic approaches with a good safety profile in adolescent and 
adult patients with CD who do not respond, lose response, or are intolerant to currently available 
treatments.
1.2.
Compound Background
Mongersen (GED-0301) inhibits the expression of Smad7, a key regulatory modulator of 
transforming growth factor-beta 1 (TGF-β1), by targeting a sequence in Smad7 messenger 
ribonucleic acid (mRNA) (Boirivant, 2006).  There is a marked overexpression of Smad7 in the 
inflamed intestine of patients with IBD, such as CD and ulcerative colitis (UC)
(Monteleone, 2001).  This is associated with a reduction in phosphorylated (p)-Smad3, a crucial 
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step in TGF-β1-mediated signal transduction.  By blocking TGF-β1 activity, high Smad7 levels 
contribute to sustained production of proinflammatory molecules (such as interferon-gamma 
[IFN-γ] and TNF-α) in IBD-affected tissues.  The identification of the role of Smad7 in IBD 
provided the rationale for the development of GED-0301.
GED-0301 is an investigational medicinal product in clinical development for the treatment of 
CD and UC.  GED-0301 is an antisense oligodeoxynucleotide (21-mer) that is complementary to 
the sequence of the mRNA transcript of Smad7.  It has a phosphorothioate backbone. It may be
described chemically as the fully neutralized sodium salt of a 3’ 5’ linked 2’-
deoxyribophosphorothioate oligonucleotide 21-mer in which each of the 20 internucleotide
linkages is an O,O-linked phosphorothioate.  Orally administered GED-0301 is formulated as a 
gastro-resistant delayed release, pH-dependent tablet designed to deliver the active substance in 
the distal GI tract with negligible systemic exposure.
Although the etiology of CD has not been completely elucidated, there has been significant 
advancement in the understanding of the disease pathogenesis.  There is evidence that the 
chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens 
that is not appropriately controlled by the normal counter-regulatory mechanisms.  One of the 
counter-regulatory mechanisms involves TGF-β1.  TGF-β1 is a multifunctional factor that has 
been shown to be involved in regulating growth, differentiation, and function of immune and 
nonimmune cells (Monteleone, 2001).  TGF-β1 has been shown to play an important role in the 
control of immune homeostasis and acts as a potent negative regulator of mucosal inflammation.  
TGF-β1 knockout mice developed a severe multiple-organ inflammatory disease, in which the 
lymphocytic infiltration of the affected organs was associated with increased production of 
TNF-α and IFN-γ.  Studies have shown that abrogation of TGF-β1 signaling in T cells alone is 
sufficient to disrupt T and B cell homeostasis and induce T cell-mediated inflammatory lesions 
in various organs, including the intestine.  It has been widely demonstrated that neutralization of 
TGF-β1 results in the induction and/or amplification of pathogenic responses responsible for the
development of experimental colitis resembling either CD or UC (Monteleone, 2012).
TGF-β1 signaling is regulated by Smads, a family of proteins that serve as substrates for TGF-β1 
type I and type II receptors.  The TGF-β type I receptor recognizes Smad2 and Smad3 which, 
upon phosphorylation of Smad3, en route to the nucleus, associate with Smad4, forming 
complexes that participate in transcriptional control of target genes.  In addition to the activating 
Smads, an inhibiting Smad also exists.  Smad7 interacts with activated receptors and prevents 
phosphorylation of Smad2 and Smad3.  The advance in the understanding of the involvement of 
the TGF-β signaling pathway in the pathogenesis of CD and the identification of the role of 
Smad7 in IBD has provided the rationale for the development of a new drug that, through the 
inhibition of Smad7 expression, could restore TGF-β1 signaling, thus inhibiting the production 
of pro-inflammatory molecules such as TNF-α and IFN-γ.
1.2.1.
Nonclinical Experience
Overall, GED-0301 exhibits an acceptable safety profile in preclinical species and the toxicology 
program for GED-0301 adequately supports the conduct of clinical studies.
Please refer to the Investigator’s Brochure (IB) for information concerning the available 
preclinical, pharmacology, toxicology and drug metabolism studies of GED-0301.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
22
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
1.2.2.
Clinical Summary
1.2.2.1.
Clinical Pharmacology
The pharmacokinetics (PK) of GED-0301 were characterized in a Phase 1 first-in-human study 
(Study GED-301-01-09) in subjects with active CD.  The systemic bioavailability of GED-0301
following oral administration at dose levels up to 160 mg/day for 7 days to human patients is 
negligible.
1.2.2.2.
Clinical Safety
Three clinical studies have been conducted to date with GED-0301: 1) Study GED-301-01-09, a 
Phase 1, dose-escalating, safety and PK study of 7 days of oral administration of GED-0301 in 
subjects with active CD; 2) Study GED-301-01-11, a Phase 2 randomized, double-blind, 
placebo-controlled, dose-finding study of GED-0301 in subjects with active CD; and 3) Study 
GED-301-02-11, a Phase 2, randomized, double-blind, placebo-controlled, long-term extension 
study to evaluate the safety and tolerability of GED-0301 40 mg for the maintenance of CD in 
remission.  A total of 139 subjects with CD have been exposed to oral GED-0301 at doses 
ranging from 10 mg to 160 mg, from 7 days to 14 days. No deaths were reported during the 
conduct of the studies.  No safety concerns that could modify the study conduct and/or 
investigational product (IP) administration arose from the studies.
Please refer to the IB for information concerning the available clinical studies and adverse event 
(AE) profile of GED-0301.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The rationale and purpose of this study is to offer both adult and adolescent subjects in the core 
Phase 3 GED-0301 studies (ie, GED-0301-CD-002 and GED-0301-CD-003) an option to receive 
long-term extension treatment with GED-0301 and to obtain extended long-term safety data of
GED-0301 for a period of up to 4 years.
As an additional safety measure, this study incorporates the Week 12 clinical criteria for 
discontinuing subjects who did not achieve a minimum level of improvement by Week 12.  
Subjects, who meet the following criteria, will be discontinued from the study at Week 12:
 
This study is double-blinded for the entire 208 weeks for the purpose of preserving the blind of 
the subject’s treatment allocation in the initial, core Phase 3 GED-0301 study. 
Subjects who have completed and achieved clinical improvement through Week 52 in Study 
GED-0301-CD-002, and through Week 12 in Study GED-0301-CD-003, are eligible to 
participate in this study.  This would allow subjects who achieved a clinical benefit an 
opportunity to continue with GED-0301 treatment for an additional 208 weeks. 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
23
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Likewise, subjects who did not achieve clinical improvement, met the early escape criteria 
(Appendix H) and were discontinued in Study GED-0301-CD-002 during the time period 
beginning at Week 12 through Week 52, and subjects who did not achieve clinical improvement, 
but were completers in Study GED-0301-CD-003 at Week 12 are also eligible to participate in 
this study.  These subjects, who experienced an insufficient clinical improvement, are provided
with the option for continued treatment at the highest maintenance dose of GED-0301 that will 
be used in the Phase 3 program.  
In addition, placebo (PBO)-treated subjects from these Phase 3 studies are offered the
opportunity to receive active GED-0301 for the first time, and potentially receive a clinical 
benefit.  
This study will provide long-term active treatment up to 4 years and provide extended long-term 
safety data for oral GED-0301.  
 
 
 
 
 
1.3.2.
Rationale for the Study Design
The study is designed as a long-term extension study of up to 4 years for subjects who previously 
participated in the core GED-0301-CD-002 or GED-0301-CD-003 Phase 3 studies.  This study is 
double-blinded for the purpose of preserving the blind of the subject’s treatment allocation in the 
initial, core Phase 3 GED-0301 study, and providing extended long-term safety data for GED-
0301 in these CD subjects through Year 4. 
 
 
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
The reason for the selected dose, schedule, and treatment regimens is to provide subjects with the 
same or highest blinded-active GED-0301 treatments based on whether the subject received 
clinical improvement from the core Phase 3 GED-0301 study treatment.
Subjects in Study GED-0301-CD-002 who achieved clinical improvement on their previous 
blinded-active GED-0301 treatment during the time period from Week 12 through Week 52 will
continue on their same treatment for 208 weeks.  Subjects who were receiving: 1) alternating 
GED-0301 40 mg once daily (QD) for 4 weeks, followed by PBO QD for 4 weeks; or 2) 
alternating GED-0301 160 mg QD for 4 weeks, followed by PBO QD for 4 weeks; or 3) 
continuous 40 mg GED-0301 QD will continue on this same blinded-active treatment regimen.  
Subjects who did not achieve clinical improvement on their above-mentioned, blinded-active 
GED-0301 treatments will be switched in this study to alternating GED-0301 160 mg QD for 
4 weeks, followed by PBO QD for 4 weeks, through Week 208, as their long-term blinded-active
treatment.  
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
24
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Subjects in Study GED-0301-CD-003 who achieved clinical improvement at Week 12 will 
receive alternating PBO QD for 4 weeks, followed by GED-0301 160 mg QD for 4 weeks, 
through Week 208 in this study.  Subjects who did not achieve clinical improvement in Study 
GED-0301-CD-003 at Week 12 will receive alternating GED-0301 160 mg QD for 4 weeks, 
followed by PBO QD for 4 weeks, through Week 208, as their long-term blinded-active
treatment in this study.
Previously blinded PBO-treated subjects who achieved clinical improvement will receive 
alternating GED-0301 160 mg QD for 4 weeks, followed by PBO QD for 4 weeks, through 
Week 208 in this study.  Previously blinded PBO-treated subjects who did not achieve clinical 
improvement will receive blinded-active GED-0301 160 mg QD induction therapy for the first 
12 weeks, and will continue on alternating PBO QD for 4 weeks, followed by GED-0301 160 mg 
QD for 4 weeks, through Week 208, as their long-term blinded-active treatment in this study.  
Previously blinded GED-0301-treated subjects who did not achieve clinical improvement and 
PBO-treated subjects will be provided with the highest maintenance dose of GED-0301 being 
tested in the Phase 3 program, using the clinical safety and efficacy data from the prior
GED-0301 studies (GED-301-01-09; GED-301-01-11; and GED-301-02-11). From these data, 
the highest maintenance treatment regimen tested will be alternating GED-0301 160 mg QD for 
4 weeks, followed by PBO QD for 4 weeks. This study allows the subjects from the previously
blinded treatment groups a chance to achieve clinical improvement by receiving extended 
GED-0301 therapy at this highest maintenance dose regimen.
All subjects will receive blinded-active GED-0301 treatment for 208 weeks, and the full 
description of the treatment assignments are detailed in Appendix G.
This study is currently designed as a double-blind, active treatment extension study.  
Nevertheless, it should be noted that the dose regimens of GED-0301 could be adjusted or 
changed during this long-term active treatment study or this study could be changed to an open-
label study, based on new information learned from any of the ongoing GED-0301 clinical 
studies.  Any modifications to the dose regimens would be changed through a protocol 
amendment, which would require regulatory health authority and ethics committee approvals 
prior to implementation.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
25
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives – Adult Subjects (≥ 18 years of age at screening of core 
study) from GED-0301-CD-002 and GED-0301-CD-003
Primary Objective
The primary objective of the study is to evaluate the long-term safety of oral GED-0301 in subjects 
with Crohn’s disease (CD).
Secondary Objective(s)
There are no secondary objectives for adult subjects in this study.
 
 
 
 
 
Table 2:
Study Endpoints – Adult Subjects from GED-0301-CD-002 and 
GED-0301-CD-003
Endpoint
Name
Description
Timeframe
Primary
Safety
!
The evaluation of safety of GED-0301, assessed by 
the type, frequency and severity of adverse events, and 
its relationship to investigational product (IP), 
discontinuation due to adverse events, and clinically 
significant changes in electrocardiograms (ECGs), 
vital signs, and/or laboratory findings
Through 
Week 208
and 4 weeks 
postdose (as 
specified in 
the Table of 
Events, 
Table 5)
Secondary
Not 
applicable
!
Secondary endpoints are not included for adult 
subjects in this study.
Not 
applicable
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
26
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 2:
Study Endpoints – Adult Subjects from GED-0301-CD-002 and 
GED-0301-CD-003 (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
CD = Crohn’s disease; 
; ECG = electrocardiogram; 
 
 
IP = investigational product; 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
27
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 3:
Study Objectives – Adolescent Subjects (12-17 years of age, inclusive) from 
GED-0301-CD-003
Primary Objective
The primary objective of the study is to evaluate the long-term safety of oral GED-0301 in adolescent 
subjects with Crohn’s disease (CD).
Secondary Objective(s)
!
To evaluate the efficacy of GED-0301 on clinical activity in subjects with CD  
!
To evaluate long-term endoscopic outcomes of GED-0301 in subjects with CD
!
To evaluate the long-term changes in linear growth in response to GED-0301 in subjects with 
CD
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
28
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 4:
Study Endpoints – Adolescent Subjects from GED-0301-CD-003
Endpoint
Name 
Description
Timeframe
Primary 
Safety
The evaluation of safety of GED-0301, assessed 
by the type, frequency and severity of adverse 
events, and its relationship to investigational 
product (IP), discontinuation due to adverse 
events, and clinically significant changes in 
electrocardiograms (ECGs), vital signs, and/or 
laboratory findings
Through Week 208 and 
4 weeks postdose (as 
specified in the Table of 
Events, Table 6)
Secondary 
Efficacy
The proportion of subjects with clinical 
remissiona at Week 40.
Week 40
The proportion of subjects with endoscopic 
remission defined as SES-CD ≤ 2 at Week 40
Week 40
The proportion of subjects who have clinical 
remissiona, defined as a PCDAI ≤ 10 points at 
Week 40.
Week 40
The change from baseline (GED-0301-CD-003) 
in weight, height, body mass index (BMI), and 
height velocity z-scores (adjusted for 
chronological age) at Week 40
Week 40
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
29
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 4:
Study Endpoints – Adolescent Subjects from GED-0301-CD-003 (Continued)
Endpoint
Name 
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
30
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 4:
Study Endpoints – Adolescent Subjects from GED-0301-CD-003 (Continued)
Endpoint
Name 
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
BMI = body mass index; 
; ECG = electrocardiogram;
 
 
IP = investigational product; PCDAI = Pediatric Crohn’s Disease Activity Index;
 
; SES-CD = Simple Endoscopic Score for Crohn’s Disease.
a Clinical remission is defined as the following: 1) Average daily liquid or soft stool frequency ≤ 3 AND abdominal 
pain score ≤1; 2) CDAI score < 150. Clinical remission using both definitions will be used for the analysis of this 
endpoint.
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352


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
31
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 3, double-blind, long-term active treatment extension study to evaluate the 
long-term safety
 of GED-0301 for 208 weeks in adult and adolescent 
subjects with CD who previously participated in either of the following two Phase 3 GED-0301 
studies:
!
Study GED-0301-CD-002 (Adult Subjects)
!
Study GED-0301-CD-003 (Adult and Adolescent Subjects)
The purpose of this study is to assess long-term safety data of GED-0301 for a period of up to 
208 weeks in adult subjects (ie, ≥ 18 years of age) who participated in the core Phase 3 
GED-0301-CD-002 and GED-0301-CD-003 studies and adolescent subjects (ie, 12 to 17 years 
of age) who participated in the core Phase 3 GED-0301-CD-003 study.  
 
Although all subjects will receive active treatment, this study is double-blinded for the entire 208 
weeks for the purpose of preserving the blind of the subject’s treatment allocation in the initial, 
core Phase 3 GED-0301 study. 
Subjects from Study GED-0301-CD-002 who completed the study at Week 52, or who met the 
early escape criteria (Appendix H) and were discontinued during the time period beginning at 
Week 12 through Week 52, may be eligible to enter this study.  
Subjects from Study GED-0301-CD-003 who completed the study at Week 12 may also be 
eligible to enter this long-term active treatment study.  
Subjects who discontinued Studies GED-0301-CD-002 or GED-0301-CD-003 prior to the 
Week 12 Visit are not eligible for this study.
This long-term active treatment study will consist of 3 periods:
!
Screening Period – up to 4 weeks (ie, 1 day to 28 days depending on when long-term 
active treatment is available for the subject at the study center)
!
Long-term Active Treatment Period – 208 Weeks (Week 0 to Week 208)
!
Follow-up Period – 4 weeks (ie, no IP taken)
At Week 12, subjects will be evaluated to determine if they should be discontinued from the 
study based on clinical criteria.  Subjects, who meet the following criteria, will be discontinued 
from the study at Week 12: 
 
Subjects who complete this study through Week 208 will have a 4-week Follow-up Visit.  
Subjects who prematurely discontinue treatment from the study at any time prior to Week 208
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
32
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
will have an ET Visit and a 4-week Follow-up Visit. The ET Visit should be scheduled as soon 
as possible after the last dose of IP.  If the ET Visit occurs 28 days after the last dose of IP, then 
the Follow-up Visit is not required.
At the Screening Visit in this study, all subjects who meet the inclusion criteria and do not meet 
the exclusion criteria will be eligible and assigned a subject identification number using a 
centralized interactive response technology system (IRTS).
Once the subject is eligible and registered in the IRTS, the assigned treatment is based on the 
clinical improvement criteria from the core GED-0301 study to determine the subject’s course of 
treatment for the entire 208 weeks in this study. 
 
Please note that all 160 mg once daily treatments are taken as four 40 mg tablets once daily in 
this study. That is, GED-0301-treated subjects who received one 160 mg tablet QD in 
GED-0301-CD-003 will receive four 40 mg tablets QD in this study. 
Subjects will receive the following treatments:
Previously-treated GED-0301 subjects in Study GED-0301-CD-002 who met the clinical 
improvement criteria at Week 52:
!
Will continue to receive their same blinded treatment, which will be:
-
Alternating PBO QD for 4 weeks and GED-0301 40 mg QD for 4 weeks, or 
-
Continuous GED-0301 40 mg QD, or
-
Alternating PBO QD for 4 weeks and GED-0301 160 mg QD for 4 weeks.
Previously-treated GED-0301 subjects in Study GED-0301-CD-003 who met the clinical 
improvement criteria at Week 12:
!
Will receive blinded treatment with:
-
Alternating PBO QD for 4 weeks and GED-0301 160 mg QD for 4 weeks.
Previously-treated PBO subjects who met the clinical improvement criteria:
-
At Week 52 in Study GED-0301-CD-002; or
-
At Week 12 in Study GED-0301-CD-003
!
Will receive blinded treatment with:
-
Alternating GED-0301 160 mg QD for 4 weeks and PBO QD for 4 weeks.
Previously-treated GED-0301 or PBO subjects who did not meet the clinical improvement 
criteria:
-
At Week 12 through Week 52 in Study GED-0301-CD-002; or
-
At Week 12 in Study GED-0301-CD-003
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
33
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
Will receive blinded treatment with:
-
Alternating GED-0301 160 mg QD for 4 weeks and PBO QD for 4 weeks, if the 
subject previously received GED-0301 treatment, or 
-
GED-0301 160 mg QD for 12 weeks, if the subject previously received PBO, and
after Week 12, subjects will receive alternating PBO QD for 4 weeks and
GED-0301 160 mg QD for 4 weeks.
See the overall study design (Figure 1) for an overview of the study blinded-active treatments.  
All subjects will receive a blinded-active GED-0301 treatment regimen for 208 weeks, and the 
full descriptions of the treatment assignments are detailed in Appendix G.
This study is currently designed as a double-blind, active treatment extension study.  
Nevertheless, it should be noted that the dose regimens of GED-0301 could be adjusted or 
changed during this long-term active treatment study or this study could be changed to an open-
label study, based on new information learned from any of the ongoing GED-0301 clinical 
studies.  Any modifications to the dose regimens would be changed through a protocol 
amendment, which would require regulatory health authority and ethics committee approvals 
prior to implementation. 
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
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ments.


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
34
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Figure 1:
Overall Study Design
Week 208 
(Year 4)
-
-
Long-term Active Treatment Period 
(Blinded-active Treatmentb)
Screening
  Perioda
Week 0 
(Enrollment)
Week 156 
(Year 3)
Week 104 
(Year 2)
Week 52 
(Year 1)
4 Weeks 
(After Last 
Dose of IP)
Follow-up
   Period
CD-002; 
CD-003
Subjects
(No IP 
  Treatment)
Week 4
Week 8
Week 12
160 mg
160 mg
160 mg
160 mg
PBO
PBO
PBO
160 mg
40 mg
40 mg
40 mg
40 mg
PBO
PBO
Alternating PBO for 4 weeks and 160 mg for 4 weeks
Alternating PBO for 4 weeks and 160 mg for 4 weeks
Alternating 160 mg for 4 weeks and PBO for 4 weeks
Alternating 40 mg for 4 weeks and PBO for 4 weeks
Continuous 40 mg
160 mg
Week -4
(Screening)
IP = investigational product; PBO = placebo 
a The Screening Period can be 1 day to 28 days in duration depending on when active treatment (IP) is available for the subject.  
b Blinded-active treatment is provided to eligible subjects from the core GED-0301-CD-002 and GED-0301-CD-003 studies during the 
Long-term Active Treatment Period for 208 weeks.  
Please note:  All 160 mg once daily treatments are taken as four 40 mg tablets once daily in the study.  See Appendix G for full 
description on the Study GED-0301-CD-004 treatment assignments.  No IP is dispensed during the Follow-up Period.  
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
35
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
3.2.
Study Duration for Subjects
Subjects may participate for a maximum of 216 weeks with 3 different study periods: up to 
4 weeks in the Screening Period; 208 weeks in the Long-term Active Treatment Period; and 
4 weeks in the Follow-up Period.  
The long-term active-treatment period of 208 weeks may be shortened in regions where 
GED-0301 becomes commercially available prior to study completion.
3.3.
End of Study
The End of Study is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol,
whichever is the later date.  There are no secondary objectives or endpoints for the adult subjects 
in this study and therefore no secondary analysis for adult subjects.
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the adult


EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
36
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
The number of subjects planned to enroll into this long-term active treatment study will be based 
on the number of eligible subjects who enter from the GED-0301-CD-002 and 
GED-0301-CD-003 studies, which include subject participation worldwide.
4.2.
Inclusion Criteria
4.2.1.
Inclusion Criteria for Adult Subjects 
Adult subjects must satisfy the following criteria to be screened and enrolled in the study:
1. Subject is a male or female ≥18 years of age at the time of signing the informed consent 
form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject must have completed through the Week 12 Visit in the core GED-0301 study 
AND either:
∀
Completed participation through the last study treatment visit
at Week 52 in Study GED-0301-CD-002 or 
at Week 12 in Study GED-0301-CD-003
OR
∀
Met the “early escape criteria” (Appendix H) and were discontinued beginning at 
the Week 12 Visit in Study GED-0301-CD-002. 
5. Females of childbearing potential (FCBP)1 must have a negative pregnancy test at 
screening and enrollment (Visits 1 and 2).  FCBP must either practice true abstinence2
from heterosexual contact or use one of the approved contraceptive options as described 
below while on IP and for at least 28 days after taking the last dose of IP: 
                                               
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).
2 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
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1 A female
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(the
(the su
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
37
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Option 1:  Any one of the following highly effective methods:  hormonal 
contraception (oral3, injection, implant, transdermal patch, vaginal ring); intrauterine 
device (IUD); tubal ligation; or partner’s vasectomy
OR
Option 2:  Male or female condom PLUS 1 additional barrier method: (a) diaphragm 
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with 
spermicide
4.2.2.
Inclusion Criteria for Adolescent Subjects 
Adolescent subjects must satisfy the following criteria to be screened and enrolled in the study:
1. Subject is a male or female, was 12 to 17 years of age at the time of obtaining 
assent/informed consent in the core GED-0301-CD-003 study and must affirmatively 
agree to participate in this study by signing an assent with a parent/legal guardian who 
can understand and voluntarily sign an ICF. Adolescent subjects who turn age 18 by the 
screening visit for the GED-0301-CD-004 study must also understand and voluntarily 
sign an ICF prior to any study-related assessments/procedures being conducted. 
2. Subject is able to swallow the IP tablets.
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements, and a parent or legal guardian is willing to supervise adherence to the 
protocol requirements.
4. Subject must have completed through the Week 12 Visit in Study GED-0301-CD-003.
5. Females of childbearing potential (FCBP)4 must have a negative pregnancy test at 
screening and enrollment (Visits 1 and 2).  FCBP must either practice true abstinence5
                                               
3 A female of childbearing potential taking an oral contraceptive may need a backup or an alternative method of 
birth control based on Investigator judgment as the subject’s Crohn’s disease may potentially decrease the 
effectiveness of oral contraceptives.
4 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).
5 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
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(the
(the su
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
38
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
from heterosexual contact or use one of the approved contraceptive options as described 
below while on IP and for at least 28 days after taking the last dose of IP:
Option 1:  Any one of the following highly effective methods:  hormonal 
contraception (oral6, injection, implant, transdermal patch, vaginal ring); intrauterine 
device (IUD); tubal ligation; or partner’s vasectomy
OR
Option 2:  Male or female condom PLUS 1 additional barrier method: (a) diaphragm 
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with 
spermicide
4.3.
Exclusion Criteria (Adult and Adolescent Subjects)
The presence of any of the following will exclude an adult and adolescent subject from screening 
and enrollment:
1. Subject had experienced a serious adverse event (SAE) related to the IP while 
participating in the core Phase 3 GED-0301 study.
2. Subject has any continuing serious medical condition, laboratory abnormality, or
psychiatric illness that occurred while participating in the core Phase 3 GED-0301 study.
3. Subject has or had a flare or worsening of CD that, in the opinion of the Investigator, 
would not be in the best interest for the subject to participate in this long-term active 
treatment study.
4. Subject has initiated biologic agents, such as TNF-α blockers or integrin antagonists
while, or after participating in the core Phase 3 GED-0301 study. 
5. Subject has been diagnosed with colorectal cancer or confirmed diagnosis of colorectal 
dysplasia (with the exception of adenomatous colonic polyps that have been completely 
resected) while participating in the core Phase 3 GED-0301 study.
6. Subject has a newly diagnosed malignancy while participating in the core Phase 3 GED-
0301 study.  (However, subject may be allowed to enter into this study on a case by case 
basis after discussion with the Sponsor.)
7. Subject is pregnant or breastfeeding.
8. Subject has been newly diagnosed with substance abuse.
9. Subject has any new condition that may put the subject at risk or confound the ability to 
interpret data from the study.
10. Subject has developed a known hypersensitivity to oligonucleotides, GED-0301 or any 
ingredient in the IP.
                                               
6 A female of childbearing potential taking an oral contraceptive may need a backup or an alternative method of 
birth control based on Investigator judgment as the subject’s Crohn’s disease may potentially decrease the 
effectiveness of oral contraceptives.
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Subject h
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ingred


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
39
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
5.
TABLE OF EVENTS
Table 5:
Table of Events for Adult Subjects (Years 1 to 4)
Screening
Period
Long-term Active Treatment Period
(Year 1)
Visit Number
1a
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
-4 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Visit Window
-28 to 0
days
Day 0
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion Criteria
X
Xa
-
-
-
-
-
-
-
-
-
-
-
-
-
Safety Assessments b
Prior / Concomitant Medications and Procedures
Xa
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xa
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
Xa
Xa
-
-
-
-
-
X
-
-
-
-
-
-
X
Contraception Education
Xa
Xa
-
-
-
-
-
X
-
-
-
-
-
-
X
Vital Signs / Weight
Xa
Xa
X
X
X
X
-
X
-
X
-
X
-
X
X
Complete Physical Examination
Xa
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
Xa
-
-
X
-
-
X
-
-
-
-
-
-
X
12-lead ECG
Xa
-
-
-
X
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Hematology) c
Xa
Xa
X
X
X
-
-
X
-
-
-
Xc
-
-
X
Clinical Lab (Chemistry) c
Xa
Xa
-
-
X
-
-
X
-
-
-
Xc
-
-
X
Clinical Lab (Coagulation) c
Xa
Xa
-
-
X
-
-
X
-
-
-
Xc
-
-
X
Clinical Lab (Complement Activation Factor) c
Xa
Xa
-
-
X
-
-
X
-
-
-
Xc
-
-
X
Clinical Lab (Urinalysis) c
Xa
Xa
-
-
X
-
-
X
-
-
-
Xc
-
-
X
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
40
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Screening
Period
Long-term Active Treatment Period
(Year 1)
Visit Number
1a
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
-4 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Visit Window
-28 to 0
days
Day 0
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Dosing
Dispense IP
-
X
X
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
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
41
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 2)
Visit Number
16
17
18
19
20
21
22
23
24
25
26
27
28
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
-
X
-
-
-
-
-
X
Contraception Education
-
-
-
-
-
-
X
-
-
-
-
-
X
Vital Signs / Weight
X
-
X
-
X
-
X
-
X
-
X
-
X
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Hematology)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Chemistry)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Complement Activation Factor)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Urinalysis)
-
-
-
-
-
-
X
-
-
-
-
-
X
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
42
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 2)
Visit Number
16
17
18
19
20
21
22
23
24
25
26
27
28
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit Window
(± 3 
days)
(± 3 
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(± 3 
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(± 3 
days)
(± 3 
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(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Dosing
Dispense IP
X
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
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
43
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 3)
Visit Number
29
30
31
32
33
34
35
36
37
38
39
40
41
Week
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
X
-
-
-
-
-
-
X
Contraception Education
-
-
-
-
-
X
-
-
-
-
-
-
X
Vital Signs / Weight
-
X
-
-
-
X
-
-
-
X
-
-
X
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Hematology)
-
-
-
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Chemistry)
-
-
-
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Complement Activation Factor)
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Urinalysis)
-
-
-
-
-
X
-
-
-
-
-
-
X
&(/*(1(
pri
prietet
1( 35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
7,2
38
38
0$
0$
0$
50$
40
144
40
144
50
5
ys)s)
(± 3 
(± 3 
days)s)
25
)25
)2
)2
)2
X
1)
,1)
X
X
X
X
,1
,1
,1
,1
-
<
5<
X
-
X
5<
5<
5<
5<
X
$5
7$5
-
-
-
-
7$
7$
7$
7$
(
-
(7
,(7
-
-
-
-
,(
,(
,(
5,(
-
5,
5,
5,
35
-
-
-
35
23
-
23
23
23
523
-
-
-
-
52
5
-
35
35
3
1(3


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
44
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 3)
Visit Number
29
30
31
32
33
34
35
36
37
38
39
40
41
Week
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Dosing
Dispense IP
X
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
&(/*(1(35235,
pri
prietet
5,(7$
X
(7
,(7
X
X
X
X
5,(
5,(
5,(
5,(
5
)250$7,21
e Corpora
e Corpora
21
7,2
38
38
0$
0$
0$
50$
40
144
40
144
50
5
ys)s)
(± 3 
(± 3 
days)s)
25
)25
)2
)2
)2
5
7$5<,1)2


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
45
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 4)
Follow-up 
Period
Visit Number
42
43
44
45
46
47
48
49
50
51
52
53
54
ETg
55
Week
160
164
168
172
176
180
184
188
192
196
200
204
208
NA
FU
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
NA
4 Weeks After 
Last Dose of IP
(± 3 days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Contraception Education
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Vital Signs / Weight
-
-
X
-
-
-
X
-
-
-
X
-
X
X
X
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Hematology)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Clinical Lab (Chemistry)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Complement Activation Factor)
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Urinalysis)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
&(/
pri
prietet
(/
(/
( 35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
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,2
,2
$7,2
53
54
53
54
0$
0$
0$
0
204
0
204
50
250
s)s)
(± 3 
(± 3 
days)
days)
(± 3 
(±
da
d
25
25
25
)25
1)2
)2
)2
X
X
X
1
< ,1
X
X
< ,1
,1
,1
5< ,
-
-
-
5<
5<
5<
5<
X
-
X
5<
5<
5<
$5<
X
$5
$5
$5
7$5
-
-
-
-
7$
(7
-
(7
(7
(7
5,(7
-
-
-
-
5,
5,(
5,(
35,(
-
-
-
-
35
235
-
23
23
523
-
-
-
-
52
52
52
52
-
52
52
52
35
-
-
-
35
( 3
(/*(1(3


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
46
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 5:
Table of Events for Adult Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 4)
Follow-up 
Period
Visit Number
42
43
44
45
46
47
48
49
50
51
52
53
54
ETg
55
Week
160
164
168
172
176
180
184
188
192
196
200
204
208
NA
FU
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
NA
4 Weeks After 
Last Dose of IP
(± 3 days)
Dosing
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
X
-
; ECG = electrocardiogram; 
; ET = early termination; 
 
; FU = follow-up; 
 
 IP = investigational product; NA = not applicable; 
a Visit 1 and Visit 2 of the GED-0301-CD-004 study may be combined into a single visit, and may be combined with the last study visit from the core GED-0301 study.  See 
Section 6.1.1 for further detailed information.  If Visit 1 and Visit 2 from this study and the last study visit from the core GED-0301 study are done separately but all are within a 
14-day period, certain evaluations do not need to be repeated.  See Sections 6.1.1 and 6.2.
b For subjects at an increased risk of colorectal cancer, pan-colonic surveillance with colonoscopy and biopsies should be done according to local guidelines.
&(/
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e Corpora
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21
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53
54
53
54
0$
0$
0$
50$
00
204
00
204
50
250
ys)
ys)
(± 3 
(± 3 
days)s)
(± 3
(±
d
25
25
25
)25
5,(
5,
5,
5,
X
X
X
X
35
235
X
23
23
523
NA
NA = not t app
p
ay be combine
y be combin
sit 1 and Visit
sit 1 and Vi
be repeated.
repeated.
cancer
ancer, pan
pan-co
5,(7$5<,1)2
52
352
(1
*(
/*
(/*


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
47
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
g Subjects who discontinue the study prior to Week 208 will have the ET Visit (ie, on the date of the last dose of IP, or very soon after the date of the last dose of IP), and have the 
Follow-up Visit, 28 days after the last dose of IP ± 3 days.  If the ET Visit occurs 28 days after the last dose of IP, then the Follow-up Visit is not required. 
 
 
&(/*(1(35235,(7$5<,1)250$7,21
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e Corpora
21
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ose of IP), and
se of IP), an
red. 
red. 
7,2
$7,2
$7
0$7


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
48
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4)
Screening
Period
Long-term Active Treatment Period
(Year 1)
Visit Number
1a
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
-4 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Visit Window
-28 to 0
days
Day 0
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion Criteria
X
Xa
-
-
-
-
-
-
-
-
-
-
-
-
-
Safety Assessments b
Prior / Concomitant Medications and Procedures
Xa
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xa
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
Xa
Xa
-
-
-
-
-
X
-
-
-
-
-
-
X
Contraception Education
Xa
Xa
-
-
-
-
-
X
-
-
-
-
-
-
X
Vital Signs / Weight
Xa
Xa
X
X
X
X
-
X
-
X
-
X
-
X
X
Height (measured using a stadiometer)
Xa
-
-
-
-
-
-
X
-
-
-
X
-
-
X
Complete Physical Examination
Xa
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
Xa
-
-
X
-
-
X
-
-
-
-
-
-
X
12-lead ECG
Xa
-
-
-
X
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Hematology) 
Xa
Xa
X
X
X
X
X
X
X
X
X
X
-
-
X
Clinical Lab (Chemistry)
Xa
Xa
-
-
X
-
-
X
-
-
-
X
-
-
X
Clinical Lab (Coagulation)
Xa
Xa
-
-
X
-
-
X
-
-
-
X
-
-
X
Clinical Lab (Complement Activation Factors)
Xa
Xa
-
-
X
-
-
X
-
-
-
X
-
-
X
Clinical Lab (Urinalysis)
Xa
Xa
-
-
X
-
-
X
-
-
-
X
-
-
X
pri
prietet
/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
7,2
11
12
11
12
0$
0$
0$
50$
32
36
2
36
50
250
ays)
ays
(±
(± 3 3 
days)
days)
(±
25
25
25
)25
-
)2
)2
)2
1)2
-
-
-
-
1)
,1)
-
,1
,1
,1
< ,1
<
X
X
5<
5<
5<
$5<
X
X
X
$5
$5
$5
7$5
-
-
-
-
7$
(7$
-
(7
(7
(7
5,(7
X
X
X
X
5,
5,
5,(
35,
-
-
-
-
35
235
-
23
23
23
523
Xa
-
52
52
52
352
-
35
35
Xa
X
3
Xa
(
1
Xa
1(
(1
actor
actors)s)
(1
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*(
/*


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
49
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Screening
Period
Long-term Active Treatment Period
(Year 1)
Visit Number
1a
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
-4 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Visit Window
-28 to 0
days
Day 0
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Efficacy Assessments
Subject Daily Diary
X
Xa
X
X
X
X
X
X
X
X
X
X
Crohn’s Disease Activity Index (CDAI) c
-
Xa
X
X
X
X
X
X
X
X
X
X
Pediatric CDAI c
-
-
-
-
-
-
-
X
-
-
-
X
ESR performed at the site, for Pediatric CDAI
-
-
-
-
-
-
-
X
-
-
-
X
Ileocolonoscopy and SES-CD
-
-
-
-
-
-
-
-
-
-
-
X
Dosing
Dispense IP
-
X
X
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
&(/
pri
prietet
(/*(1
*(
/*
(/
,(7$5<
-
-
-
-
$5<
-
$5
$5
$5
7$5
-
-
-
-
7$
(7
(
,(
< ,1)250$7,21
e Corpora
e Corpora
21
7,2
11
12
11
12
0$
0$
0$
50$
32
36
32
36
50
250
ays)
ays
(± 3
(± 3
days)
days)
(±
25
25
25
)25
)2
)2
)2
X
X
X
X
1)
,1)
X
,1
,1
,1
< ,1
5<
(1(35235,(


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
50
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 2)
Visit Number
16
17
18
19
20
21
22
23
24
25
26
27
28
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
-
X
-
-
-
-
-
X
Contraception Education
-
-
-
-
-
-
X
-
-
-
-
-
X
Vital Signs / Weight
X
-
X
-
X
-
X
-
X
-
X
-
X
Height (measured using a stadiometer)
-
-
-
-
-
-
X
-
-
-
-
-
X
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Hematology)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Chemistry) 
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Complement Activation Factors)
-
-
-
-
-
-
X
-
-
-
-
-
X
Clinical Lab (Urinalysis)
-
-
-
-
-
-
X
-
-
-
-
-
X
&(/*(1(3
pri
prietet
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25
0$
0$
0$
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88
92
88
92
50
5
s)s)
(± 3 
(± 3 
days)s)
25
)25
)2
)2
)2
X
1)
,1)
X
X
X
X
,1
,1
,1
,1
X
<
5<
-
X
-
X
5<
5<
5<
5<
-
$5
7$5
-
-
-
-
7$
7$
7$
7$
(
-
(7
5,(7
-
-
-
-
5,(
5,(
5,(
5,(
-
5
35
-
-
-
35
23
-
23
23
23
523
-
-
-
-
52
35
-
35
35
35
-
-
-
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(


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
51
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 2)
Visit Number
16
17
18
19
20
21
22
23
24
25
26
27
28
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
 
 
 
 
Dosing
Dispense IP
X
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
&(/*(1(3
pri
prietet
3523
X
X
X
X
52
5
X
35
35
5<
5<
5<
5< 1)
< ,1)
235,(7$5<
5<
)250$7,21
e Corpora
e Corpora
21
7,2
25
25
0$
0$
0$
50$
88
92
88
92
50
5
ys)s)
(± 3 
(± 3 
days)s)
25
)25
1)2


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
52
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 3)
Visit Number
29
30
31
32
33
34
35
36
37
38
39
40
41
Week
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
X
-
-
-
-
-
-
X
Contraception Education
-
-
-
-
-
X
-
-
-
-
-
-
X
Vital Signs / Weight
-
X
-
-
-
X
-
-
-
X
-
-
X
Height (measured using a stadiometer)
-
-
-
-
-
X
-
-
-
-
-
-
X
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Hematology)
-
-
-
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Chemistry)
-
-
-
-
-
X
-
-
-
-
-
-
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Complement Activation Factors)
-
-
-
-
-
-
-
-
-
-
-
-
X
Clinical Lab (Urinalysis)
-
-
-
-
-
X
-
-
-
-
-
-
X
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prietet
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40
144
40
144
50
5
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(± 3 
(± 3 
days)s)
25
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X
X
X
X
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X
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X
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5<
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X
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7$5
-
X
-
X
7$
7$
7$
7$
(
-
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5,(7
-
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-
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5,(
5,(
5,(
5,(
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35
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52
5
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35
-
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-
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3
(


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
53
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 3)
Visit Number
29
30
31
32
33
34
35
36
37
38
39
40
41
Week
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
Dosing
Dispense IP
X
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
&(/*(1(3
pri
prietet
3523
X
X
X
X
52
5
X
35
35
5<
235,(7$5< 1)250$7,21
e Corpora
e Corpora
21
7,2
38
38
0$
0$
0$
50$
40
144
40
144
50
5
s)s)
(± 3 
(± 3 
days)s)
25
)25
)2
)2
)2
1)
< ,1)
5<,


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
54
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 4)
Follow-up 
Period
Visit Number
42
43
44
45
46
47
48
49
50
51
52
53
54
ETf
55
Week
160
164
168
172
176
180
184
188
192
196
200
204
208
NA
FU
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
NA
4 Weeks After 
Last Dose of IP
(± 3 days)
Safety Assessments b
Prior / Concomitant Medications and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Contraception Education
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Vital Signs / Weight
-
-
X
-
-
-
X
-
-
-
X
-
X
X
X
Height (measured using a stadiometer)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
-
Complete Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Limited Physical Examination
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
12-lead ECG
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Hematology)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Clinical Lab (Chemistry)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
Clinical Lab (Coagulation)
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Complement Activation Factors)
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
Clinical Lab (Urinalysis)
-
-
-
-
-
-
X
-
-
-
-
-
X
X
X
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(± 3 
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X
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
55
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 6:
Table of Events for Adolescent Subjects (Years 1 to 4) (Continued)
Long-term Active Treatment Period
(Year 4)
Follow-up 
Period
Visit Number
42
43
44
45
46
47
48
49
50
51
52
53
54
ETf
55
Week
160
164
168
172
176
180
184
188
192
196
200
204
208
NA
FU
Visit Window
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
(± 3 
days)
NA
4 Weeks After 
Last Dose of IP
(± 3 days)
Dosing
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
X
-
&(/
pri
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53
54
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0$
0$
50$
00
204
00
204
50
250
ys)
ys
(± 3 
(± 3 
days)s)
(± 3
(±
d
25
25
25
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1)
/*
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$5<
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5<,1
(7$


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
56
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
  CDAI = Crohn’s Disease Activity Index; ECG = electrocardiogram; 
; ESR = erythrocyte sedimentation rate; 
ET = early termination; 
; FU = follow-up; 
 
 IP = investigational product; NA = not applicable, PCDAI = Pediatric Crohn’s Disease 
Activity Index; SES-CD = Simple Endoscopic Score for Crohn’s Disease.
a Visit 1 and Visit 2 of the GED-0301-CD-004 study may be combined into a single visit, and may be combined with the last study visit from the core GED-0301 study.  See 
Section 6.1.1 for further detailed information.  If Visit 1 and Visit 2 from this study and the last study visit from the core GED-0301 study are done separately but all are within a
14-day period, certain evaluations do not need to be repeated.  See Sections 6.1.1 and 6.2.
b For subjects at an increased risk of colorectal cancer, pan-colonic surveillance with colonoscopy and biopsies should be done according to local guidelines.
c Note that an abdominal examination is needed for CDAI,
 and PCDAI assessments.
f Subjects who discontinue the study prior to Week 208 will have the ET Visit (ie, on the date of the last dose of IP, or very soon after the date of the last dose of IP), and have the 
Follow-up Visit, 28 days after the last dose of IP ± 3 days.  If the ET Visit occurs 28 days after the last dose of IP, then the Follow-up Visit is not required. 
 
  
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
57
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
6.
PROCEDURES
The following procedures/assessments will be conducted according to the schedule indicated in 
the Table of Events.  Table 5 refers to the Table of Events for adult subjects, and Table 6 refers 
to the Table of Events for adolescent subjects.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days prior to the date of the first dose of IP (study 
enrollment) unless noted otherwise below.  The duration of the Screening Period depends on 
when active treatment (ie, IP/study drug) is available for the subject at the study center.
6.1.1.
Screening Visit
Visits may be completed separately, or combined into a single visit in the following scenarios:
!
The Screening Visit 1 from this study and the last study visit from the core GED-0301 
study may be combined and completed on the same day.
!
The Screening Visit 1 and the Enrollment Visit 2 from this study may be combined and 
completed on the same day, if the GED-0301-CD-004 study drug is available for the 
subject at the study center.  
!
The Screening Visit 1 and the Enrollment Visit 2 from this study and the last study visit 
from the core GED-0301 study may be combined and completed on the same day, if the 
GED-0301-CD-004 study drug is available for the subject at the study center.
If 2 visits are combined into a single visit in this study, or if 2 or 3 visits are combined into a 
single visit from both studies (ie, the core GED-0301 study and this extension GED-0301 study), 
any visit assessments/procedures which are normally done separately at multiple visits are done 
only once and not repeated.
If the Screening Visit 1 from this study and the last study visit from the core GED-0301 study are 
both done separately but are within 14 days of each other, the following Visit 1 clinical and 
laboratory evaluations do not need to be repeated if they were done at the last study visit from 
the core GED-0301 study:  hematology, chemistry, coagulation, complement activation factors, 
urinalysis, pregnancy test, ECG, and physical examination.
If all 3 visits (ie, Visit 1 and Visit 2 from this study and the last study visit from the core 
GED-0301 study) are done separately but all are within a 14-day period, the following clinical, 
 and laboratory evaluations do not need to be repeated if they were done at the last study 
visit from the core GED-0301 study:  hematology, chemistry, coagulation, complement 
activation factors, urinalysis, pregnancy test, 
, ECG, physical examination, CDAI, 
 
After informed consent has been obtained, the following assessments will be performed at or 
following Screening Visit 1 and prior to study enrollment, as specified in the Table of Events
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&


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
58
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
(Table 5 or Table 6), if they were not already completed at the last study visit from the core
GED-0301 study:
!
Demographics including initials, date of birth, gender, race, and ethnicity (if allowed 
by local regulations).
!
Inclusion/exclusion criteria:  Subjects must meet all inclusion criteria (Section 4.2) 
and must not have any of the conditions specified in the exclusion criteria 
(Section 4.3) to qualify for participation in the study.  The subject’s source documents 
must support his/her qualifications for the study (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 core study’s medical history).
!
Prior and concomitant procedures evaluation:  All procedures occurring at or after
Screening Visit 1 should be recorded.
!
Prior and concomitant medications evaluation:  All ongoing medications from the 
core GED-0301 study will be electronically carried forward and should not be re-
recorded in Prior and Concomitant Medications electronic case report form (eCRF) in
this study.  However, any new medications (prescription and nonprescription, 
including vitamins) taken by the subject at and after Screening Visit 1 or at any time 
during this study must be recorded.  Additional instructions can be found in the eCRF 
Completion Guidelines.
!
Adverse event evaluation:  Adverse event (AE) assessment begins when the subject 
signs the informed consent form and is assessed continuously throughout the study, 
until 28 days following the last dose of IP.  All ongoing AEs from the core
GED-0301 study will be electronically carried forward and should not be re-recorded 
in the AE eCRF in this study. However, any new AEs or worsening AEs which occur 
at and after Screening Visit 1 or at any time during this study must be recorded.  
Worsening of a subject’s CD should be considered as worsening of the disease under 
study, and should not be captured as an AE unless it meets any of the criteria of a 
serious adverse event (SAE). Refer to Section 10 for details pertaining to AEs.  
Additional instructions can be found in the eCRF Completion Guidelines.
!
Pregnancy test:  A pregnancy test is required for all female subjects of childbearing 
potential.  A local urine pregnancy test will be performed at Screening Visit 1, if not 
done at the last study visit from the core GED-0301 study.  All local urine pregnancy 
test kits will be provided by the central laboratory.  Urine and confirmatory serum
pregnancy (ie, serum pregnancy test of the beta-subunit of human chorionic 
gonadotropin [β-hCG]) tests should be performed if the FCBP has missed a menstrual 
period, or the contraception method has changed at any time during the study.
!
Contraception education (Section 6.5.5)
!
Vital signs and weight:  Vital signs, including seated blood pressure, temperature, and 
heart rate will be taken.  Weight (to be done in street clothes, no shoes) will also be 
measured and recorded, if not done at the last study visit of the core GED-0301 study.
!
Height, only for the adolescent subjects and should be measured using a stadiometer.
ts s 
of the
of the
at or after
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dicat
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ns fro
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nd should n
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Screening V
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peri
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!
C


EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
59
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
Complete physical examination (Section 6.5.1), if not done at the last study visit of 
the core GED-0301 study.
!
12-lead electrocardiogram (ECG) (Section 6.5.2), if not done at the last study visit of 
the core GED-0301 study.
!
Clinical laboratory evaluations will be performed by a central laboratory and will
include the following laboratory assessments, if not done at the last study visit of the 
core GED-0301 study.  Details pertaining to the central laboratory assessments and 
panels are included in Section 6.5.3:
∀
Hematology panel
∀
Chemistry panel 
∀
Coagulation panel
∀
Complement activation factor panel
∀
Urinalysis panel
!
Subject daily diary (Section 6.6.1)
∀
A new or updated electronic device diary will be provided to the subject at 
Screening Visit 1 for the collection of the subject daily diary in this study.
∀
Subject will receive instructions pertaining to the use of the electronic device and 
the importance of diary compliance
 
through Week 40 for an adolescent subject.
∀
In order to achieve consistent diary recording, the subject is instructed by the site 
personnel (at each visit if necessary) that he/she is required to enter diary data,
each day,
 through 
Week 40 for an adolescent subject.
∀
Site staff must assess the subject’s diary compliance 
 
 through Week 40 for an adolescent subject.
6.2.
Treatment Period
The subject will begin study treatment upon confirmation of all eligibility and availability of IP 
at the study center. All subsequent visits after the Enrollment Visit (which is the Visit 2/Week 0 
Visit) are scheduled based on the date of the Visit 2/Week 0 Visit ± 3 days, according to the 
timeframes specified in Table 5 for adult subjects and Table 6 for adolescent subjects.  The 
Follow-up Visit is scheduled 28 days (4 weeks) after the date of the last dose of IP ± 3 days.
The following Visit 2 clinical and laboratory evaluations do not need to be repeated if they were 
completed within 14 days of Visit 1:  hematology, chemistry, coagulation, complement 
activation factors, urinalysis, pregnancy test, and physical examination.
The following Visit 2 clinical, 
 laboratory evaluations do not need to be repeated if 
they were completed within 14 days of the last study visit from the core GED-0301 study (or 
within 14 days of the combined Visit 1 and last study visit from the core GED-0301 
study):  hematology, chemistry, coagulation, complement activation factors, urinalysis, 
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EDMS Doc. Number:
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pregnancy test, 
, physical examination, CDAI, 
 
The following evaluations will be performed at the frequency specified in Table 5 for adult 
subjects and Table 6 for adolescent subjects. The evaluations should be performed prior to 
dosing on the visit day, unless otherwise specified.
!
Inclusion/exclusion criteria: Subjects must meet all inclusion criteria (Section 4.2) 
and must not have any of the conditions specified in the exclusion criteria 
(Section 4.3) to qualify for participation in the study, up through the day of 
enrollment at the Enrollment Visit 2.
!
Prior and concomitant procedures evaluation (continuously assessed)
!
Prior and concomitant medications evaluation (continuously assessed)
!
AE evaluation (continuously assessed)
!
Pregnancy test:  A local urine pregnancy test will be performed on all FCBP at the 
Enrollment Visit, and the visits identified in Table 5 and Table 6.  A local urine test 
will be performed by the site at the Enrollment Visit, prior to administration of IP, to 
ensure an immediate, negative test result.  All local urine pregnancy test kits will be 
provided by the central laboratory.  Urine and serum pregnancy tests should be 
performed if the FCBP has missed a menstrual period, or the contraception method 
has changed at any time during the study.
!
Contraception education
!
Vital signs and weight
!
Height, only for the adolescent subjects and should be measured using a stadiometer.
!
Physical examinations:  The following physical examinations will be performed 
based on the Table of Events as specified in Table 5 and Table 6 and as described in 
Section 6.5.1:
∀
Complete physical examination
∀
Limited physical examination
(A limited physical examination is not done, if Visit 1 and Visit 2 are combined 
and/or completed on the same day as the last study visit in the core GED-0301 
study.  In this case, only a complete physical examination is done.)
∀
Abdominal examination
(An abdominal examination for the abdominal mass assessment is completed for 
the CDAI, 
and PCDAI calculations when physical examinations are not 
done.)
!
12-lead ECG
!
Clinical laboratory evaluations (Section 6.5.3) according to the timeframes in Table 5
and Table 6
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EDMS Doc. Number:
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∀
Hematology panel
∀
Chemistry panel
∀
Coagulation panel
∀
Complement activation factor panel
∀
Urinalysis panel
!
Subject daily diary assessment (Section 6.6.1):
∀
Adolescent subjects complete subject daily diary through Week 40
!
Crohn’s Disease Activity Index (CDAI) assessment (Section 6.6.2)
∀
 
 
o
Adolescent subjects will be assessed for the CDAI through Week 40
 
!
Pediatric Crohn’s Disease Activity Index (PCDAI) assessment (Section 6.6.4)
∀
The PCDAI score is an efficacy assessment only for adolescent subjects and is a 
self-assessment questionnaire.  The subject self-assessment questionnaire items 
that are included in the PCDAI scoring will be extracted symptom data obtained 
from the subject at the scheduled visit.
!
Erythrocyte sedimentation rate (ESR) only for adolescent subjects, performed locally 
at the site (Section 6.6.4.1) for the PCDAI calculation
 
 
  
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
Dispense IP:  The IP will be dispensed to the subject as specified in Table 5, Table 6
and Section 7.2. The subject should take the first dose in the office at the study site at 
the Enrollment Visit 2, and be witnessed by the site personnel.  However, the IP can 
be dispensed to the subject at a combined Visit 1 and 2, if the GED-0301-CD-004 IP
is available for the subject at the study center.
o
The Principal Investigator, Sub-investigator or Study Coordinator should 
actually witness, if possible, the subject taking the first dose, and record 
date and time in the source document record.  The IP, four 40-mg tablets or 
matching placebo, should be taken by the subject once daily during the Long-
term Active Treatment Period. Subjects will be instructed to take 4 tablets in 
the morning, 30 minutes before breakfast with a glass of water, and they will 
also be instructed to refer to the label for storage instructions.
!
Return and count IP: A detailed record of the doses taken and doses missed between 
visits and at visits should be recorded in the Study Drug Record eCRF and the 
subject’s source documents.  Also, a record of the overall number of tablets dispensed 
and tablets returned at each visit must be maintained in the subject’s source 
documents and recorded in the Drug Accountability eCRF.
6.2.1.
Unscheduled Visits
Unscheduled visits, if needed, may occur at any time, in particular for safety reasons (or efficacy 
reasons) as deemed necessary by the Investigator or site staff, or for any reason that the subject 
must return to study center as it pertains to the study (eg, to pick up additional or replacement 
IP).  All assessments contained in Table 5 for adult subjects and Table 6 for adolescent subjects
will be made available to the site staff in the Unscheduled Visit eCRF, in order to perform the 
necessary unscheduled assessments and/or procedures.
6.3.
Early Termination Visit
The Early Termination (ET) Visit evaluations will be performed for subjects who are early 
withdrawn from treatment, prior to Week 208, for any reason as soon as possible after the 
decision to permanently discontinue treatment has been made.
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EDMS Doc. Number:
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These subjects who discontinue the treatment prior to Week 208 will have the ET Visit (ie, on 
the date of the last dose of IP, or very soon after the date of the last dose of IP), and have the 
Follow-up Visit, 28 days after the last dose of IP ± 3 days.  If the ET Visit occurs 28 days after 
the last dose of IP, then the Follow-up Visit is not required.
The following evaluations will be performed at the frequency specified in the Table of Events 
(Table 5) for adult subjects and (Table 6) for adolescent subjects.
!
Prior and concomitant procedures evaluation
!
Prior and concomitant medications evaluation
!
AE evaluation 
!
Pregnancy test:  A local urine pregnancy test will be performed on all FCBP.
!
Contraception education
!
Vital signs and weight
!
Height, only for the adolescent subjects and should be measured using a stadiometer
!
Complete physical examination (Section 6.5.1)
!
12-lead ECG
!
Clinical laboratory evaluations
∀
Hematology panel
∀
Chemistry panel 
∀
Coagulation panel
∀
Complement activation factor panel
∀
Urinalysis panel
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
  
 
 
 
!
Return and count IP (Section 6.2)
6.4.
Follow-up Period
All subjects will be followed for 28 days after the last dose of IP for the safety evaluations (eg, 
AE reporting) as well as for SAEs made known to the Investigator at any time thereafter that are 
suspected of being related to IP, as described in Section 10.1.
Subjects who discontinue the treatment prior to Week 208 will have the ET Visit (ie, on the date 
of the last dose of IP, or very soon after the date of the last dose of IP), and have the Follow-up 
Visit, 28 days after the last dose of IP ± 3 days.  If the ET Visit occurs 28 days after the last dose 
of IP, then the Follow-up Visit is not required.
The following evaluations will be performed at the frequency specified in the Table of Events 
(Table 5 and Table 6) for the Follow-up Visit:
!
Prior and concomitant procedures evaluation
!
Prior and concomitant medications evaluation
!
AE evaluation
!
Pregnancy test:  A local urine pregnancy test will be performed on all FCBP. 
!
Vital signs and weight
!
Limited physical examination (Section 6.5.1)
!
Clinical laboratory evaluations
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
∀
Hematology panel
∀
Chemistry panel 
∀
Urinalysis panel
6.4.1.
Study Completion
The study completion for an individual subject is defined as reaching the Visit 55/Follow-up
Visit in the study, which includes completion of the IP treatment at the Week 208 Visit, and 
completion of the Follow-up Visit, which is 4 weeks (28 days) after last dose of IP ± 3 days. A 
subject who discontinues early prior to Week 208 is considered an early termination and will 
have the ET Visit (see Section 6.3) and a Follow-up Visit (see Section 6.4).
6.4.2.
Lost to Follow-up
Subjects will be considered lost to follow-up when they fail to attend study visits without stating 
an intention to withdraw from the study.  The Investigator should show due diligence by 
documenting in the source documents the steps taken to contact the subject through multiple 
telephone calls and/or emails and one registered letter.  After all reasonable attempts have been 
made to contact the subject, the subject should be recorded as “lost to follow-up” in the eCRF.
6.5.
Safety Assessments
6.5.1.
Physical Examination
A complete physical examination will include evaluation of the skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, abdominal, neurological, lymphatic, and musculoskeletal systems. 
Gynecological and urogenital examinations will not be performed unless for cause.
Limited physical examinations will include evaluation of the skin, respiratory, cardiovascular, 
abdominal, lymphatic, and musculoskeletal systems.
An abdominal examination will be performed at every visit (including those visits at which a 
complete or partial physical examination is not being performed) to assess the presence of an 
abdominal mass for the CDAI, 
 and PCDAI calculations.
Clinically significant abnormal findings (with the exception of the disease under study [CD]) 
identified prior to the very first dose of IP taken from the core study, should have been recorded 
on the Medical History eCRF in the core Phase 3 study.  Any clinically significant findings 
identified during this study will be recorded as AEs on the AE eCRF.
6.5.2.
Electrocardiogram
Subjects will have a 12-lead ECG at the frequency specified in Table 5 and Table 6. Sites are to 
utilize their own local ECG machines 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: normal; abnormal, not 
clinically significant; or abnormal, clinically significant.  “Abnormal, clinically significant” 
results if not related to medical condition or diagnosis, should be recorded as an AE on the AE 
eCRF.
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35


EDMS Doc. Number: 
GED-0301
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6.5.3.
Clinical Laboratory Assessments
Clinical laboratory evaluations will be performed by a central laboratory to include the following 
laboratory assessments performed at the frequency specified in Table 5 and Table 6:
!
Hematology panel will include: complete blood count (CBC) with differential, 
including red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count (with differential), and
platelet count.
!
Chemistry serum panel will include: total protein, albumin, calcium, phosphorous, 
glucose, total cholesterol, 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, magnesium, chloride, carbon dioxide, blood urea nitrogen (BUN), 
creatinine, and lactate dehydrogenase (LDH). 
!
Coagulation panel will include: prothrombin time (PT) and activated partial 
thromboplastin time (APTT).
!
Complement activation factor panel will include:  compliment activation factors Bb, 
C3a and C5a.
!
Urinalysis panel will include:  specific gravity, pH, glucose, ketones, protein, blood, 
bilirubin, leukocyte esterase, nitrite, and urobilinogen. The urinalysis will be 
completed at the central laboratory, not locally at the site.  Microscopic urinalysis 
(bacteria, casts, crystals, epithelial cells, RBC, and WBC) will be performed only if 
the dipstick urinalysis is abnormal.
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 laboratory requisition 
form.
Note: “Abnormal, clinically significant” results, if not related to a medical condition or 
diagnosis, should be recorded as an AE on the AE eCRF.
6.5.4.
Clinically Significant Abnormal Findings
Clinically significant abnormal findings or results (clinical laboratory assessments, physical 
examinations, ECGs) if not related to a medical condition or diagnosis, which are identified prior 
to the very first dose of IP taken from the core study, should have been recorded on the Medical 
History eCRF in the core Phase 3 study.  Clinically significant abnormal findings or results, not 
related to a medical condition or diagnosis, during this study should be recorded as AEs on the 
AE eCRF.  Any clinically significant abnormal findings or results findings or results related to 
the disease under study, CD, should not be recorded an AE on the AE eCRF.  Only if CD meets 
any of the criteria as an SAE, is it recorded on the AE eCRF.
6.5.5.
Contraception Education
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for FCBP. The Investigator will educate all FCBP about the different options of 
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EDMS Doc. Number:
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contraceptive methods or abstinence, as appropriate, at the Screening and Enrollment Visits, 
throughout the study as necessary and re-emphasize contraception use every 6 months and at the 
Week 208 and ET Visits to ensure the subject continues her contraception methods through 28 
days after the last dose of IP.  The subject will be re-educated every time her contraceptive 
measures/methods or ability to become pregnant changes during the study. The female subject's 
chosen form of contraception must be effective by the time the female subject is enrolled into the 
study (for example, hormonal contraception should be initiated at least 28 days before enrollment 
to study treatment). An FCBP taking an oral contraceptive may need a backup or an alternative 
method of birth control based on Investigator judgment as the subject’s Crohn’s disease may 
potentially decrease the effectiveness of oral contraceptives.
There are no data on the effects of GED-0301 in pregnant women and data in animals are 
limited. Results of the animal and in vitro studies can be found in the IB. All FCBP must use 
one of the approved contraceptive options, as described in the eligibility criteria, or must practice 
abstinence from heterosexual contact while on IP 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 an
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. 
6.5.6.
Cancer Surveillance
For subjects at increased risk of colorectal cancer, pan-colonic surveillance with colonoscopy 
and biopsies should be done according to local guidelines.
6.6.
Efficacy Assessments
6.6.1.
Subject Daily Diary
During Screening Visit 1, an electronic subject diary device (Appendix B) will be given to each 
subject. The subject (and the parents / guardians of adolescent subjects) will receive instructions 
by the site personnel pertaining to the use of the electronic device and the importance of diary 
compliance throughout the study.  On an ongoing basis, site personnel are expected to provide 
education and support to the subject (and to the parents / guardians of adolescent subjects) about 
the use of the electronic device.  In order to achieve consistent daily diary recording, the subject
is instructed by the site personnel (at each visit if necessary) that he/she is required to enter diary 
data, each day,
 and through Week 40 if an 
adolescent subject in the study.  Site personnel must also assess the subject’s compliance with 
reporting of the daily diary data entries
, and through Week 
40 for an adolescent subject.
The daily diary data will be extracted from the electronic devices and used for calculation of the 
CDAI 
 efficacy parameters when the diary is used.
The electronic subject diary device will record the following information for the subject to assess 
his/her CD activity each day:
!
Number of liquid or very soft stools per 24 hours
!
Abdominal pain/cramps 
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EDMS Doc. Number: 
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!
General well-being 
!
Fever over 100°F (37.8°C)
!
Use of diphenoxylate/atropine, loperamide, or opiates for diarrhea
6.6.2.
Crohn’s Disease Activity Index
The CDAI (Appendix C) is the most commonly used measure in clinical studies evaluating the
efficacy of new therapies in CD patients with predominantly inflammatory disease (Best, 1976; 
Sandborn, 2002). The daily diary will assess how CD affects the subject’s quality of life and the 
effect of treatment on CD activity.  The CDAI consists of a questionnaire with responses scored 
numerically and weighted. Scores (range 0 to 600) are then ranked according to severity of the 
disease.  Mild active disease is defined by a score of ≥ 150 and ≤ 219, moderate active disease is 
defined by a score of ≥ 220 and ≤ 450, whereas severe disease is defined as a CDAI score > 450.  
Remission is defined as a CDAI score < 150.
Clinical parameters needed for calculation of the CDAI will be collected by the subject via an 
electronic diary device and by the site at the scheduled visit via a separate electronic device.
The CDAI consists of 8 variables:
1. Total number of liquid or very soft stools (total for previous 7 days)
2. Abdominal pain/cramps rating (total for previous 7 days)
3. General well-being rating (total for previous 7 days)
4. Total number of listed categories the subject has experienced during the last 7 days
!
Arthritis or arthralgia
!
Iritis or uveitis
!
Erythema nodosum, pyoderma gangrenosum, or aphthous ulcers 
!
Anal fissures, fistula, or abscess 
!
Other fistula (specified by site personnel)
!
Fever higher than 100°F or 37.8°C during previous week 
5. Antidiarrhea drug therapy taken (eg, loperamide, diphenoxylate, or opiates)
6. Abdominal mass presence
7. Anemia based on hematocrit value entered into formula:
a.
For men = 47 – hematocrit value
b. For women = 42 – hematocrit value
8. Body weight in kilograms (kg) entered into formula:
([standard weight in kg – actual weight in kg] / [standard weight in kg]) x 100%
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6.6.4.
Pediatric Crohn’s Disease Activity Index (Adolescent Subjects)
The PCDAI (Appendix E) is an instrument that was developed and validated for numerical 
assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI 
has a scoring range of 0 to 100. Mild disease corresponds to scores of 11 – 30; moderate to 
severe disease corresponds to scores > 30. Remission (ie, no disease activity) is defined as a 
PCDAI score ≤ 10.
The PCDAI includes subjective patient historical information, physical examination findings, 
objective laboratory parameters, data on weight gain/loss, and height velocity. The category of 
severity for each index item is assigned a score: 0 = normal; 5 = mild abnormality; 10 = severe 
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EDMS Doc. Number: 
GED-0301
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abnormality. The PCDAI also includes 3 laboratory parameters (ie, hematocrit, erythrocyte 
sedimentation rate and albumin level) which are part of the calculation.  For hematocrit and 
erythrocyte sedimentation rate, the maximum score = 5.  For albumin level, the maximum 
score = 10.
Clinical parameters needed for calculation of the PCDAI will be collected by the subject and the 
site at the scheduled visit via an electronic device.
The PCDAI consists of the following 11 variables:
1.
Abdominal pain (1 week)
2. Stools per day (1 week)
3. Patient functioning / General well-being (1 week)
4. Weight
5. Height velocity (current visit height compared with height measured 6-12 months earlier 
expressed as a standard deviation score) 
6. Abdominal tenderness, mass, guarding
7. Peri-rectal disease
8. Extra-intestinal manifestations (fever, arthritis, uveitis, erythema nodosum, pyoderma 
gangrenosum)
9. Hematocrit (%) for men/women
10. Erythrocyte sedimentation rate (mm/hr)
11. Albumin (g/dL)
 
 
 
 
 
6.6.4.1.
Erythrocyte Sedimentation Rate
The erythrocyte sedimentation rate (ESR) will be tested only for adolescent subjects at visits 
when the PCDAI is performed at the frequency specified in Table 6.  The ESR result is generated
at the site from a supply kit provided by the central laboratory, and the site will record the ESR 
result into the appropriate electronic entry screen for calculating the PCDAI.
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
71
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.6.
Ileocolonoscopy
All previous GED-0301-CD-003 subjects 
 adolescents) will have an 
ileocolonoscopy performed during the Long-term Active Treatment Period at Week 40.  An
ileocolonoscopy is not required for previous GED-0301-CD-002 subjects.  
  
Video images of all endoscopic procedures will be captured and sent to a qualified centralized 
reader for calculation of the SES-CD to assess efficacy at Week 40.  
 
 
For subjects at increased risk of colorectal cancer, pan-colonic surveillance with colonoscopy 
and biopsies should be done according to local guidelines.
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
6.6.8.
Simple Endoscopic Score for CD
The SES-CD (Appendix F) is a validated endoscopic index that closely correlates with the 
Crohn’s Disease Endoscopic Index of Severity (CDEIS) and is often considered the standard for 
endoscopic evaluation in subjects with CD. However, the SES-CD is considered more suitable 
for clinical trials due to its simplicity and has been widely adopted for this purpose 
(Daperno, 2004).
6.6.9.
Weight, Height, BMI, and Height Velocity (Adolescent Subjects)
Age-specific z-scores (based on chronological age and bone age) will be calculated for weight, 
height, body mass index (BMI), and height velocity. The z-scores are measurements of the 
deviation of the patient’s growth parameter (weight, height, BMI, or height velocity) from the 
expected growth parameter of an age (chronological and bone) and sex-matched population. The 
z-score is calculated as the observed growth parameter – reference population parameter mean 
divided by the standard deviation of the reference population parameter.  Height velocity will be
calculated based on height measurements from the 6 to 12 months preceding the study according 
to the following formula: (Present Height [cm] - Previous Height [cm])/Interval (months) 
Between Measurements x 12.
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
73
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                               
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
74
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
 
 
 
 
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
75
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
Mongersen (GED-0301) will be provided as 40-mg gastro-resistant, delayed release, pH-
dependent tablets. Placebo will be provided as identically appearing tablets.
7.2.
Treatment Administration and Schedule
Beginning at Week 0 through Week 12, subjects will receive blinded-active GED-0301 (160 mg 
QD or 40 mg QD) treatment as one of the following numbered treatment groups: 
1) continuous 160 mg QD for 12 weeks; 
2) 160 mg QD for 4 weeks, PBO QD for 4 weeks, 160 mg QD for 4 weeks;
3) PBO QD for 4 weeks, 160 mg QD for 4 weeks, PBO QD for 4 weeks; 
4) continuous 40 mg QD for 12 weeks;
5) PBO QD for 4 weeks, 40 mg QD for 4 weeks, PBO QD for 4 weeks.  
Beginning at Week 12 through Week 208, subjects from the above-numbered treatment groups 
will continue to receive blinded-active GED-0301 treatment for 196 weeks as the following: 
1) alternating PBO QD for 4 weeks with 160 mg QD for 4 weeks, through Week 208; 
2) alternating PBO QD for 4 weeks with 160 mg QD for 4 weeks, through Week 208;
3) alternating 160 mg QD for 4 weeks with PBO QD for 4 weeks, through Week 208;
4) continuous 40 mg QD, through Week 208;
5) alternating 40 mg QD for 4 weeks with PBO QD for 4 weeks, through Week 208.
Subjects will receive 1 blister card when IP is administered.  Four tablets are taken once daily
during the 208-week Long-term Active Treatment Period. Subjects will be instructed to take 
4 tablets in the morning, 30 minutes before breakfast with a glass of water, and they will also be 
instructed to refer to the label for storage instructions.
Please note:  All 160 mg QD treatments are taken as four 40 mg tablets once daily in the study.
Treatment and administration schedules are described in Table 7, Table 8, Table 9, and Table 10.  
The treatment described in each box is the treatment dispensed at a particular week visit.  For 
example, if the subject was previously on PBO (with no clinical improvement) in the core
GED-0301 study, the subject would receive the IP in this study as:
!
blinded GED-0301 160 mg QD for a 4-week supply at the Week 0 Visit;
!
blinded GED-0301 160 mg QD for a 4-week supply at the Week 4 Visit; 
!
blinded GED-0301 160 mg QD for a 4-week supply at the Week 8 Visit; 
!
blinded PBO QD for a 4-week supply at the Week 12 Visit; 
!
alternating blinded GED-0301 160 mg QD for a 4-week supply followed by blinded 
PBO QD for a 4-week supply at Week 16 through Week 208; and
!
no IP at the Week 208 Visit.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
76
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 7:
Investigational Product Dispensing Schedule for the Treatment Period at Year 1
Treatment 
Group from 
Core
GED-0301 
Study
Long-term Active Treatment Period
(All Treatment is Blinded)
(Year 1)
Week
0
Week
4
Week
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Week 
52
PBO
(with no 
improvement)
160 
mg QD
160 
mg QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
GED-0301
40 mg or 
160 mg on/off, 
or 
40 mg daily, or 
160 mg QD for 
12 weeks (with 
no 
improvement), 
or PBO (with 
improvement)
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
GED-0301
160 mg on/off 
or 160 mg QD 
for 12 weeks 
(with 
improvement)
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 
mg QD
PBO
QD
160 mg 
QD
GED-0301
40 mg daily 
(with 
improvement)
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
GED-0301
40 mg on/off 
(with 
improvement)
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO = placebo; QD = once daily.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
77
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 8:
Investigational Product Dispensing Schedule for the Treatment Period at Year 2
Treatment 
Group from 
Core
GED-0301 
Study
Long-term Active Treatment Period
(All Treatment is Blinded)
(Year 2)
Week
56
Week
60
Week
64
Week 
68
Week 
72
Week 
76
Week 
80
Week 
84
Week 
88
Week 
92
Week 
96
Week 
100
Week 
104
PBO
(with no 
improvement)
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
GED-0301
40 mg or 
160 mg on/off, 
or 
40 mg daily, or 
160 mg QD for 
12 weeks (with 
no 
improvement), 
or PBO (with 
improvement)
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
GED-0301
160 mg on/off
or 160 mg QD 
for 12 weeks
(with 
improvement)
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
GED-0301
40 mg daily 
(with 
improvement)
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
GED-0301
40 mg on/off 
(with 
improvement)
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
PBO = placebo; QD = once daily.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
78
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 9:
Investigational Product Dispensing Schedule for the Treatment Period at Year 3
Treatment 
Group from 
Core
GED-0301 
Study
Long-term Active Treatment Period
(All Treatment is Blinded)
(Year 3)
Week
108
Week
112
Week
116
Week 
120
Week 
124
Week 
128
Week 
132
Week 
136
Week 
140
Week 
144
Week 
148
Week 
152
Week 
156
PBO
(with no 
improvement)
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
GED-0301
40 mg or 
160 mg on/off, 
or 
40 mg daily, or 
160 mg QD for 
12 weeks (with 
no 
improvement), 
or PBO (with 
improvement)
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
GED-0301
160 mg on/off 
or 160 mg QD 
for 12 weeks 
(with 
improvement)
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
GED-0301
40 mg daily 
(with
improvement)
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
GED-0301
40 mg on/off 
(with 
improvement)
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO = placebo; QD = once daily.   
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44
50
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BO
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
79
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 10:
Investigational Product Dispensing Schedule for the Treatment Period at Year 4
Treatment 
Group from 
Core GED-
0301 Study
Long-term Active Treatment Period
(All Treatment is Blinded)
(Year 4)
Week
160
Week
164
Week
168
Week 
172
Week 
176
Week 
180
Week 
184
Week 
188
Week 
192
Week 
196
Week 
200
Week 
204
Week 
208
PBO
(with no 
improvement)
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
No IP
GED-0301
40 mg or 
160 mg on/off, 
or 
40 mg daily, or 
160 mg QD for 
12 weeks (with 
no 
improvement), 
or PBO (with 
improvement)
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
No IP
GED-0301
160 mg on/off
or 160 mg QD 
for 12 weeks
(with 
improvement)
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
PBO
QD
160 mg 
QD
No IP
GED-0301
40 mg daily 
(with 
improvement)
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
40 mg 
QD
No IP
GED-0301
40 mg on/off 
(with 
improvement)
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
PBO
QD
40 mg 
QD
No IP
IP = investigational product; PBO = placebo; QD = once daily. 
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50
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
80
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
7.2.1.
Dose Modification or Interruption 
Dose modification is not permitted.  Any inadvertent interruption in IP schedule will not alter the 
current dose or dose interval, nor will the length of the study be extended to account for days of 
IP missed.
7.2.2.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP (mongersen 
[GED-0301] or matching PBO).  Overdose for this protocol, on a per-dose basis, is defined as 
ingestion of more than the prescribed dose (ie, more than four tablets) within the same calendar 
day whether by accident or intentionally. Adverse events associated with an overdose must be 
collected on the AE page of the eCRF (see Section 10.1) for all overdosed subjects, but the 
overdose itself is not considered an AE. Other required or optional nonstudy drugs intended for 
prophylaxis of certain side effects, etc, are excluded from this definition.
Detailed information about any Celgene drug overdose in this study, regardless of whether the 
overdose was accidental or intentional, should be reported on the Investigational Drug Overdose
eCRF page.
7.3.
Method of Treatment Assignment
Eligible subjects will receive GED-0301 treatment for 4-week intervals during this 208-week 
Long-term Active Treatment Study as either: 1) four 40-mg tablets; 2) one 40-mg tablet and 
three PBO tablets; or 3) four PBO tablets.
Investigational product will be managed via an IRTS.  Eligible subjects will enter the Long-term 
Active Treatment Period at the Enrollment Visit (Week 0/Visit 2), and will be assigned to 
receive IP as blinded-active treatment as described in Table 7, Table 8, Table 9, and Table 10, up 
through Week 208.
Designated study personnel at the investigational sites will be assigned password-protected, 
coded identification numbers, which give them authorization to access the IRTS to enroll
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 IRTS will assign 
an enrollment identification number.  Confirmation of the enrollment 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 enrollment number assigned by IRTS.
7.4.
Packaging and Labeling
GED-0301 tablets are packaged in blister cards fitted with induction seals and tamper-evident 
child-resistant seals.
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 
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
81
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applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
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 must be stored as indicated on the 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). 
7.6.
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 the Table of Events 
(Table 5 and Table 6).  The subjects will be instructed to return the IP containers, including any 
unused IP, 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 Follow-up Period.
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.
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All medications (prescription and nonprescription), treatments, and therapies taken by the subject 
from screening throughout their entire participation in 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.
8.1.
Permitted Concomitant Medications for CD and Procedures
At any time during the study (from Screening Visit 1 through Week 208/Visit 54 and Follow-
up/Visit 55), background concomitant CD medications, such as oral aminosalicylates, 
immunosuppressants and/or corticosteroids can be discontinued, adjusted or initiated, as 
clinically indicated at the discretion of the Investigator, with no required lead-in time prior to 
enrollment and with no dose restriction. The only exceptions are GED-0301-CD-003 subjects 
who were on stable doses of corticosteroids and achieved clinical improvement by Week 12 in 
Study GED-0301-CD-003.  These subjects should follow the guidance for a corticosteroid 
tapering procedure (Section 8.1.1) upon entrance into this study.
8.1.1.
Corticosteroid Tapering Procedure
GED-0301-CD-003 subjects who achieved clinical improvement by Week 12 in Study 
GED-0301-CD-003 are eligible to start corticosteroid tapering beginning at the Screening Visit 1
in Study GED-0301-CD-004, at the discretion of the investigator, according to the following 
schedule:
!
For prednisone doses > 10 mg (or equivalent), 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.
8.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are prohibited during the Screening Period and from the 
Enrollment Visit (ie, Week 0/Visit 2) through the last study treatment visit 
(ie, Week 208/Visit 54), or the ET Visit for subjects who discontinue prematurely during the 
study:
!
Use of any biologic agents, including TNF-α blockers or integrin antagonists.  If 
biologic agents are initiated, the subject must be discontinued from the study.
8.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications for any subjects and no required procedures for 
previous GED-0301-CD-002 subjects. 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
83
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
Key elements of the statistical analyses for this study are described in this section; details will be 
documented in a Statistical Analysis Plan (SAP). The statistical analyses for this study will be 
the responsibility of the Sponsor or its designee. 
9.2.
Study Population Definitions
The safety and efficacy analyses will be based on the long-term active treatment population, 
which will consist of all subjects who enter the long-term active treatment study and receive at 
least 1 dose of IP during the long-term active treatment study.
9.3.
Sample Size and Power Considerations
No sample size and power calculations are performed for this long-term active treatment study.
9.4.
Background and Demographic Characteristics
Subjects’ age, weight, and other continuous variables will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history will be summarized using frequency tabulations by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, completed, discontinued, along with 
primary reason for discontinuation) will be summarized using frequency and percent.  Protocol 
deviations/violations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
The efficacy endpoints will be summarized descriptively.
 
9.7.
Safety Analysis
Safety will be assessed by clinical review of all relevant parameters including treatment-
emergent adverse events (TEAEs), laboratory tests, vital signs, weight, and ECGs.  No 
inferential testing for statistical significance will be performed.
Treatment-emergent adverse events will be classified using the MedDRA classification system.  
All TEAEs will be summarized by system organ class, preferred term, severity, and relationship 
to IP.  The TEAEs leading to death or to discontinuation from treatment and serious TEAEs 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.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
84
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Laboratory, vital signs, weight, and ECG data will be summarized descriptively by time point.  
In addition, shift tables showing the number of subjects with values low, normal, and high 
compared to the normal ranges at baseline versus postbaseline will be provided for laboratory 
tests.
9.8.
Interim Analysis
Unblinded analyses of safety 
 
 data may be performed by a group independent of the study team and not 
involved with the study conduct. Unblinded group-level data may be distributed outside of this 
group; however, subject-level data will remain blinded.
9.9.
Other Topics
9.9.1.
Internal Celgene Safety Monitoring During the GED-0301 Program: Role of the 
Safety Management Team
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).  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 GED-0301 development 
program.  The scope, conduct, processes, and accountabilities of the SMT are specified in the 
SMT Charter.
9.9.2.
External Safety Monitoring: Role of the Independent DMC
Safety monitoring will also be performed by an external, independent Data Monitoring 
Committee (DMC). The DMC will review unblinded data to evaluate safety during the 
study. The DMC is comprised of independent physician experts and a statistician for whom 
there is no identified conflict of interest. The DMC will be convened regularly, at least once a 
year, or ad hoc at the request of the SMT. The DMC scope, conduct, processes, and 
accountabilities are specified in a charter.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
85
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.2.2 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an IP 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.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for GED-0301 overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well as 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 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.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
86
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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Mild
!
Asymptomatic or mild symptoms; clinical or diagnostic observations only
!
Intervention not indicated
!
Activities of daily life (ADLs) minimally or not affected
!
No or minimal intervention/therapy may be required 
Moderate 
!
Symptom(s) cause moderate discomfort
!
Local or noninvasive intervention indicated
!
More than minimal interference with ADLs but able to carry out daily social and 
functional activities
!
Drug therapy may be required
Severe (could be 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.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the 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:
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.
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Su
S


EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in a female subject of childbearing potential 
are immediately reportable events.  
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abnorm
bnormalal


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential, regardless of disease state) occurring while the subject 
is on IP, or within at least 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 email, phone or facsimile, or other appropriate method, using the Pregnancy 
Initial Report Form, or approved equivalent form.  
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), 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 
SAEs made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the 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/Independent Ethics Committee (IRB/IEC) of the SAE and providing them with all 
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
90
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
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/IEC.
10.5.1.
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.
10.6.
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 GED-0301 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, 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 IPs 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
(In Japan, Celgene KK shall notify the Heads of the Institutes in addition to the Investigators):
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity;
!
In Japan, measures taken in the foreign countries to ensure subject safety, study 
reports that indicate potential risk of cancer, etc., or biannual SAE report according to 
the local regulations.
Where required by local legislation, the Investigator shall notify his/her IRB/IEC 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/IEC.  (See Section 14.3 for record retention 
information.)
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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EDMS Doc. Number:
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
91
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP:
!
Adverse event
!
Lack of efficacy 
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Other (to be specified on the eCRF)
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Lack of efficacy 
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
92
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization 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. 
12.2.
Emergency Identification of Investigational Products
During the 208-week blinded-active treatment period, the blind must not be broken during the 
course of this period of the study unless in the opinion of the Investigator, it is absolutely 
necessary to safely treat the subject.  If it is medically imperative to know what IP the subject is 
receiving, IP should be temporarily discontinued if, in the opinion of the Investigator, continuing 
IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the IRTS by using 
an emergency unblinding personal identification number (PIN), and the Investigator should call 
IRTS for unblinded dose information.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
93
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that 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/IEC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  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 ICF and are 
screened for entry into the study.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
94
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
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 ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/IEC for written 
approval.  Written approval must be obtained before implementation of the amended version 
occurs.  The written signed approval from the IRB/IEC should specifically reference the 
Investigator name, protocol number, study title and amendment number(s) that is applicable. 
Amendments that are administrative in nature do not require IRB/IEC approval but will be 
submitted to the IRB/IEC for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/IEC 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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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
95
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/IEC and their occupation and qualifications. If the IRB/IEC 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/IEC 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/IEC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/IEC and, if applicable, 
between a Coordinating Investigator and the IRB/IEC. 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/IEC prior to use.
13.7.
Ongoing Information for Institutional Review Board/Independent 
Ethics Committee
If required by legislation or the IRB/IEC, the Investigator must submit to the IRB/IEC:
!
Information on serious or unexpected AEs as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/IEC, 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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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
96
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the IP 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-ROMs.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures. This data will be electronically verified through use of programmed edit 
checks specified by the clinical team.  Discrepancies in the data will be brought to the attention 
of the clinical team, and investigational site personnel, if necessary.  Resolutions to these issues 
will be reflected in the database.  An audit trail within the system will track all changes made to 
the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed ICFs for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/IEC;
!
Composition of the IRB/IEC;
!
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 case report forms (if paper) and of documentation of corrections for all
subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
97
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
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 or institution should take measures to prevent accidental or premature destruction of 
these documents.
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EDMS Doc. Number: 
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Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
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15.
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 (SOPs).
15.1.
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 Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a GCP 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 GCP guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, United States Food and Drug 
Administration, European Medicines Agency, and 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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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
99
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
 
 
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations. 
 
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EDMS Doc. Number: 
GED-0301
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17.
REFERENCES
 
Baumgart DC, Sandborn WJ. Crohn’s disease.  Lancet 2012;380:1590-605.
Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in 
inflammatory bowel disease: a population-based study. Gastroenterology 2005 Sep;129(3):827-
36.
Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn’s disease activity index;
national cooperative Crohn’s disease study. Gastroenterology 1976;70(3):439-44.
Boirivant M, Pallone F, Di Giacinto C, Fina D, Monteleone I, Marinaro M, et al. Inhibition of 
Smad7 with a specific antisense oligonucleotide facilitates TGF-β1-mediated suppression of 
colitis. Gastroenterology 2006;131(6):1786-98.
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.
Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and 
validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. 
Gastrointest Endosc 2004;60:505-12.
Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, et al. The second 
European evidence-based consensus on the diagnosis and management of Crohn's disease: 
current management. J Crohns Colitis 2010 Feb;4(1):28-62.
 
 
 
Griffiths AM, Nicholas D, Smith C, Munk M, Stephens D, Durno C, et al. Development of a 
quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to 
age and IBD type. J Pediatr Gastroenterol Nutr 1999;28(4):S46-S52.
 
 
 
 
Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al. Development 
and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr 
1991;12(4):439-47.
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EDMS Doc. Number: 
GED-0301
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Kansal S, Wagner J, Kirkwood CD, Catto-Smith AG. Enteral nutrition in Crohn’s disease: an 
underused therapy. Gastroenterol Res Pract 2013, Article ID 482108, 11 pages 
htt://dx.doi.org/10.1155/2013/482108.
Kelsen, J, Baldassano, RN. Inflammatory bowel disease: the difference between children and 
adults. Inflamm Bowel Dis 2008;14(Suppl 2):S9-S11. 
 
 
 
 
Lewis SJ, Heaton KW.  Stool form scale as a useful guide to intestinal transit time.  Scand J 
Gastroenterol 1997;32(9):920–4.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of the American 
College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol 
2009;104(2):465-83.
Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn's 
disease in population-based patient cohorts from North America: a systematic review. Aliment 
Pharmacol Ther 2002 Jan;16(1):51-60.
Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and 
environmental influences. Gastroenterology 2004 May;126(6):1504-17.
MacDonald TT, Monteleone G. Immunity, inflammation and allergy in the gut. Science 
2005;307(5717):1920-5.
Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and 
adolescence: special considerations. Gastroenterol Clin North Am 2003;32(3):967-95.
Markowitz J, Kugathasan S, Dubinsky M, Mei L, Crandall W, LeLeiko N, et al. Age of 
diagnosis influences serologic responses in children with Crohn’s disease: a possible clue to 
etiology? Inflamm Bowel Dis 2009;15(5):714-9.
Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking 
Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J Clin Invest 
2001;108(4):601-9.
Monteleone G, Caruso R, Pallone F. Role of Smad7 in inflammatory bowel diseases. World J 
Gastroenterol 2012;18(40):5664-8.
 
 
Pigneur B, Seksik P, Viola S, Viala J, Beaugerie L, Girardet JP, et al. Natural history of Crohn's 
disease: comparison between childhood- and adult-onset disease. Inflamm Bowel Dis 2010; 
16(6):953-61.
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EDMS Doc. Number: 
GED-0301
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, et al. Consensus 
guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J 
Crohns Colitis 2014;8(10):1179-207.
Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, Modigliani R, et al. A review of 
activity indices and efficacy endpoints for clinical trials of medical therapy in adults with 
Crohn's disease. Gastroenterology 2002;122(2):512-30.
 
 
 
 
 
Van Limbergent J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, et al. 
Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. 
Gastroenterology 2008;135(4):1114-22.
Vavricka SR, Brun L, Ballabeni P, Pittet V, Prinz Vavricka BM, Zeitz J, et al. Frequency and 
risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. 
Am J Gastroenterol 2011Jan;106(1):110-9.
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EDMS Doc. Number: 
GED-0301
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 11:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADL
Activities of daily life
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
APTT
Activated partial thromboplastin time
5-ASA
5-aminosalicylic acid
AST
Aspartate aminotransferase (SGOT)
β-hCG
Beta-subunit of human chorionic gonadotropin
BMI
Body mass index
BUN
Blood urea nitrogen
CBC
Complete blood count
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CIOMS VI
Council for International Organizations for Medical Sciences, Working 
Group VI
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EEN
Exclusive enteral nutrition
ESR
Erythrocyte sedimentation rate
ET
Early Termination
FCBP
Females of childbearing potential
GCP
Good Clinical Practice
GI
Gastrointestinal
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diogram
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Exclusive 
35
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EDMS Doc. Number:
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Table 11:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICC
Intra-class correlation
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
IND
Investigational New Drug
IP
Investigational product
IRB
Institutional Review Board
IRTS
Interactive response technology system
IUD
Intrauterine device
kg
Kilograms
LDH
Lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mRNA
Messenger ribonucleic acid
p
Phosphorylated
PBO
Placebo
PCDAI
Pediatric Crohn’s Disease Activity Index
PK
Pharmacokinetics 
PT
Prothrombin time
QD
Once daily
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EDMS Doc. Number: 
GED-0301
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Table 11:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SMT
Safety Management Team
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TGF-β1
Transforming growth factor-beta 1
TNF-α
Tumor necrosis factor-alpha
UC
Ulcerative colitis
VAS
Visual Analog Scale
WBC
White blood cell
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APPENDIX B. SUBJECT DAILY DIARY
Instructions:  You will be given an electronic diary. Your diary should be recorded daily and 
should reflect a 24-hour period.  Please record your diary continuously throughout the study.  
The scores for abdominal pain and general well-being should reflect the average pain or well-
being for that entire day.  In case you experience fever, enter the temperature measured, if above 
100#F.  It you miss a day and you cannot recall all the information, complete the date and the 
information you do recall.
Date
Number 
of liquid
or very 
soft
stools per 
24 hours
Abdominal Pain/Cramps 
0 = None
1 = Mild - aware, but tolerable
2 = Moderate - interferes with 
usual activities
3 = Severe - incapacitating
General Well-Being 
0 = Generally Well
1 = Slightly Under 
Par
2 = Poor
3 = Very Poor
4 = Terrible.
Fever 
over 
100°F 
(37.8°C)
Y = Yes
N = No
Use of 
diphenoxylate/ 
atropine, 
loperamide, or 
opiates for 
diarrhea
Y = Yes
N = No
Sunday
___ / ___ / ___
mm      dd       yy
Monday
___ / ___ / ___
mm      dd       yy
Tuesday
___ / ___ / ___
mm      dd       yy
Wednesday
___ / ___ / ___
mm      dd       yy
Thursday
___ / ___ / ___
mm      dd       yy
Friday
___ / ___ / ___
mm      dd       yy
Saturday
___ / ___ / ___
mm      dd       yy
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Yes
N = 
N = N
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EDMS Doc. Number: 
GED-0301
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
APPENDIX C. CROHN’S DISEASE ACTIVITY INDEX (CDAI) SCORE
Source:  Best, 1976
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GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
7,21
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EDMS Doc. Number: 
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APPENDIX E. PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX
 One week
Abdominal Pain
None
0
Mild – Brief, does not interfere with activities
5
Moderate/severe - Daily, longer lasting, affects activities, nocturnal
10
Stools (per day)
0–1 liquid stool, no blood
0
Up to 2 semi-formed with small blood, or 2–5 liquid
5
Any gross bleeding, or ≥ 6 liquid, or nocturnal diarrhea
10
Patient Functioning / 
General Well-Being 
No limitation of activities, well
0
Occasional difficulty in maintaining age-appropriate activities, below par 
5
Frequent limitation of activity, very poor
10
  Examination
Weight
Weight gain or voluntary weight stable/loss
0
Involuntary weight stable, weight loss (1-9% )
5
Weight loss ≥10%
10
Height Velocity†
≥ -1 SD  
0
< -1 SD, > -2 SD
5
≤ -2 SD
10
    -or-
Height†† (at diagnosis)
< 1 channel decrease 
0
≥ 1, < 2 channel decrease
5
≥ 2 channel decrease 
10
Abdomen
No tenderness, no mass
0
Tenderness, or mass without tenderness
5
Tenderness, involuntary guarding, definite mass
10
Perirectal Disease
None, asymptomatic tags
0
1–2 indolent fistula, scant drainage, no tenderness
5
Active fistula, drainage, tenderness, or abscess
10
Extra-intestinal Manifestations†††
None
0
1 manifestation
5
≥ 2 manifestations
10
  Laboratory
Hematocrit (%) 
M = Male
F = Female
M/F  ≤ 10 years: ≥ 33
0
M  11–14 years: ≥ 35
F  11–19 years: ≥ 34
M  15–19 years: ≥ 37
M/F  ≤ 10 years: 28–32
2.5
M  11–14 years: 30–34
F  11–19 years: 29–33
M  15–19 years: 32–36
M/F  ≤ 10 years: < 28
5
M  11–14 years: < 30
F  11–19 years: < 29
M  15–19 years: < 32
Continued
Score
  Subtotal
Pediatric Crohn’s Disease Activity Index
Patient’s study identification number:
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EDMS Doc. Number: 
GED-0301
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110
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†
Height velocity is calculated as cm / year based on current visit height compared to height over last 6–12 months.  Height velocity 
is plotted on standardized curve (versus age) and expressed as SD score.
††
Height-channel represents lines on the standard percentile chart, for example, 10 – > 25 – > 50 percentile is 2 channels difference.
††† Extra-intestinal implies fever of ≥ 38.5ºC for 3 days over past week, definite arthritis, uveitis, Erythema nodosum, or Pyoderma 
gangrenosum.
APPENDIX E. PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX
(Continued)
 Laboratory (Continued)
ESR (mm / hr)
< 20
0
20–50
2.5
> 50
5
Albumin (g / dL)
≥ 3.5
0
3.1–3.4
5
≤ 3.0
10
TOTAL 
PCDAI
SCORE
Printed name of person entering scores
Signature of person entering scores
Date
Source: Hyams, 1991.
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EDMS Doc. Number: 
GED-0301
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111
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
APPENDIX F.
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE 
(SES-CD)
Definitions of the Simple Endoscopic Score for Crohn’s Disease (SES-CD) variables
Source: Daperno, 2004.
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EDMS Doc. Number: 
GED-0301
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112
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
APPENDIX G. THE STUDY GED-0301-CD-004 TREATMENT TABLE
Core
GED-0301
Study:
GED-0301 Treatment Received 
from Core GED-0301 Study:
Time Point in 
Core GED 
Study When 
Subject 
Eligible for
CD-004:
Did Subject 
Meet the 
Clinical 
Improvement 
Criteria from 
the Core
GED 
Treatment?
Treatment Regimen to Receive 
in Study GED-0301-CD-004:
CD-002
Blinded PBO QD through 
Week 52
At Week 12 
Visit through
Week 52 Visit
No
Blinded 160 mg QD for 12 weeks; followed by alternating 
blinded PBO QD for 4 weeks / blinded 160 mg QD for 4 
weeks, through Week 208
CD-002
Blinded PBO QD through 
Week 52
Week 52 Visit
Yes
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-002
Blinded 160 mg QD through 
Week 12; followed by alternating 
blinded PBO QD for 4 weeks / 
blinded 40 mg QD for 4 weeks 
through Week 52
At Week 12 
Visit through
Week 52 Visit
No
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-002
Blinded 160 mg QD through 
Week 12; followed by alternating 
blinded PBO QD for 4 weeks / 
blinded 40 mg QD for 4 weeks 
through Week 52
Week 52 Visit
Yes
Alternating blinded PBO QD for 4 weeks / 
blinded 40 mg QD for 4 weeks, through Week 208
Please note:  All 160 mg QD treatments are taken as four 40 mg tablets once daily in the study.
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7$
7$
7$
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No
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EDMS Doc. Number: 
GED-0301
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APPENDIX G. THE STUDY GED-0301-CD-004 TREATMENT TABLE (Continued)
Core
GED-0301
Study:
GED-0301 Treatment Received 
from Core GED-0301 Study:
Time Point in 
Core GED 
Study When 
Subject 
Eligible for
CD-004:
Did Subject 
Meet the 
Clinical 
Improvement 
Criteria from
the Core
GED 
Treatment?
Treatment Regimen to Receive 
in Study GED-0301-CD-004:
CD-002
Blinded 160 mg QD through 
Week 12; followed by continuous 
blinded 40 mg QD through Week 
52
At Week 12 
Visit through
Week 52 Visit
No
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-002
Blinded 160 mg QD through 
Week 12; followed by continuous 
blinded 40 mg QD through Week 
52
Week 52 Visit
Yes
Continuous blinded 40 mg QD, through Week 208
CD-002
Blinded 160 mg QD through 
Week 12; followed by alternating 
blinded PBO QD for 4 weeks / 
blinded 160 mg QD for 4 weeks 
through Week 52
At Week 12 
Visit through
Week 52 Visit
No
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-002
Blinded 160 mg QD through 
Week 12; followed by alternating 
blinded PBO QD for 4 weeks / 
blinded 160 mg QD for 4 weeks 
through Week 52
Week 52 Visit
Yes
Alternating blinded PBO QD for 4 weeks / 
blinded 160 mg QD for 4 weeks, through Week 208
Please note:  All 160 mg QD treatments are taken as four 40 mg tablets once daily in the study.
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prietet
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e Corpora
e Corpora
21
Treat
reatment 
m
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in Stud
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nded PBO Q
nded PB
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7$
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7$
7$
7$
3
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12
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k 52 Visit
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EDMS Doc. Number: 
GED-0301
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114
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
APPENDIX G. THE STUDY GED-0301-CD-004 TREATMENT TABLE (Continued)
Core
GED-0301
Study:
GED-0301 Treatment Received 
from Core GED-0301 Study:
Time Point in 
Core GED 
Study When 
Subject 
Eligible for
CD-004:
Did Subject 
Meet the 
Clinical 
Improvement 
Criteria from
the Core
GED 
Treatment?
Treatment Regimen to Receive 
in Study GED-0301-CD-004:
CD-003
Blinded PBO QD through 
Week 12
Week 12 Visit
No
Blinded 160 mg QD for 12 weeks; followed by alternating 
blinded PBO QD for 4 weeks / blinded 160 mg QD for 4 
weeks, through Week 208
CD-003
Blinded PBO QD through 
Week 12
Week 12 Visit
Yes
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-003
Blinded 160 mg QD through 
Week 12
Week 12 Visit
No
Alternating blinded 160 mg QD for 4 weeks /
blinded PBO QD for 4 weeks, through Week 208
CD-003
Blinded 160 mg QD through 
Week 12
Week 12 Visit
Yes
Alternating blinded PBO QD for 4 weeks /
blinded 160 mg QD for 4 weeks, through Week 208
PBO = placebo; QD = once daily.
Please note:  All 160 mg QD treatments are taken as four 40 mg tablets once daily in the study.
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EDMS Doc. Number  
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
115
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
APPENDIX H. THE STUDY GED-0301-CD-002 EARLY ESCAPE 
CRITERIA
The GED-0301-CD-002 study “early escape criteria” definition:  
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
116
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
0$7,21
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EDMS Doc. Number: 
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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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
3
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Addition of Adolescent Subjects into the GED-0301-CD-004 Study
The primary purpose of this protocol amendment is the addition of the adolescent subjects into 
this long-term active treatment extension study who previously participated in the Phase 3 
GED-0301-CD-003 study.  As a result, new sections were added to the protocol that apply
specifically to adolescent subjects.  Furthermore, the objectives, end points, inclusion/exclusion 
criteria, table of events, procedures and assessments sections were separated out for the adult and 
adolescent subjects throughout the protocol, where appropriate, to clearly indicate protocol 
information which applies specifically to adult versus adolescent subjects.
Revised Sections: 
-
Protocol Summary (Objectives)
o
Secondary Objectives (Adult Subjects)
o
Secondary Objectives (Adolescent Subjects) – newly added
 
-
Protocol Summary (Study Design)
-
Protocol Summary (Overview of Key Safety Assessments)
-
-
Protocol Summary (Overview of Key Efficacy Assessments [Adolescent Subjects])
-
Protocol Summary (Overview of Other Study Assessments)
-
Protocol Summary (Statistical Methods)
-
Section 1.1 (Disease Background)
-
Section 1.3.1 (Study Rationale and Purpose)
-
Section 1.3.2 (Rationale for the Study Design)
-
Section 2 (Study Objectives and Endpoints)
o
Table 1 (Study Objectives – Adult Subjects [≥ 18 years of age at screening of 
core study] from GED-0301-CD-002 and GED-0301-CD-003)
o
Table 2 (Study Endpoints – Adult Subjects from GED-0301-CD-002 and 
GED-0301-CD-003)
o
Table 3 (Study Objectives – Adolescent Subjects [12-17 years of age, 
inclusive] from GED-0301-CD-003)
o
Table 4 (Study Endpoints – Adolescent Subjects from GED-0301-CD-003)
-
Section 3.1 (Study Design)
-
Section 4.2 (Inclusion Criteria)
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
o
Section 4.2.1 (Inclusion Criteria for Adult Subjects) – separated out to clearly 
identify the inclusion criteria specifically for adult subjects 
o
Section 4.2.2 (Inclusion Criteria for Adolescent Subjects) – newly added to 
clearly identify the inclusion criteria specifically for adolescent subjects, with 
accompanied Footnotes #5, 6 and 7 regarding the adolescent pregnancy 
language
-
Section 4.3 (Exclusion Criteria [Adult and Adolescent Subjects]) – identical for both 
adult and adolescent subjects and only the name of this section was changed for 
emphasis.
-
Section 5 (Table of Events)
o
Table 5 (Table of Events for Adult Subjects) – separated out to identify the 
assessments/procedures for adult subjects
o
Table 6 (Table of Events for Adolescent Subjects) – newly added to identify 
the assessments/procedures for adolescent subjects
-
Section 6 (Procedures)
-
Section 6.1.1 (Screening Visit)
-
Section 6.2 (Treatment Period)
-
Section 6.2.1 (Unscheduled Visits)
-
Section 6.3 (Early Termination Visit)
-
Section 6.4 (Follow-up Period)
-
Section 6.5.2 (Electrocardiogram)
-
Section 6.5.3 (Clinical Laboratory Assessments)
-
Section 6.6.1 (Subject Daily Diary)
-
Section 6.6.4 (Pediatric Crohn’s Disease Activity Index) – newly added
-
Section 6.6.4.1 (Erythrocyte Sedimentation Rate) – newly added
-
Section 6.6.6 (Ileocolonoscopy) – newly added
-
Section 6.6.8 (Simple Endoscopic Score for CD) – newly added
-
Section 6.6.9 (Weight, Height, BMI, and Height Velocity [Adolescent Subjects]) – newly 
added
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
5
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
-
Section 8.1 (Permitted Concomitant Medications for CD and Procedures)
-
Section 8.1.1 (Corticosteroid Tapering Procedure)
-
Section 8.3 (Required Concomitant Medications and Procedures)
-
Section 9.6 (Efficacy Analysis)
-
Section 17 (References)
-
Section 18 (Appendices)
o
Appendix A (Table of Abbreviations)
o
Appendix E (Pediatric Crohn’s Disease Activity Index) – newly added
o
Appendix F (Simple Endoscopic Score for Crohn’s Disease) – newly added
 
 
 
 
 
Revised Sections: 
-
Protocol Summary (Objectives)
o
Secondary Objectives (Adolescent Subjects)
-
Protocol Summary (Study Design)
-
Protocol Summary (Overview of Key Efficacy Assessments [Adolescent Subjects])
-
Section 1.3.1 (Study Rationale and Purpose)
-
Section 1.3.2 (Rationale for the Study Design)
-
Section 2 (Study Objectives and Endpoints)
o
Table 1 (Study Objectives – Adult Subjects [≥ 18 years of age at screening of 
core study] from GED-0301-CD-002 and GED-0301-CD-003)
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
6
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
o
Table 2 (Study Endpoints – Adult Subjects from GED-0301-CD-002 and 
GED-0301-CD-003)
-
Section 3.1 (Study Design)
-
Section 5 (Table of Events)
o
Table 5 (Table of Events for Adult Subjects)
-
Section 6.2 (Treatment Period)
o
Bullets for Ileocolonoscopy
-
Section 6.3 (Early Termination Visit)
o
Bullets for Ileocolonoscopy
-
Section 6.6.6 (Ileocolonoscopy) – newly added
-
Section 6.6.8 (Simple Endoscopic Score for CD) – newly added
-
-
Section 8.1 (Permitted Concomitant Medications for CD and Procedures)
-
Section 8.3 (Required Concomitant Medications and Procedures)
-
Appendix F – Simple Endoscopic Score for Crohn’s Disease – newly added
Addition of the Week 12 Clinical Criteria for Discontinuation
The Week 12 clinical criteria were added for discontinuing subjects who did not achieve a 
minimum level of improvement by Week 12 in this active treatment extension study.  Subjects
who meet the following criteria will be discontinued from the study at Week 12:
 
Revised Sections: 
-
Protocol Summary (Study Design)
-
Section 1.3.1 (Study Rationale and Purpose)
-
Section 3.1 (Study Design)
Revision of Inclusion Criteria – Inclusion Criteria for Adult Subjects
!
Inclusion Criterion #4 was revised to allow subjects to enter this study who had met the 
“early escape criteria” from Study GED-0301-CD-002 “at” the Week 12 Visit, rather 
than “after” the Week 12 Visit.
!
Inclusion Criterion #4 was also updated to clarify that subjects must have completed the 
previous GED-0301 study through the Week 12 “Visit” in order to qualify for this study.
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23
52
352


EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
7
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Revised Sections: 
-
Section 4.2 (Inclusion Criteria)
-
Appendix H (The Study GED-0301-CD-002 Early Escape Criteria)
Revision of Inclusion Criterion #5 (Contraception Language)
The Inclusion Criterion #5 for female subjects was revised to state that females of childbearing 
potential (FCBP) must either practice true abstinence1 from heterosexual contact or use one of 
the approved contraceptive options as described in Inclusion Criterion #5 while on 
investigational product (IP) and for at least 28 days after taking the last dose of IP.  This is 
consistent with the new female contraception language for the GED-0301 Program.
In addition, the Inclusion Criterion #5 requiring male subjects to use barrier contraception when 
engaging in sexual activity was removed.  Based on the pharmacokinetic results from previous 
and ongoing GED-0301 studies, there is minimal concern for GED-0301 entering blood at such 
high concentrations that it could present into semen and therefore, there is no cause for study 
drug exposure to female partners of male subjects.
Revised Sections: 
-
Section 4.2.1 (Inclusion Criteria for Adult Subjects)
-
Section 6.5.5 (Contraception Education)
-
Section 10.4 (Pregnancy)
-
Section 10.4.2 (Male Subjects) – entire section was deleted since it no longer applies.
Revision of Exclusion Criteria 
!
Exclusion Criterion #4 was revised to emphasize that a subject is prohibited from 
entering this study who may have initiated biologic agents “while or after participating in 
the previous Phase 3 GED-0301 study.”
!
Exclusion Criterion #9 was added to exclude a subject who has any new condition that 
may put the subject at risk or confound the ability to interpret data from the study.  As a 
result, the former Exclusion Criterion #9 was changed to Exclusion Criterion #10.
Revised Section: 
-
Section 4.3 (Exclusion Criteria [Adult and Adolescent Subjects])
The Early Escape Timing in Study GED-0301-CD-002 Changed from “After” to “At” 
Week 12 Visit
Sections throughout the protocol have added language emphasizing that subjects can enter this 
study who meet the “early escape criteria” and were discontinued from Study GED-0301-CD-
002 beginning “at” the Week 12 Visit, rather than “after” the Week 12 Visit.  
                                               
1 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
8
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Revised Sections: 
-
Protocol Summary (Study Design)
-
Section 1.3.1 (Study Rationale and Purpose)
-
Section 1.3.3 (Rationale for Dose, Schedule and Regimen Selection)
-
Section 3.1 (Study Design)
-
Appendix G (The Study GED-0301-CD-004 Treatment Table)
Visit 1 and Visit 2 in GED-0301-CD-004 can be Combined and Completed on the Same Day 
as the Last Study Visit in the Core GED-0301 Study
Visit 1 and Visit 2 from this study may be combined and completed on the same day, if the 
GED-0301-CD-004 study drug is available for the subject at the study center.  Also, Visit 1 and 
Visit 2 from this study and the last study visit from the core GED-0301 study can be combined 
into a single study visit and done on the same day, if the GED-0301-CD-004 study drug is 
available for the subject at the study center.  If 2 visits are combined into a single visit in this 
study, or if 2 or 3 visits are combined into a single visit from both studies (ie, the core GED-0301 
study and this extension GED-0301 study), any visit assessments/procedures which are normally 
done separately at multiple visits are done only once and not repeated.  
The reason for this change is that it will allow the subject to receive study drug immediately at a 
combined Visit 1 and 2, and not have the subject come back to the study center for a separate 
Visit 2, if study drug is available at the study center.
Revised Sections: 
-
Section 5 (Table of Events)
o
Table 5 (Table of Events for Adult Subjects ([Years 1 to 4]) – Year 1

Assessments for the Visit 2 column contain an Xa, identifying the 
procedures which do not need to be repeated, if Visits 1 and 2 are 
combined into a single visit.

Visit window for Visit 1 was changed from -28 to -1 days to -28 to 0 
days since Visit 1 and Visit 2 may be done on the same day.
o
Footnote “a” – was revised for clarification based on the above change
-
Section 6.1.1 (Screening Visit)
-
Section 6.2 (Treatment Period)
o
Limited physical examination – not done if Visits 1 and 2 are done on the 
same day
o
Dispense IP – the IP can be dispensed to the subject at a combined Visit 1 and 
2, if the GED-0301-CD-004 IP is available for the subject at the study center.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
9
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
If Visit 1 and Visit 2 in GED-0301-CD-004 and the Last Study Visit in the Core GED-0301 
Study are Done Separately but Within a 14-Day Period, Certain Evaluations Not Repeated 
If the Screening Visit 1 from this study and the last study visit from the core GED-0301 study are 
both done separately but are within 14 days of each other, the following Visit 1 clinical and 
laboratory evaluations do not need to be repeated if they were done at the last study visit from 
the core GED-0301 study:  hematology, chemistry, coagulation, complement activation factors, 
urinalysis, pregnancy test, ECG, and physical examination. 
If all 3 visits (ie, Visit 1 and Visit 2 from this study and the last study visit from the core 
GED-0301 study) are done separately but all are within a 14-day period, the following clinical, 
 and laboratory evaluations do not need to be repeated if they were done at the last study 
visit from the core GED-0301 study:  hematology, chemistry, coagulation, complement 
activation factors, urinalysis, pregnancy test, 
, ECG, physical examination, CDAI, 
 
The reason for this change is that it will decrease subject and site burden and will prevent
unnecessary repeat of study assessments if the above-mentioned study visits are completed 
separately within a 14-day period.
Revised Sections:
-
Section 5 (Table of Events)
o
Footnote “a” – was revised for clarification based on the above change
-
Section 6.1.1 (Screening Visit) 
-
Section 6.2 (Treatment Period)
Visit 1 Serum Pregnancy Test is No Longer Required
A Visit 1 serum pregnancy test is no longer needed and has been replaced by a local urine 
pregnancy test.  The reason is that Visit 1 in this study is a basically a continuation of the core 
GED-0301 study and only a local urine test is required.
Revised Section: 
-
Section 6.1.1 (Screening Visit) – Sub-bullet Pregnancy test
Inclusion of Section 8.1.1 (Corticosteroid Tapering Procedure)
The corticosteroid tapering procedure was added solely for previous GED-0301-CD-003 subjects 
who were on stable doses of corticosteroids and achieved clinical improvement by Week 12 in 
Study GED-0301-CD-003.  These subjects should follow the guidance for a corticosteroid 
tapering procedure (Section 8.1.1) upon entrance into this study.
Revised Sections: 
-
Section 8.1 (Permitted Concomitant Medications for CD and Procedures)
-
Section 8.1.1 (Corticosteroid Tapering Procedure) – newly added section
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
10
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
Inclusion of Section 9.9.2 (External Safety Monitoring: Role of the Independent DMC)
Safety monitoring for this study will be performed by an external, independent Data Monitoring 
Committee (DMC), along with the other Phase 3 GED-0301 studies, as part of the external safety 
monitoring for the GED-0301 Program.  This section was intended to be included in the original 
protocol, but was inadvertently missed.
Revised Section: 
-
Section 9.9.2 (External Safety Monitoring: Role of the Independent DMC) – newly added
section
Subject Dosing Instructions (Emphasis that Subjects Take 4 Tablets of IP Each Day) 
Sections of the protocol were updated with clearer subject dosing instructions; emphasizing that 
“4 tablets” of the investigational product (IP) must be taken each day.  That is, subjects will be 
instructed to take “4 tablets” in the morning, 30 minutes before breakfast with a glass of water.
Revised Sections: 
-
Protocol Summary (Study Treatments)
-
Section 6.2 (Treatment Period; sub-bullet Dispense IP)
-
Section 7.2 (Treatment Administration and Schedule)
All 160 mg Daily Treatments are Taken as Four 40 mg Tablets 
Sections of the protocol have an added statement emphasizing that all 160 mg once daily (QD) 
treatments are taken as “four 40 mg tablets” daily in the study.
Revised Sections: 
-
Section 3.1 (Study Design)
-
Figure 1 (Overall Study Design)
-
Section 7.2 (Treatment Administration and Schedule)
-
Appendix G (The Study GED-0301-CD-004 Treatment Table)
Change in the Cancer Surveillance Language
The language in this section had changed since there is no clear, global guidance with respect to 
screening programs for colorectal cancer.  Therefore, Section 6.5.6 was updated to include a 
general statement indicating that subjects with increased risk of colorectal cancer should have 
undergone a colonoscopy with pan-colonic surveillance biopsies according to local guidelines.  
In Section 5, Table 5 (Table of Events), Footnote b, the text was revised to emphasize the same 
information.
Revised Sections:
-
Section 5 (Table of Events, formerly Table 3)
-
Section 6.5.6 (Cancer Surveillance)
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
11
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
  
Changes in the Appendices
The appendices were changed for multiple reasons:  1) to add the adolescent-specific key clinical 
efficacy assessments; 2)
 
 
Revised Sections:
-
Appendix E – Pediatric Crohn’s Disease Activity Index was added and the Inflammatory 
Bowel Disease Questionnaire was removed.
-
Appendix F – Simple Endoscopic Score for Crohn’s Disease was added 
 
.
  
The amendment also includes several other minor clarifications and corrections:
!
For the Medical Monitor/Emergency Contact Information (Page 2 of the Protocol), the 
medical monitor title and contact information was updated.
!
International Conference on Harmonisation has been corrected throughout the protocol 
to: International Council for Harmonisation.
!
Throughout several sections and tables within the protocol document, the words 
“previous” or “prior” GED-0301 study was changed to “core” GED-0301 study for 
clarification and consistency purposes.
!
In the Protocol Summary (Indication), Section 1.1 (Disease Background), Section 1.2 
(Compound Background), Section 1.2.1 (Nonclinical Experience) and Section 1.2.2.2 
(Clinical Safety), the text was updated to be consistent in documentation throughout the 
GED-0301 Program.  As a result of the changes, Section 1.1.1 (Transforming Growth 
Factor-Beta 1 Signaling Pathway in Crohn’s Disease) was no longer required and 
therefore deleted.   In Section 17 (References), the references (Ballas, 2001) and 
(Ottenhof, 2011) were removed since the text in the Protocol Summary (Indication) and 
Section 1.2 (Compound Background) were updated and these references are no longer 
applicable.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
12
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
In the Protocol Summary (Study Design) and Section 3.1 (Study Design), text was added 
in Paragraph 3 in each section to emphasize that this study can only accept adult subjects 
from Study GED-0301-CD-002, since both adult and adolescent subjects are included in 
Study GED-0301-CD-003.
!
In the Protocol Summary (Study Population), text was added to emphasize that this study 
can only accept subjects from the Study GED-0301-CD-002 or Study GED-0301-CD-003 
if they have completed at least through the Week 12 “Visit” in each of those studies.
!
In the Protocol Summary (Study Treatments), Section 1.3.3 (Rationale for Dose, 
Schedule and Regimen Selection) and Section 3.1 (Study Design), text was added in the 
applicable paragraph to emphasize that any modifications to the dose regimens in the 
study would be changed through a protocol amendment, which would require regulatory 
health authority and ethics committee approvals prior to implementation.
!
In Section 1.2 (Compound Background) and Section 17 (References), the appropriate 
reference (Boirivant, 2006) was added to support the statement regarding Smad7, as a 
key regulatory modulator of transforming growth factor-beta 1 (TGF-β1).
!
In Section 3.1 (Study Design) and Figure 1 (Overall Study Design), the descriptions of 
the treatment groups were updated to more clearly describe the treatment; for example, 
“alternating” PBO for 4 weeks “and” 160 mg for 4 weeks.
!
In Section 3.1 (Study Design) and Section 5 (Table 5 and Table 6) Footnote “a” for each
table, new text was added to further emphasize that the Visit 1 assessments and 
procedures in this study are not repeated if the early termination (ET) or last study 
treatment visit from the previous GED-0301 study and Visit 1 from this study are 
completed on the same day.
!
In Section 3.2 (Study Duration for Subjects) and Protocol Summary (Length of Study), a
paragraph was added to point out that the long-term active-treatment period of 208 weeks 
may be shortened in regions where GED-0301 becomes commercially available prior to 
study completion.
!
In Section 3.3 (End of Study), the word “secondary” was added to the applicable sentence 
since there are secondary endpoints from the adolescent population as part of the study 
analysis.  Also, a sentence was added to further clarify that there are no secondary 
objectives or endpoints for the adult subjects in this study and therefore no secondary 
analysis for adult subjects.
!
In Section 4.2.1 (Inclusion Criteria for Adult Subjects), Footnote #4 was added to 
Inclusion Criterion #5 stating that subjects taking an oral contraceptive may need a 
backup or alternative method of birth control based on Investigator 
judgment. Section 6.5.5 (Contraception Education) was also updated with this 
information.  The option to change or initiate an additional birth control method may be 
implemented in cases when the Investigator suspects that the effectiveness of oral 
contraceptives may be reduced based on the severity and extent of the subject’s Crohn’s 
disease (CD), which may affect gastrointestinal absorption or transit of oral 
contraceptives. 
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EDMS Doc. Number:
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
13
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
!
In Section 4.3 (Exclusion Criteria [Adult and Adolescent Subjects]), Exclusion Criterion 
#5 has additional language to clarify that subjects are excluded when they have a 
“confirmed diagnosis of” colorectal dysplasia.  
!
In Section 5, Table 5 (Table of Events, formerly Table 3), the abdominal examination for 
the abdominal mass assessment was removed from the table since it had caused some 
confusion.  Even though removed, the abdominal examination for the abdominal mass 
assessment is performed at each visit when the CDAI 
 assessments are required.  
Therefore, in Section 5, Table 5 (Table of Events) Footnote d and Section 6.5.1 (Physical 
Examination), text was revised to emphasize that an abdominal examination will be 
performed at every visit (including those visits at which a complete or partial physical 
examination is not being performed) to assess the presence of an abdominal mass for the 
CDAI,
 and PCDAI calculations.
!
In Section 6.4.2 (Lost to Follow-up), some of the content was changed to provide more 
flexibility on how and how many times a site may contact a subject if lost to follow-up.  
This language is consistent now with all the Phase 3 GED-0301 studies.
!
In Section 6.6.1 (Screening Visit), the text in the two sub-bullets “prior concomitant 
medications evaluation” and “adverse event evaluation” were revised to emphasize that 
ongoing concomitant medications and ongoing AEs from the core GED-0301 study will 
be electronically carried forward and do not need to be recorded in the appropriate eCRFs 
for this study.
!
In Section 6.6.2 (Crohn’s Disease Activity Index), some of the content was corrected or 
updated to emphasize that clinical parameters needed for calculation of the CDAI will be 
collected by the subject via an electronic diary device and by the site at the scheduled 
visit via a separate electronic device. Also, under the list of categories the subject has 
experienced within the past 7 days, erythema nodosum and pyoderma gangrenosum were 
switched to the category with aphthous ulcers (previously in the same category with 
iritis/uveitis).
!
 
 
!
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-004
Celgene Corporation
Confidential and Proprietary
14
GED-0301-CD-004 Amendment 1 Final: 06 Jan 2017
 
 
!
In Section 7.1 (Description of Investigational Products) and Protocol Summary (Study 
Treatments), the text in the first sentence was updated to emphasize that GED-0301 will 
be provided as 40-mg “gastro-resistant, delayed release, pH-dependent” tablets and are 
not regular “coated” tablets.
!
In Section 7.2 (Treatment Administration and Schedule), the title names of Tables 4 to 7
(Investigational Product Dispensing Schedule for the Treatment Periods at Year 1, Year 
2, Year 3, and Year 4, respectively) were changed to better define the intended purpose, 
which is to identify visits when IP dispensing occurs, not when dosing occurs.  
!
In Section 7.2.2 (Overdose), the timeframe for overdose as previously defined was 
revised to be within the same calendar day and no longer within a 24-hour period.
!
In Section 7.3 (Method of Treatment Assignment), the table numbers were updated from 
Table 4 to Tables 7 to 10.
!
In Section 7.4 (Packaging and Labeling), the text was corrected to state that blister cards 
with child-resistant seals are used in this study and not opaque high-density polyethylene 
bottles with child-resistant caps.
!
In Section 17 (References), the following references were added based on the addition of
new information or assessments related to the addition of the adolescent population
content within the protocol:  
; Daperno, 2004; 
 
Griffiths, 1999; Hyams, 1991; Kansal, 2013; Kelsen, 2008;
 
Lewis, 1997; Mamula, 2003; Markowitz, 2009; 
; Pigneur, 2010; 
Ruemmele; 2014; 
; 
; Van Limbergen, 2008; 
!
In Section 18 (Appendices), Appendix A (Table of Abbreviations) was updated with the 
removal of 4 abbreviations (ie, AS ODN, CpG, DNA and RNase) since text within the 
protocol was updated and these abbreviations are no longer applicable.  The abbreviation 
DMC was added since Section 9.9.2 (External Safety Monitoring: Role of the 
Independent DMC) within the protocol was added.  Also, other abbreviations were added 
based on the addition of the new pediatric and adolescent information.
Appendix A
Appendix
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, LONG-TERM ACTIVE TREATMENT EXTENSION STUDY OF MONGERSEN 
(GED-0301) IN SUBJECTS WITH CROHN’S DISEASE
STUDY DRUG:
GED-0301
PROTOCOL NUMBER:
GED-0301-CD-004
DATE FINAL:
12APR2018
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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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................5
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION....................................................................................................9
3.
STUDY OBJECTIVES...........................................................................................10
4.
INVESTIGATIONAL PLAN .................................................................................11
4.1.
Overall Study Design and Plan ...............................................................................11
4.2.
Study Endpoints .....................................................................................................14
4.3.
Stratification, Randomization, and Blinding............................................................15
4.4.
Sample Size Determination and Power Considerations ...........................................15
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................16
5.1.
Treatment Grouping Approaches ............................................................................16
5.2.
Reporting Conventions ...........................................................................................16
5.3.
Time Points ............................................................................................................17
5.3.2.
Baseline Definitions ...............................................................................................17
5.4.
Analysis Population................................................................................................17
6.
SUBJECT DISPOSITION......................................................................................19
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................20
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................21
8.1.
Demographics and Baseline Characteristics ............................................................21
8.2.
Baseline Disease Characteristics.............................................................................21
9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT.........................23
9.1.
Treatment Duration.................................................................................................23
9.2.
Treatment Compliance............................................................................................23
9.3.
Overdose ................................................................................................................23
10.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................24
10.1.
Concomitant Medications .......................................................................................24
10.2.
Concomitant Procedures.........................................................................................24
11.
EFFICACY ANALYSIS ........................................................................................25
11.1.
Missing Data Handling ...........................................................................................25
11.2.
Analyses of Efficacy Endpoints ..............................................................................25
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
3
11.2.1.
Primary Efficacy Endpoint......................................................................................25
11.2.2.
Analyses of Secondary Efficacy Endpoints.............................................................25
      
12.
SAFETY ANALYSIS ............................................................................................26
12.2.
Adverse Events.......................................................................................................26
12.2.1.
Overall Summary of TEAEs ...................................................................................27
12.2.2.
All TEAEs..............................................................................................................27
12.2.3.
Drug-related TEAEs...............................................................................................27
12.2.4.
TEAEs by Maximum Severity................................................................................27
12.2.5.
Serious TEAEs.......................................................................................................27
12.2.6.
TEAEs Leading to Drug Withdrawal ......................................................................27
12.2.7.
Deaths ....................................................................................................................28
12.3.
Clinical Laboratory Evaluations..............................................................................28
12.4.
Vital Signs and Body Weight..................................................................................29
12.5.
Electrocardiogram ..................................................................................................29
15.
INTERIM ANALYSIS...........................................................................................32
16.
CHANGES TO THE STATISTICAL CONSIDERATIONS SECTION OF 
THE PROTOCOL ..................................................................................................33
17.
REFERENCES.......................................................................................................34
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
4
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Study Objectives – Adult Subjects (≥ 18 years of age at screening of core 
study) from GED-0301-CD-002 .............................................................................10
Table 3:
Protocol-specified Endpoints – Adult Subjects from GED-0301-CD-002................14
Table 6:
Laboratory Marked Abnormalities Criteria .............................................................35
LIST OF FIGURES
Figure 1
Overall Study Design..............................................................................................13
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Meaning
AE
Adverse event
ALT
Alternating
APTT
Activated partial thromboplastin time 
ATC
Anatomical Therapeutic Chemical
ATC2
Anatomical Therapeutic Chemical: Therapeutic (Level 2)
BMI
Body mass index
BUN
Blood urea nitrogen
CBC
Complete blood count
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CIC
Clinical Improvement Criteria
DAO
Data as observed
EAIR
Exposure-adjusted incidence rate 
ECG
Electrocardiograms
ET
Early Termination
IP
Investigational product
IRTS
Interactive response technology system 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
8
Abbreviation
Meaning
LDH
Lactic dehydrogenase 
LOCF
Last observation carried forward
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
NRI
Nonresponder imputation 
PBO
Placebo
PT
Preferred term
Q1
25th percentile
Q3
75th percentile
QD
Once Daily
RBC
Red blood cell
SAP
Statistical analysis plan
SD
Standard deviation
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SGOT
Serum glutamic-oxaloacetic transaminase 
SGPT
Serum glutamic-pyruvic transaminase 
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell
WHODD
World Health Organization Drug Dictionary 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
9
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol GED-0301-CD-004 “A Phase 3, Long-term Active Treatment Extension Study of 
Mongersen (GED-0301) in Subjects with Crohn’s Disease” as amended on 06 Jan 2017. It 
contains definitions of analysis populations, derived variables and statistical methods for the 
analysis of efficacy and safety.
The study was terminated early by Celgene following an October 2017 recommendation of the 
Data Monitoring Committee. As such, changes are made to some protocol-specified analyses; 
these changes are described in relevant sections and summarized in Section 16.
In this SAP, GED-0301 160 mg once daily (QD), GED-0301 40 mg QD, and placebo QD are 
referred to as GED 160, GED 40, and PBO, respectively. Subjects will be assigned to receive 
one of 5 GED-0301 treatment regimens during the study, based on the treatment received during 
the core GED-0301 Phase 3 study (GED-0301-CD-002), and whether the subject met the clinical 
improvement criteria. For the first 12 weeks of the study, subjects will receive blinded, active 
GED-0301 treatment as one of the following numbered treatment groups:
1) continuous GED 160 for 12 weeks;
2) GED 160 for 4 weeks, PBO for 4 weeks, GED 160 for 4 weeks;
3) PBO for 4 weeks, GED 160 for 4 weeks, PBO for 4 weeks;
4) continuous GED 40 for 12 weeks;
5) PBO for 4 weeks, GED 40 for 4 weeks, PBO for 4 weeks.
Beginning at Week 12 through Week 208, subjects from the above-numbered treatment groups 
will continue to receive blinded, active GED-0301 treatment for 196 weeks as the following:
1) alternating PBO for 4 weeks and GED 160 for 4 weeks, through Week 208;
2) alternating PBO for 4 weeks and GED 160 for 4 weeks, through Week 208;
3) alternating GED 160 for 4 weeks and PBO for 4 weeks, through Week 208;
4) continuous GED 40, through Week 208;
5) alternating GED 40 for 4 weeks and PBO for 4 weeks, through Week 208.
The treatment regimens of alternating GED 160 for 4 weeks and PBO for 4 weeks (irrespective 
of whether GED 160 or PBO is administered first in this extension study), continuous GED 40, 
alternating GED 40 for 4 weeks and PBO for 4 weeks, are referred to as GED 160 ALT, GED 
40, and GED 40 ALT, respectively. Investigational product (IP) refers to GED 160, GED 40, or 
PBO.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
10
3.
STUDY OBJECTIVES
Table 2:
Study Objectives – Adult Subjects (≥ 18 years of age at screening of core 
study) from GED-0301-CD-002
Primary Objective
The primary objective of the study is to evaluate the long-term safety of oral GED-0301 in subjects with 
Crohn’s disease (CD).
Secondary Objective(s)
There are no secondary objectives for adult subjects in this study.
 
 
 
 
As Study GED-0301-CD-003, where adolescent subjects were to be enrolled, was not initiated 
before the early termination of this study, the study objectives for adolescent subjects are no 
longer applicable.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
11
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
To streamline this SAP, the Study Design section of the protocol is copied below, with the 
understanding that the references to Study GED-0301-CD-003 are no longer applicable since the 
study was not initiated before the study termination.
This is a Phase 3, double-blind, long-term active treatment extension study to evaluate the 
long-term safety
 of GED-0301 for 208 weeks in adult and adolescent 
subjects with CD who previously participated in either of the following two Phase 3 GED-0301 
studies:
!
Study GED-0301-CD-002 (Adult Subjects)
!
Study GED-0301-CD-003 (Adult and Adolescent Subjects)
The purpose of this study is to assess long-term safety data of GED-0301 for a period of up to 
208 weeks in adult subjects (ie, ≥ 18 years of age) who participated in the core Phase 3 
GED-0301-CD-002 and GED-0301-CD-003 studies and adolescent subjects (ie, 12 to 17 years 
of age) who participated in the core Phase 3 GED-0301-CD-003 study.  
 
Although all subjects will receive active treatment, this study is double-blinded for the entire 208 
weeks for the purpose of preserving the blind of the subject’s treatment allocation in the initial, 
core Phase 3 GED-0301 study. 
Subjects from Study GED-0301-CD-002 who completed the study at Week 52, or who met the 
early escape criteria (Appendix H of the protocol) and were discontinued during the time period 
beginning at Week 12 through Week 52, may be eligible to enter this study.  
Subjects from Study GED-0301-CD-003 who completed the study at Week 12 may also be 
eligible to enter this long-term active treatment study.  
Subjects who discontinued Studies GED-0301-CD-002 or GED-0301-CD-003 prior to the 
Week 12 Visit are not eligible for this study.
This long-term active treatment study will consist of 3 periods:
!
Screening Period – up to 4 weeks (ie, 1 day to 28 days depending on when long-term 
active treatment is available for the subject at the study center)
!
Long-term Active Treatment Period – 208 Weeks (Week 0 to Week 208)
!
Follow-up Period – 4 weeks (ie, no IP taken)
At Week 12, subjects will be evaluated to determine if they should be discontinued from the 
study based on clinical criteria.  Subjects, who meet the following criteria, will be discontinued 
from the study at Week 12: 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
12
 
Subjects who complete this study through Week 208 will have a 4-week Follow-up Visit.  
Subjects who prematurely discontinue treatment from the study at any time prior to Week 208
will have an ET Visit and a 4-week Follow-up Visit.  The ET Visit should be scheduled as soon 
as possible after the last dose of IP.  If the ET Visit occurs 28 days after the last dose of IP, then 
the Follow-up Visit is not required.
At the Screening Visit in this study, all subjects who meet the inclusion criteria and do not meet 
the exclusion criteria will be eligible and assigned a subject identification number using a 
centralized interactive response technology system (IRTS).
Once the subject is eligible and registered in the IRTS, the assigned treatment is based on the 
clinical improvement criteria from the core GED-0301 study to determine the subject’s course of 
treatment for the entire 208 weeks in this study. 
 
Please note that all 160 mg once daily treatments are taken as four 40 mg tablets once daily in 
this study. That is, GED-0301-treated subjects who received one 160 mg tablet QD in 
GED-0301-CD-003 will receive four 40 mg tablets QD in this study. 
Subjects will receive the following treatments:
Previously-treated GED-0301 subjects in Study GED-0301-CD-002 who met the clinical 
improvement criteria at Week 52:
!
Will continue to receive their same blinded treatment, which will be:
-
Alternating PBO QD for 4 weeks and GED-0301 40 mg QD for 4 weeks, or 
-
Continuous GED-0301 40 mg QD, or 
-
Alternating PBO QD for 4 weeks and GED-0301 160 mg QD for 4 weeks.
Previously-treated GED-0301 subjects in Study GED-0301-CD-003 who met the clinical 
improvement criteria at Week 12:
!
Will receive blinded treatment with:
-
Alternating PBO QD for 4 weeks and GED-0301 160 mg QD for 4 weeks.
Previously-treated PBO subjects who met the clinical improvement criteria:
-
At Week 52 in Study GED-0301-CD-002; or
-
At Week 12 in Study GED-0301-CD-003
!
Will receive blinded treatment with:
-
Alternating GED-0301 160 mg QD for 4 weeks and PBO QD for 4 weeks.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
13
Previously-treated GED-0301 or PBO subjects who did not meet the clinical improvement 
criteria:
-
At Week 12 through Week 52 in Study GED-0301-CD-002; or
-
At Week 12 in Study GED-0301-CD-003
!
Will receive blinded treatment with: 
-
Alternating GED-0301 160 mg QD for 4 weeks and PBO QD for 4 weeks, if the 
subject previously received GED-0301 treatment, or 
-
GED-0301 160 mg QD for 12 weeks, if the subject previously received PBO, and 
after Week 12, subjects will receive alternating PBO QD for 4 weeks and 
GED-0301 160 mg QD for 4 weeks.
See the overall study design (Figure 1) for an overview of the study blinded-active treatments.  
All subjects will receive a blinded-active GED-0301 treatment regimen for 208 weeks, and the 
full descriptions of the treatment assignments are detailed in Appendix G of the protocol.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
14
4.2.
Study Endpoints
Table 3:
Protocol-specified Endpoints – Adult Subjects from GED-0301-CD-002 
Endpoint
Name
Description
Timeframe
Primary
Safety
!
The evaluation of safety of GED-0301, assessed by 
the type, frequency and severity of adverse events, and 
its relationship to investigational product (IP), 
discontinuation due to adverse events, and clinically 
significant changes in electrocardiograms (ECGs), 
vital signs, and/or laboratory findings
Through 
Week 208 
and 4 weeks 
postdose
Secondary
Not 
applicable
!
Secondary endpoints are not included for adult 
subjects in this study.
Not 
applicable
 
 
 
 
 
 
 
 
 
CD = Crohn’s disease; 
; ECG = electrocardiogram; 
 
 
 IP = investigational product; 
 
.
As Study GED-0301-CD-003, where adolescent subjects were to be enrolled, was not initiated 
before the early termination of this study, the protocol-specified endpoints for adolescent 
subjects are no longer applicable.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
15
 
 
 
 
 
 
 
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
There is no randomization or stratification in this study. Eligible subjects will be assigned via an 
IRTS to receive one of 5 double-blind GED-0301 treatment regimens (Section 2) during the 
study, based on the treatment received during the initial, core GED-0301 Phase 3 study, and 
whether the subject met the clinical improvement criteria.
4.4.
Sample Size Determination and Power Considerations
No sample size and power calculations are performed for this long-term active treatment study.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
16
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Treatment Grouping Approaches
In listings, treatment will be displayed in 5 treatment regimens (corresponding to the 5 numbered 
treatment groups in Section 2), as follows:
!
GED 160 12WK/PBO/GED 160 ALT
!
GED 160/PBO ALT
!
PBO/GED 160 ALT
!
GED 40
!
PBO/GED 40 ALT
The following treatment grouping will be used in tables. 
!
GED 40 ALT
!
GED 40
!
GED 160 ALT (combining all variants of this regimen)
!
GED Total
5.2.
Reporting Conventions
The following reporting conventions apply generally to tables, listings, and figures:
!
P-values will not be reported.
!
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.
!
 
 
!
 
!
Change from baseline is calculated as the post-baseline value minus the baseline value. 
Percent change from baseline is calculated as 100 x (change from baseline / baseline). To 
assess change from baseline, a baseline value and at least 1 post-baseline value are 
required.
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GED-0301
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Celgene 
Confidential and Proprietary
17
!
All laboratory data will be reported using standard international units.
!
 
5.3.
Time Points
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3.2.
Baseline Definitions
For the efficacy 
 analyses, and the summary of baseline disease characteristics, the 
baseline value in this extension study is defined as the baseline value calculated in the core
study. For the lab, vital signs, weight, and ECG analyses, the baseline value is defined as the last 
assessment on or before the date of the first dose of GED-0301 since participating in the core
study.
5.4.
Analysis Population
All analyses will be based on the Long-term Active Treatment Population, which will consist of 
all subjects who enter the long-term active treatment study and receive at least 1 dose of IP 
during the long-term active treatment study.
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Celgene 
Confidential and Proprietary
19
6.
SUBJECT DISPOSITION
The number of subjects screened, the numbers and percentages of subjects enrolled and not 
enrolled, and the numbers and percentages of the eligibility criteria failed will be summarized 
based on all subjects screened.
The number and percentage of subjects included in the analysis population will be summarized 
based on all subjects enrolled.
Subject disposition (entered, completed, discontinued, along with the primary reason for 
discontinuation) will be summarized for
!
Week 12 (based on all subjects enrolled)
!
Long-term Active Treatment Period (based on all subjects enrolled)
!
Follow-up Period (based on all subjects who enter the Follow-up Period).
 
 
 
 
 
 
 
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 enrolled.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
20
7.
PROTOCOL DEVIATIONS/VIOLATIONS
Protocol violations and deviations will be summarized using the long-term active treatment
population.
A listing of all protocol violations and deviations in the study will be provided.
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GED-0301
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Celgene 
Confidential and Proprietary
21
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics, as collected or calculated in the core GED-0301 
Phase 3 study, will be summarized based on the long-term active treatment population. 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 = weight (kg)/[height(m)]2; kg/m2)
The following characteristics will be summarized as categorical variables:
!
Age (< 65, ≥ 65 years; < 40, 40 – < 65, 65 – < 75, ≥ 75 years)
!
Sex (Male, Female)
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Collected or Reported, Other)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown, Not Reported)
!
Region (North America, Western Europe, Eastern Europe, Asia Pacific)
!
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, passive smoker, smokeless 
tobacco user) 
8.2.
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized as continuous variables:
!
Baseline CDAI score
!
Baseline SES-CD score (central read)
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
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Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
23
9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT
9.1.
Treatment Duration
Treatment duration will be summarized for Weeks 0-208 using the long-term active treatment 
population.
 
 
Treatment duration will be summarized as a continuous variable, and as a categorical 
variable with the following exposure intervals:
!
Weeks 0-208: ≤ 13, > 13 – ≤ 26, > 26 – ≤ 39, > 39 – ≤ 52, > 52 – ≤ 65, > 65 – ≤ 78, > 78
– ≤ 91, > 91 – ≤ 104, > 104 – ≤ 117, > 117 – ≤ 130, > 130 – ≤ 143, > 143 – ≤ 156, > 156
– ≤ 169, > 169 – ≤ 182, > 182 – ≤ 195, > 195 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 (except the screening and follow-up visits). 
These records will be used to calculate treatment compliance. Treatment compliance will be 
summarized for Weeks 0-208 using the long-term active treatment population.
 
 
 
 
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.
9.3.
Overdose
A subject data listing of overdose records will be provided.
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Celgene 
Confidential and Proprietary
24
10.
CONCOMITANT MEDICATIONS AND PROCEDURES
Concomitant medications and procedures during the Long-term Active Treatment Period will be 
summarized for Weeks 0-208 using the long-term active treatment population. 
10.1.
Concomitant Medications
 
 
Concomitant medications will be coded according to the ATC coding scheme of the WHODD, 
and 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 alphabetical order and PTs within each SOC in descending order of frequency.
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Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
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25
11.
EFFICACY ANALYSIS
The efficacy endpoints will be summarized descriptively.
11.1.
Missing Data Handling
Continuous endpoints by time point will be summarized based on data as observed (DAO), 
where only subjects with sufficient data at the time point under consideration will be included in 
the summary of that time point.
11.2.
Analyses of Efficacy Endpoints
11.2.1.
Primary Efficacy Endpoint
There is no primary efficacy endpoint in this study.
11.2.2.
Analyses of Secondary Efficacy Endpoints
As Study GED-0301-CD-003, where adolescent subjects were to be enrolled, was not initiated 
before the early termination of this study, there are no secondary efficacy endpoints.
 
 
 
      
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
26
12.
SAFETY ANALYSIS
Safety will be evaluated via descriptive statistics and point estimates. No inferential testing for 
statistical significance will be performed.
 
 
 
 
 
12.2.
Adverse Events
Adverse events (AE) will be coded according to the MedDRA. Unless otherwise specified, AEs 
will be summarized by SOC and PT, with SOCs sorted in alphabetical order and PTs within each 
SOC in descending order of subject incidence of the GED Total group combining all GED-0301 
treatment regimens.
For the analysis of AEs, the following point estimates are provided, unless otherwise specified:
!
Subject incidence: Subject incidence (ie, 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.
!
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
27
 
A subject data listing of all AEs (including treatment-emergent AEs [TEAEs] and non-TEAEs) 
will be provided.
12.2.1.
Overall Summary of TEAEs
An overall summary of the following TEAE categories will be provided for Weeks 0-208:
!
Any TEAE
!
Any drug-related TEAE
!
Any severe TEAE 
!
Any serious TEAE
!
Any serious drug-related TEAE
!
Any TEAE leading to drug interruption
!
Any TEAE leading to drug withdrawal
!
Any TEAE leading to death
12.2.2.
All TEAEs
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence of the GED Total group combining all GED-0301 treatment regimens) for 
Weeks 0-208.
12.2.3.
Drug-related TEAEs
Drug-related TEAEs will be summarized for Weeks 0-208.
12.2.4.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, and severe) for Weeks 0-
208. 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.
12.2.5.
Serious TEAEs
Serious TEAEs will be summarized for Weeks 0-208.
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided.
12.2.6.
TEAEs Leading to Drug Withdrawal
TEAEs leading to drug withdrawal will be summarized for Weeks 0-208.
A subject data listing of AEs leading to drug withdrawal will be provided.
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12.2.6.
2.2.6.


GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
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12.2.7.
Deaths
A subject data listing of all deaths will be provided.
12.3.
Clinical Laboratory Evaluations
The following protocol-specified parameters from the central laboratory will be summarized:
!
Hematology panel will include: complete blood count (CBC) with differential, including 
red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume 
(MCV), white blood cell (WBC) count (with differential), and platelet count. 
!
Serum chemistry panel will include: total protein, albumin, calcium, phosphorous, 
glucose, total cholesterol, 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, magnesium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, 
and lactic dehydrogenase (LDH), . 
!
Coagulation assessment will include: prothrombin time and activated partial 
thromboplastin time (APTT) 
!
Complement activation factor panel will include: compliment activation factors Bb,
C3a and C5a.
!
Urinalysis will include specific gravity and pH. 
Summary statistics of observed values and changes from baseline will be provided by time point
(time points include the scheduled visits for labs, the follow-up visit, and the end of Weeks 0-
208).
Frequency summaries (shift tables) of shifts from baseline to post-baseline time points (time 
points include the scheduled visits for labs, the end of Weeks 0-208, and the worst value of 
Weeks 0-208) 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 hematology and serum chemistry.
A summary of laboratory marked abnormalities as defined in Section 18.1 will be provided for 
Weeks 0-208.
 
 
 
A separate summary of laboratory marked 
abnormalities will also be presented by normal baseline and abnormal baseline. 
 
 
 
 
A subject data listing of all laboratory data (including urinalysis) will be provided.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
29
12.4.
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
(time points include the scheduled visits for vital signs/body weight, the follow-up visit, and the 
end of Weeks 0-208).
A subject data listing of all vital signs and body weight will be provided.
12.5.
Electrocardiogram
A frequency summary (shift table) of the shift from baseline to the end of Weeks 0-208 in
investigator clinical interpretation of ECG (normal; abnormal, not clinically significant; and 
abnormal, clinically significant) will be provided. 
 
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and 
25


GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
30
&(/*(1(35235,(7$5<,1)250$7,21


GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
31
 
&(/*(1(35235,(7$5<,1)250$7,21


GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
32
15.
INTERIM ANALYSIS
There will be no interim analysis. 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
33
16.
CHANGES TO THE STATISTICAL CONSIDERATIONS
SECTION OF THE PROTOCOL
Due to the early termination of the study, the following changes to the Statistical Considerations 
section of the protocol have been made in this SAP.
 
 
!
Protocol specifies interim analyses may be performed. This SAP excludes those analyses.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
34
17.
REFERENCES
There are no references.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
35
&(/*(1(35235,(7$5<,1)250$7,2


GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-004
Celgene 
Confidential and Proprietary
36
&(/*(1(35235,(7$5<,1)250$7,21