Clinical trial NCT02596893
Conditions: Crohn Disease
Keywords: Crohn's Disease GED-0301 Mongersen IBD Safety Efficacy
Sponsor: Celgene
Start date: 2015-12-08; Completion date: 2018-01-05
Enrollment: 701 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of study is to test the effects of an experimental medication GED-0301 (mongersen) in patients who have active Crohn's disease. The study will test GED-0301 compared to placebo for 52 weeks. The study treatment is blinded which means that patients and the study doctor will not know which treatment has been assigned. Patients in this study will be allowed treatment with stable doses of oral aminosalicylates, oral corticosteroids, immunosupressants and antibiotics for the treatment of Crohn's disease.

After 12 weeks in the study until the end of the study, patients who do not have an improvement in their Crohns disease symptoms will have the option to enter a long term active treatment study. Participants who discontinued the study anytime or completed the study at Week 52 were then observed for an additional 4 weeks.

Detailed description:

Arms: arm 1: GED-0301 160 mg once daily (QD) for 12 weeks; followed by placebo QD for 4 weeks; followed by alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the the Week 52 Visit arm 2: GED-0301 160 mg once daily (QD) for 12 weeks; followed by placebo QD for 4 weeks; followed by alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the Week 52 Visit arm 3: GED-0301 160 mg once daily (QD) for 12 weeks; followed by continuous GED-0301 40 mg QD, until the Week 52 Visit arm 4: Placebo once daily (QD) until the Week 52 Visit
Interventions: intervention 1: GED-0301 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
1
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
TITLE PAGE
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF 
MONGERSEN (GED-0301) FOR THE TREATMENT OF
SUBJECTS WITH ACTIVE CROHN’S DISEASE
PROTOCOL NUMBER:
GED-0301-CD-002 
DATE FINAL:
03 Aug 2015
DATE AMENDMENT 1 FINAL:
23 Sep 2015
DATE AMENDMENT 2 FINAL:
25 Oct 2016
DATE AMENDMENT 3 FINAL:
15 Aug 2017
EudraCT NUMBER:
2015-001925-18
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-002
Celgene Corporation
Confidential and Proprietary
2
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
24-hour Urgent Medical Contact for sites:
(alternate)
Medical Monitor Contact Information:
Americas:
Name: 
Office:
Mobile from 
 
Mobile from abroad: 
US toll free number: 
e-mail: 
APAC:
Name: 
Office: 
Mobile: 
e-mail: 
EMEA:
Name: 
Mobile: 
 
e-mail: 
Sponsor Contact Information:
Name:
Title:
Address:
Celgene Corporation
86 Morris Avenue, Summit, NJ  07091
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-002
Celgene Corporation
Confidential and Proprietary
3
GED-0301-CD-002 Amendment 3 Final: 15 Aug 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-002
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-002 Amendment 3 Final: 15 Aug 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)/Ethics Committee (EC) 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-002
Celgene Corporation
Confidential and Proprietary
5
GED-0301-CD-002 Amendment 3 Final: 15 Aug 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-002
Celgene Corporation
Confidential and Proprietary
6
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, randomized, double-blind, placebo-controlled, multicenter study to investigate the 
efficacy and safety of mongersen (GED-0301) for the treatment of subjects with active 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, 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.
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-002
Celgene Corporation
Confidential and Proprietary
7
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Objectives
Primary Objective
!
To evaluate the efficacy of GED-0301 compared with placebo on clinical activity at
Week 12 in subjects with active CD
Secondary Objectives
!
To evaluate the efficacy of GED-0301 compared with placebo on endoscopic outcomes 
in subjects with active CD
!
To evaluate the long-term efficacy of GED-0301 compared with placebo on clinical 
activity in subjects with active CD
!
To evaluate the efficacy of GED-0301 compared with placebo on corticosteroid-free 
clinical remission in subjects with active CD
!
To evaluate the safety and tolerability of GED-0301 in subjects with active CD
Endpoints 
Primary Endpoint
!
The proportion of subjects achieving clinical remission, defined as a CDAI score < 150,
at Week 12
Secondary Endpoints
!
The proportion of subjects achieving clinical remission, defined as a CDAI score < 150, 
at Week 52 
!
The proportion of subjects with endoscopic response-50 (ER-50), defined as a reduction 
of at least 50% in the SES-CD compared with baseline, at Week 52
!
The proportion of subjects who have a clinical response, defined as a decrease from 
baseline in CDAI ≥ 100 points, at Week 12
 
!
The proportion of subjects who achieve corticosteroid-free clinical remission (CDAI 
<150) at Week 52 among subjects receiving oral corticosteroids for CD at baseline 
!
The proportion of subjects achieving sustained clinical remission, defined as a CDAI 
score < 150, at both Week 12 and Week 52
!
The proportion of subjects with endoscopic response-25 (ER-25), defined as a reduction 
of at least 25% in the SES-CD compared with baseline, at Week 12
!
The proportion of subjects with endoscopic remission, defined as SES-CD ≤ 2, at Week
52
!
Type, frequency, severity, seriousness, and relationship of AEs to IP
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
8
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
!
Number of subjects who discontinue investigational product (IP) due to any AE
!
Clinically significant changes in vital signs, electrocardiograms (ECGs) and/or laboratory 
findings
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of 3 treatment regimens of oral GED-0301 versus placebo in subjects 
with active CD (defined by a CDAI score ≥ 220 and ≤ 450 and a total SES-CD ≥ 6 at screening, 
or the ileum segmental SES-CD ≥ 4 at screening). Approximately 1064 subjects will be 
randomized in a 1:1:1:1 ratio (266 subjects per GED-0301 arm [total 798] and 266 subjects in the 
placebo arm) to receive 1 of 3 double-blind, oral GED-0301 treatment regimens, or identically 
appearing placebo, once daily (QD) for 52 weeks. The total number of subjects with a total SES-
CD score ≥ 6 is targeted to comprise approximately 80% of the study population.
Treatment assignment at baseline (Week 0/Visit 2) will be stratified via an Interactive Web 
Response System (IWRS) based on concomitant use of corticosteroids (yes/no); concomitant use 
of immunosuppressants (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate 
[MTX]) (yes/no), and previous exposure to biologics (ie, infliximab, adalimumab, certolizumab
or vedolizumab) (yes/no).  The total number of subjects with previous exposure to biologics is 
targeted to comprise approximately 35% of the study population.
Subjects will receive double-blind, oral GED-0301 or identically appearing placebo (QD) as 
follows (Table 4):
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
the Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit;
!
Placebo QD until the Week 52 Visit.
Subjects who complete the GED-0301-CD-002 study at the Week 52 Visit may enter the Long-
term Active-treatment Study (GED-0301-CD-004). Subjects who meet the criteria for early 
escape beginning at the Week 12 Visit and thereafter until the Week 52 Visit, may (a) continue 
in the study at the discretion of the Investigator based on the totality of clinical data, (b) enter the 
Long-term Active-treatment Study (GED-0301-CD-004), or (c) discontinue the study.
The criteria for early escape are defined as 
 
(Table 7).
Subjects may discontinue the study at any time. Subjects who discontinue from the study at 
Week 12 (either because they meet the early escape criteria or for any other reason), will 
complete the Week 12 Visit. Subjects who prematurely discontinue from the study at any other 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
9
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
time prior to the Week 52 Visit, including subjects who early escape into the Long-term Active-
treatment Study, will complete the Early Termination (ET) Visit (Section 6.3). The ET Visit
should be scheduled as soon as possible after the last dose of IP. 
Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from 
the study, will have a 4-week Follow-up Visit. If the ET Visit occurs 28 days or more after the
last dose of IP, then the Follow-up Visit is not required. 
Subjects entering the Long-term Extension Study will not have the Follow-up Visit. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs) and applicable regulatory requirements.  
Study Population
The study population will consist of female and male subjects 18 years of age and older at the 
time of signing the Informed Consent Form (ICF).  
The key inclusion criteria for this study are as follows:
!
Diagnosis of CD with a duration of at least 3 months prior to the Screening Visit
!
Presence of ileitis, ileocolitis or colitis, as determined by ileocolonoscopy at screening.
!
Active disease, defined as a CDAI score ≥ 220 and ≤ 450 at screening
!
Must have a 7-day average stool frequency ≥ 3.5 or abdominal pain ≥ 1.5 at screening.
!
Must have a total SES-CD ≥ 6 at screening, or the ileum segmental SES-CD ≥ 4 at 
screening
!
Must have failed or experienced intolerance to at least one of the following: budesonide; 
systemic corticosteroids; immunosuppressants (ie, azathioprine [AZA], 6-mercaptopurine 
[6-MP], or methotrexate [MTX]); or biologics for the treatment of CD (ie, infliximab, 
adalimumab, certolizumab or vedolizumab, see Appendix H for details) 
The key exclusion criteria for this study are as follows:
!
Diagnosis of ulcerative colitis (UC), indeterminate colitis, ischemic colitis, microscopic 
colitis, radiation colitis or diverticular disease-associated colitis
!
Local manifestations of CD such as abscesses, short bowel syndrome, or other disease 
complications for which surgery might be indicated or could confound the evaluation of 
efficacy
!
Strictures with prestenotic dilatation, requiring procedural intervention, or with 
obstructive symptoms. In addition, colonic strictures that are not passable with an adult 
colonoscope, or strictures in the ileum or ileocecal valve that are fibrotic in nature, will 
be excluded.
!
Any intestinal resection within 6 months or any intra-abdominal surgery within 3 months 
prior to the Screening Visit
!
Prior treatment with mycophenolic acid, tacrolimus, sirolimus, cyclosporine, thalidomide 
or apheresis (eg, Adacolumn®) within 8 weeks prior to the Screening Visit
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
10
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
!
Use of intravenous (IV) corticosteroids within 2 weeks prior to the Screening Visit
!
Use of topical GI treatments such as 5-aminosalicylic acid (5-ASA) or corticosteroid 
enemas or suppositories within 2 weeks prior to the Screening Visit
!
Use of bile acid sequestrants, (eg, cholestyramine) within 3 weeks prior to the Screening
Visit
!
Prior treatment with biologics for the treatment of CD (approved or investigational),
other than infliximab, adalimumab, certolizumab or vedolizumab 
!
Prior treatment with more than 3 biologics for the treatment of CD (ie, infliximab, 
adalimumab, certolizumab or vedolizumab). Treatment with a biologic within 8 weeks 
prior to the Screening Visit, or 5 elimination half lives, whichever is longer. (See
Table 8 for elimination half-life timeframes of biologics.)
Permitted concomitant medications during the study include:
!
Oral aminosalicylates (sulfasalazine [SSZ] or 5-aminosalicylic acid [ASA] compounds), 
provided that treatment has been given at a stable dose for at least 2 weeks prior to the 
Screening Visit. The dose of oral aminosalicylates must remain stable through the 
duration of the study or early termination from the study.  If oral aminosalicylates have 
been recently discontinued, treatment must have been stopped at least 2 weeks prior to 
the Screening Visit.
!
Oral corticosteroids, provided that the dose (prednisone ≤ 20 mg/day or equivalent, 
budesonide ≤ 9 mg/day) has been stable for 3 weeks prior to the Screening Visit.  If oral 
corticosteroids were recently discontinued, discontinuation must have been completed at 
least 3 weeks prior to the Screening Visit.  Corticosteroid doses should remain stable 
until the subject is eligible to start corticosteroid tapering, beginning at the Week 12 Visit 
(see Section 6.7 for details).
!
Immunosuppressants, such as AZA, 6-MP, or MTX, provided that treatment was initiated 
≥ 12 weeks prior to the Screening Visit, must be at a stable dose for ≥ 8 weeks prior to 
the Screening Visit and remain stable for the duration of the study. If 
immunosuppressants have been recently discontinued, treatment must have been stopped 
at least 8 weeks prior to the Screening Visit.
!
Antibiotics used for the treatment of CD (eg, ciprofloxacin, metronidazole), provided that 
the dose has been stable for at least 2 weeks prior to the Screening Visit. If antibiotics 
have been recently discontinued, discontinuation must have been completed at least 2 
weeks prior to the Screening Visit.
!
Acetaminophen and low-dose aspirin for cardiovascular prophylaxis are allowed.
Note:  The dose of concomitant CD medications noted above may not be increased above the 
baseline dose during the study. No new CD therapy can be prescribed once the subject has been 
screened in the study. 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
11
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Length of Study
Subjects will participate for a maximum of 60 weeks in this study: up to 4 weeks in the 
Screening Period; 52 weeks in the Double-blind Treatment Period; and 4 weeks in the Follow-up 
Period.
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 and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Subjects will receive double-blind, oral GED-0301 or identically appearing placebo QD as 
follows:
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit;
!
Placebo QD until the Week 52 Visit.
Additional information pertaining to treatment is described in Section 7.
Overview of Key Efficacy Assessments
!
Crohn’s Disease Activity Index (Section 6.6.2)
!
Simple Endoscopic Score for Crohn’s Disease (Section 6.6.6)
Overview of Key Safety Assessments
!
Type, frequency, severity, seriousness, and relationship of AEs to IP
!
Number of subjects who discontinue IP due to any AE
!
Clinically significant changes in ECGs, vital signs, and/or laboratory findings
Statistical Methods
The intent-to-treat (ITT) population will be the primary population for the efficacy analysis.  The 
ITT population will consist of all subjects who are randomized and receive at least 1 dose of IP.  
Subjects will be included in the treatment group to which they were randomized for the efficacy 
analysis using the ITT population.
For the efficacy analyses of the first 12 weeks of the study, the 3 GED-0301 treatment groups 
will be pooled, due to the same treatment of GED-0301 160 mg QD received during the first 12 
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352


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
12
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
weeks, and the treatment comparisons will be made between GED-0301 160 mg QD and 
placebo.  For the efficacy analyses beyond Week 12, the treatment comparisons will be made 
between each of the 3 GED-0301 treatment groups and placebo.
Binary endpoints will be analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors.  Subjects who have insufficient data for response 
determination for the time point under consideration will be considered nonresponders for that 
time point.
 
 
 
 
 
Formal statistical tests are planned for the primary and secondary efficacy endpoints.  In order to 
control the family-wise Type I error rate at the 0.05 level, formal statistical tests will be carried 
out using a gatekeeping closed testing procedure.
The safety analysis will be based on the safety population, which will consist of all subjects who 
are randomized and receive at least 1 dose of IP.  Subjects will be included in the treatment 
group corresponding to the IP they actually received for the analysis using the safety population.
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.  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 postbaseline will be provided for laboratory 
tests.
With a total of approximately 1064 subjects and a randomization ratio of 1:1:1:1, this study will 
randomize approximately 266 subjects into each of the 3 GED-0301 treatment groups and the 
placebo group.  The study sample size is driven by the comparison of each of the three GED-
0301 treatment groups with placebo with respect to the proportion of subjects with ER-50 at 
Week 52.  The study has > 90% power (at a 2-sided significance level of 0.05 and not accounting 
for multiplicity adjustment; same for the power statements below) to demonstrate the superiority 
of GED-0301 160 mg QD (approximately 798 subjects) over placebo with respect to clinical 
remission at Week 12, assuming response rates of 36% and 22% for the GED-0301 160 mg QD 
and placebo groups, respectively.  The study has > 90% power to demonstrate the superiority of 
a GED-0301 treatment regimen over placebo with respect to clinical remission at Week 52, 
assuming response rates of 36% and 22% for the GED-0301 and placebo groups, respectively.  
The study has 90% power to demonstrate the superiority of a GED-0301 treatment regimen over 
placebo with respect to ER-50 at Week 52, assuming response rates of 20% and 10% for the 
GED-0301 and placebo groups, respectively.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
13
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................20
1.1.
Disease Background ...............................................................................................20
1.2.
Compound Background ..........................................................................................21
1.2.1.
Nonclinical Experience...........................................................................................22
1.2.2.
Clinical Summary...................................................................................................22
1.2.2.1.
Clinical Pharmacology............................................................................................22
1.2.2.2.
Clinical Safety........................................................................................................22
1.3.
Rationale ................................................................................................................23
1.3.1.
Study Rationale and Purpose ..................................................................................23
1.3.2.
Rationale for the Study Design ...............................................................................23
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................24
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................26
3.
OVERALL STUDY DESIGN ................................................................................30
3.1.
Study Design ..........................................................................................................30
3.1.1.
Study Duration for Subjects....................................................................................33
3.1.2.
Early Termination Visit ..........................................................................................33
3.1.3.
Lost to Follow-up ...................................................................................................33
3.2.
End of Study...........................................................................................................33
4.
STUDY POPULATION.........................................................................................35
4.1.
Number of Subjects ................................................................................................35
4.2.
Inclusion Criteria....................................................................................................35
4.3.
Exclusion Criteria...................................................................................................36
5.
TABLE OF EVENTS.............................................................................................39
6.
PROCEDURES......................................................................................................43
6.1.
Screening Period.....................................................................................................43
6.1.1.
Screening Visit .......................................................................................................43
6.2.
Double-blind Treatment Period...............................................................................45
6.2.1.
Unscheduled Visits.................................................................................................47
6.3.
Early Termination...................................................................................................47
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
14
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
6.4.
Follow-up Period....................................................................................................48
6.5.
Safety Assessments.................................................................................................48
6.5.1.
Physical Examination .............................................................................................48
6.5.2.
Electrocardiogram ..................................................................................................48
6.5.3.
Clinical Laboratory Assessments ............................................................................49
6.5.4.
Stool Assessment....................................................................................................49
6.5.5.
Clinically Significant Abnormal Findings...............................................................50
6.5.6.
Contraception Education.........................................................................................50
6.6.
Efficacy Assessments .............................................................................................50
6.6.1.
Subject Daily Diary ................................................................................................50
6.6.2.
Crohn’s Disease Activity Index ..............................................................................51
6.6.5.
Ileocolonoscopy......................................................................................................53
6.6.6.
Simple Endoscopic Score for CD............................................................................53
6.7.
Corticosteroid Tapering Procedure..........................................................................53
 
7.
DESCRIPTION OF STUDY TREATMENTS........................................................58
7.1.
Description of Investigational Product(s)................................................................58
7.2.
Treatment Administration and Schedule .................................................................58
7.2.1.
Dose Modification or Interruption...........................................................................58
7.2.2.
Overdose ................................................................................................................58
7.3.
Method of Treatment Assignment...........................................................................58
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
15
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
7.4.
Packaging and Labeling..........................................................................................61
7.5.
Investigational Product Accountability and Disposal ..............................................61
7.6.
Investigational Product Compliance........................................................................61
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................62
8.1.
Permitted Concomitant Medications and Procedures...............................................62
8.2.
Prohibited Concomitant Medications and Procedures..............................................62
8.3.
Required Concomitant Medications and Procedures................................................63
9.
STATISTICAL CONSIDERATIONS ....................................................................64
9.1.
Overview................................................................................................................64
9.2.
Study Population Definitions ..................................................................................64
9.3.
Sample Size and Power Considerations...................................................................64
9.4.
Background and Demographic Characteristics........................................................65
9.5.
Subject Disposition.................................................................................................65
9.6.
Efficacy Analysis....................................................................................................65
9.6.1.
Statistical Methods .................................................................................................65
9.6.2.
Multiplicity.............................................................................................................66
9.6.3.
Subgroup Analyses.................................................................................................66
9.7.
Safety Analysis.......................................................................................................66
9.8.
Interim Analysis .....................................................................................................66
9.9.
Other Topics...........................................................................................................67
9.9.3.
Internal Celgene Safety Monitoring During the GED-0301 Program: Role of 
the Safety Management Team.................................................................................67
9.9.4.
External Safety Monitoring: Role of the Independent DMC....................................67
10.
ADVERSE EVENTS..............................................................................................68
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................68
10.2.
Evaluation of Adverse Events.................................................................................68
10.2.1.
Seriousness.............................................................................................................68
10.2.2.
Severity/Intensity....................................................................................................69
10.2.3.
Causality ................................................................................................................70
10.2.4.
Duration .................................................................................................................71
10.2.5.
Action Taken..........................................................................................................71
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352


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
16
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
10.2.6.
Outcome.................................................................................................................71
10.3.
Abnormal Laboratory Values..................................................................................71
10.4.
Pregnancy...............................................................................................................71
10.4.1.
Females of Childbearing Potential ..........................................................................72
10.5.
Reporting of Serious Adverse Events......................................................................72
10.5.1.
Safety Queries ........................................................................................................73
10.6.
Expedited Reporting of Adverse Events..................................................................73
11.
DISCONTINUATIONS .........................................................................................74
11.1.
Treatment Discontinuation......................................................................................74
11.2.
Study Discontinuation ............................................................................................74
12.
EMERGENCY PROCEDURES.............................................................................76
12.1.
Emergency Contact.................................................................................................76
12.2.
Emergency Identification of Investigational Products .............................................76
13.
REGULATORY CONSIDERATIONS...................................................................77
13.1.
Good Clinical Practice............................................................................................77
13.2.
Investigator Responsibilities ...................................................................................77
13.3.
Subject Information and Informed Consent.............................................................78
13.4.
Confidentiality........................................................................................................78
13.5.
Protocol Amendments.............................................................................................78
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................78
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................79
13.8.
Termination of the Study ........................................................................................79
14.
DATA HANDLING AND RECORDKEEPING.....................................................80
14.1.
Data/Documents.....................................................................................................80
14.2.
Data Management...................................................................................................80
14.3.
Record Retention....................................................................................................80
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................82
15.1.
Study Monitoring and Source Data Verification......................................................82
15.2.
Audits and Inspections............................................................................................82
16.
PUBLICATIONS ...................................................................................................83
17.
REFERENCES.......................................................................................................84
18.
APPENDICES........................................................................................................87
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
17
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
APPENDIX A:
TABLE OF ABBREVIATIONS....................................................................87
APPENDIX B:
DEFINITIONS FOR EFFICACY OUTCOMES ...........................................90
APPENDIX C:
SUBJECT DAILY DIARY............................................................................91
APPENDIX D.
CROHN’S DISEASE ACTIVITY INDEX (CDAI) SCORE ..........................92
APPENDIX E.
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE 
(SES-CD) ...............................................................................................................93
 
APPENDIX H.
DEFINITION OF CD TREATMENT FAILURE AND 
INTOLERANCE ..................................................................................................112
APPENDIX M.
HALF LIVES OF BIOLOGICS ..................................................................121
APPENDIX O: CRITERIA FOR TEMPORARY INTERRUPTION OF IP OR STUDY 
DISCONTINUATION BASED ON LIVER FUNCTION TEST 
ABNORMALITIES..............................................................................................123
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
18
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................26
Table 2:
Study Endpoints .....................................................................................................26
Table 3:
Table of Events.......................................................................................................39
Table 4:
IP Dispensing Schedule: Double-blind Treatment Period........................................60
Table 5:
Sample Size and Power Calculations ......................................................................65
Table 6:
Abbreviations and Specialist Terms........................................................................87
Table 7:
Definitions for Efficacy Outcomes..........................................................................90
Table 8:
Elimination Half Lives of Biologics......................................................................121
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
19
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................32
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
20
GED-0301-CD-002 Amendment 3 Final: 15 Aug 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.  
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 (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.  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 at 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 which are associated with intestinal activity (eg, peripheral arthritis, 
erythema nodosum, aphthous ulcers); or not (eg, pyoderma gangrenosum, uveitis, 
spondylarthropathy, primary sclerosing cholangitis); non CD-specific autoimmune diseases 
which represent a major susceptibility to autoimmunity only (eg, hemolytic anemia, vitiligo, 
diabetes mellitus, psoriasis) as well as CD-related complications due to metabolic or anatomical 
abnormalities (eg, thromboembolic events, osteopathy, nephrolithiasis) (Vavricka, 2011;
Bernstein, 2005). Additionally, patients with CD are at increased risk of developing small bowel 
and colorectal cancer (Baumgart, 2012). 
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, natalizumab, and vedolizumab.  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). 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
21
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
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).  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 a TNF-α blocker, the response to a second 
TNF-α blocker is significantly lower.  The TNF-α blockers may predispose 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 patients with 
CD who do not respond, lose response, or are intolerant to currently available treatments.
1.2.
Compound Background 
GED-0301 inhibits the expression of Smad7, a key regulatory modulator of 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 UC 
(Monteleone, 2001).  This is associated with a reduction in p-Smad3, a crucial step in TGF-β1-
mediated signal transduction.  By blocking TGF-β1 activity, high Smad7 levels contribute to 
sustained production of proinflammatory molecules (such as 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 mongersen (GED-0301).
GED-0301 is an investigational medicinal product in clinical development for the treatment of 
CD and ulcerative colitis (UC). GED-0301 is an antisense oligodeoxynucleotide (21-mer) that is 
complementary to the sequence of the messenger ribonucleic acid (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 transforming growth factor-β1 (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 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 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
22
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
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, inhibiting Smad also exists.  Smad7, on the other hand, 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.
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 
 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 completed to date:  
, a Phase 1, dose-
escalating, safety and PK study of 7 days of oral administration of GED-0301 in subjects with 
active CD,
 a Phase 2 randomized, double-blind, placebo-controlled, 
dose-finding study of GED-0301 in subjects with active CD and 
, 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.  
 
 
 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.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
23
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The purpose of this Phase 3 study is to demonstrate the efficacy and safety of GED-0301 in 
subjects with active CD to support its registration for the indication of the treatment of active 
CD. Active CD is defined as a CDAI score ≥ 220 and ≤ 450 at screening and a total Simple 
Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6 at screening, or the ileum segmental SES-
CD ≥ 4 at screening. Subjects must have failed or experienced intolerance to at least one of the 
following: budesonide; systemic corticosteroids; immunosuppressants (eg, azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]); or biologics (ie, infliximab, adalimumab, 
certolizumab or vedolizumab).
1.3.2.
Rationale for the Study Design
GED-0301-CD-002 is a double-blind, placebo-controlled study that will evaluate both short-term 
and long-term efficacy, as well as safety, of GED-0301 in subjects with active CD.  Efficacy will 
be based on clinical activity, as measured by the Crohn’s Disease Activity Index (CDAI) or 
average daily liquid or stool frequency and abdominal pain score, and endoscopic outcomes, as 
measured by the SES-CD.  Crohn’s Disease Activity Index, the current standard for evaluation of 
clinical disease activity, is a validated, reproducible and responsive measure of CD that has been 
widely used in clinical trials for approximately 35 years. 
 
 
  The SES-CD is a validated endoscopic index that is 
considered the most suitable endoscopic outcome measure due to its ease of use and close 
correlation with the Crohn’s Disease Endoscopic Index of Severity (CDEIS), considered the gold 
standard for endoscopic evaluation.
The primary efficacy measure will be clinical remission (defined as a CDAI score < 150) during 
the Treatment Phase at Week 12.  Key secondary efficacy measures will include: clinical 
remission at Week 52; endoscopic response-50 ([ER-50], defined as a reduction of at least 50% 
compared with baseline in SES-CD) at Week 52; clinical response (defined as a decrease from 
baseline in CDAI ≥ 100 points) at Week 12; 
 
 steroid-free clinical remission at Week 52; sustained clinical remission at both Week 12 
and Week 52; endoscopic response-25 ([ER-25], defined as a reduction of at least 25% compared 
with baseline in SES-CD) at Week 12; and the evaluation of endoscopic remission (defined as 
SES-CD ≤2) at Week 52. 
 
 
Laboratory evaluations, AEs, vital signs, electrocardiograms (ECGs), pregnancy tests and 
physical examinations will be monitored during the study to evaluate safety.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
24
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
Three oral dose regimens of GED-0301 versus placebo are being evaluated for the treatment of 
subjects with active CD:
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit.
The doses and dose regimens for this study were selected based on pre-clinical data and clinical 
data from the Phase 1 study 
 and the Phase 2 dose-finding study 
 in subjects with active CD. 
The key considerations for the selection of the appropriate dose and dosing regimens were:
1. the very low systemic exposure in animals without signs of toxicity when given orally in 
doses at least 10 times higher, by body weight, than the proposed GED-0301 160 mg QD 
dose in humans;
2. the negligible systemic exposure of GED-0301 in humans;
3. the demonstrated efficacy of GED-0301 in Phase 1 and Phase 2 studies;
4. the similar safety profile of the various GED-0301 dose treatment groups in Study 
; comparable numbers and types of TEAEs across all treatment groups, 
including the placebo treatment group were observed, with few SAEs or AEs leading to 
discontinuation of IP.
Study 
 demonstrated GED-0301 40 mg QD and 160 mg QD to be efficacious 
and safe after 2 weeks of treatment in subjects with steroid dependent or refractory CD.  
 
 
 
 
  
Therefore, these data, in addition to the similar and favorable safety profiles of GED-0301 40 mg 
QD and 160 mg QD, provide supportive evidence for the selection of 160 mg QD as the initial 
dose of GED-0301 for a 12-week treatment induction of clinical remission and endoscopic 
response
 
.  The 12-week duration was selected in order to optimize therapeutic benefit, since it is 
expected that it would take a longer duration of treatment to achieve endoscopic benefit, such as 
endoscopic response, than to achieve clinical signs and symptoms benefit or clinical remission, 
in a moderate to severe CD population.  Also, there is no consensus about the appropriate timing 
to assess the endoscopy evaluation, ranging from 10 to 26 weeks in different clinical studies 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
25
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
(Dave, 2012).  In addition, endoscopic assessments at time points later than 12 weeks in placebo-
controlled studies have posed the problem of limited comparative data due to the low number of 
placebo subjects remaining beyond the 12-week time point.  Hence, the 12-week time point was 
selected for the endoscopic endpoint in this study.
Three active dosing regimens will be evaluated following the initial 12-week treatment with 
GED-0301 160 mg QD, in which two different doses (160 mg QD and 40 mg QD) and different 
dosing schedules (continuous and alternating) will be evaluated in order to determine dose and 
dosing regimen that provides the best benefit to risk for subjects with active CD.
Two doses, 160 mg QD and 40 mg QD, were selected to be evaluated after the initial 160 mg 
QD 12-week treatment since the 160 mg QD dose is expected to provide the highest level of 
efficacy, and the 40 mg QD dose is the lowest efficacious dose, which has been demonstrated in 
subjects with active CD 
.  This is clinically pertinent, since subjects 
who achieve clinical response or clinical remission after the initial 12-week treatment may 
require a lower dose than that initially needed for the treatment of moderate to severe CD.
Three different dosing regimens will be evaluated: one continuous dosing regimen (GED-0301 
40 mg QD) and two alternating dosing regimens (GED-0301 40 mg QD for 4 weeks on/4 weeks 
off and GED-0301 160 mg QD for 4 weeks on/4 weeks off).  Consequently, these 3 different 
dosing regimen strategies correspond to incremental increases of 2-fold differences between each 
of the 3 arms in total IP exposure during the 40-week long-term maintenance treatment.  The 
alternating dosing regimen is supported by findings from Study 
, in which after 
2 weeks of dosing, the majority of subjects had a prolonged clinical improvement up to Week 12, 
suggesting that patients may not need continuous dosing.  This strategy may be more 
advantageous for longer term treatment in patients with CD, including the potential for a more 
favorable benefit to risk profile than a continuous dosing regimen.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
26
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of GED-0301 compared with placebo on 
clinical activity at Week 12 in subjects with active Crohn’s disease (CD).
Secondary Objectives
The secondary objectives are: 
!
To evaluate the efficacy of GED-0301 compared with placebo on endoscopic outcomes in 
subjects with active CD;
!
To evaluate the long-term efficacy of GED-0301 compared with placebo on clinical activity in 
subjects with active CD;
!
To evaluate the efficacy of GED-0301 compared with placebo on corticosteroid-free clinical 
remission in subjects with active CD;
!
To evaluate the safety and tolerability of GED-0301 in subjects with active CD.
 
 
 
 
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Efficacy
(Clinical 
remission)
The proportion of subjects achieving clinical remission,
defined as a CDAI score < 150, at Week 12
Week 12
Secondary
Efficacy
The proportion of subjects achieving clinical 
remission, defined as a CDAI score < 150, at Week 
52 
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352


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
27
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Efficacy
The proportion of subjects with endoscopic response-
50 (ER-50), defined as a reduction of at least 50% in 
the SES-CD compared with baseline, at Week 52
Week 52
Efficacy
The proportion of subjects who have a clinical response,
defined as a decrease from baseline in CDAI ≥ 100 points,
at Week 12
Week 12
 
 
Efficacy
The proportion of subjects who achieve corticosteroid-free 
clinical remission (CDAI <150) at Week 52 among 
subjects receiving oral corticosteroids for CD at baseline 
Week 52
Efficacy
The proportion of subjects achieving sustained clinical 
remission, defined as a CDAI score < 150 at both Week 
12 and Week 52 
Week 12 and 
Week 52
Efficacy
The proportion of subjects with endoscopic response-25 
(ER-25), defined as a reduction of at least 25% from 
baseline in SES-CD, at Week 12 
Week 12
Efficacy
The proportion of subjects with endoscopic remission, 
defined as SES-CD ≤ 2, at Week 52
Week 52
Safety
Type, frequency, severity, seriousness, and relationship of 
AEs to IP
Through 
Week 52
Safety
Number of subjects who discontinue IP due to any AE
Through 
Week 52
Safety
Clinically significant changes in vital signs, ECGs, and/or 
laboratory findings
Through 
Week 52
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
28
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
29
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; CD = Crohn’s disease; CDAI = Crohn's Disease Activity Index; ECG = electrocardiogram; 
IP = investigational product;
 
; SES-CD = Simple Endoscopic Score for Crohn's disease
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352


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
30
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of 3 treatment regimens of oral GED-0301 versus placebo in subjects 
with active CD (defined by a CDAI score ≥ 220 and ≤ 450 and a total SES-CD ≥ 6 at screening, 
or the ileum segmental SES-CD ≥ 4 at screening). Approximately 1064 subjects will be 
randomized in a 1:1:1:1 ratio (266 subjects per GED-0301 arm [total 798]; 266 subjects in the 
placebo arm) to receive 1 of 3 double-blind, oral GED-0301 treatment regimens, or identically 
appearing placebo once daily (QD) for 52 weeks. The total number of subjects with a total SES-
CD score ≥ 6 is targeted to comprise approximately 80% of the study population.
Treatment assignment at baseline (Week 0/ Visit 2) will be stratified via an Interactive Web 
Response System (IWRS) based on concomitant use of corticosteroids (yes/no); concomitant use 
of immunosuppressants (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate 
[MTX]) (yes/no), and previous exposure to biologics (ie, infliximab, adalimumab, certolizumab 
or vedolizumab) (yes/no).  The total number of subjects with previous exposure to biologics is 
targeted to comprise approximately 35% of the study population.
Subjects will receive double-blind, oral GED-0301 or identically appearing placebo QD as 
follows (Table 4):
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
the Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit;
!
Placebo QD until the Week 52 Visit.
Subjects who complete the GED-0301-CD-002 study at the Week 52 Visit may enter the Long-
term Active-treatment Study (GED-0301-CD-004). Subjects who meet the criteria for early 
escape beginning at the Week 12 Visit and thereafter until the Week 52 Visit, may (a) continue 
in the study at the discretion of the Investigator based on the totality of clinical data, (b) enter the 
Long-term Active-treatment Study (GED-0301-CD-004), or (c) discontinue the study.
The criteria for early escape are defined as 
 
(Table 7).
Subjects may discontinue the study at any time. Subjects who discontinue from the study at 
Week 12 (either because they meet the early escape criteria or for any other reason), will 
complete the Week 12 Visit. Subjects who prematurely discontinue from the study at any other 
time prior to the Week 52 Visit, including subjects who early escape into the Long-term Active-
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
31
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
treatment Study, will complete the Early Termination Visit (Section 6.3). The ET Visit should be 
scheduled as soon as possible after the last dose of IP. 
Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from 
the study, will have a 4-week Follow-up Visit. If the ET Visit occurs 28 days or more after the 
last dose of IP, then the Follow-up Visit is not required. 
Subjects entering the Long-term Extension Study will not have the Follow-up Visit. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs) and applicable regulatory requirements.
&(/*(1(35235,(7$5<,1)250$7,21
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
32
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Figure 1:
Overall Study Design
IP = Investigational Product; QD = once daily
Subjects who complete the GED-0301-CD-002 study at the Week 52 Visit may enter the Long-term Active-treatment Study (GED-0301-CD-004). Subjects who 
meet the criteria for early escape beginning at the Week 12 Visit and thereafter until the Week 52 Visit, may (a) continue in the study at the discretion of the 
Investigator based on the totality of clinical data, (b) enter the Long-term Active-treatment Study (GED-0301-CD-004), or (c) discontinue the study. The criteria 
for early escape are defined in Table 7. Subjects who discontinue from the study at Week 12 (either because they meet the early escape criteria or for any other 
reason) will complete the Week 12 Visit. Subjects who prematurely discontinue from the study at any other time prior to the Week 52 Visit, including subjects 
who early escape into the Long-term Active-treatment Study (GED-0301-CD-004), will complete the Early Termination (ET) Visit (Section 6.3). 
Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from the study, will have a 4-week Follow-up Visit. If the ET Visit 
occurs ≥28 days after the last dose of investigational product (IP), then the Follow-up Visit is not required. Subjects entering the Long-term Extension Study will 
not have the Follow-up Visit.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
33
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
3.1.1.
Study Duration for Subjects 
Subjects will spend up to 60 weeks in this study: up to 4 weeks in the Screening Period;
52 weeks in the Double-blind Treatment Period; and 4 weeks in the Follow-up Period.
3.1.2.
Early Termination Visit
The Early Termination Visit is based on the subject’s withdrawal from the study prior to the 
Week 52 Visit, with the exception of the Week 12 Visit (whereby the subject will complete the 
Week 12 Visit). This includes subjects who early escape into the Long-term Active-treatment 
Study after Week 12. In addition, the Investigator may discontinue the subject from the study at 
any time based on his/her assessment of clinical efficacy and/or safety. The decision to 
discontinue a subject remains the responsibility of the treating physician, and will not be delayed
or refused by the sponsor. When a subject withdraws or is discontinued from the study, every 
effort should be made to complete as many safety and efficacy assessments as reasonably 
appropriate.  Refer to the Table of Events (Table 3) for the assessments to be performed at the 
ET Visit. The ET Visit should be scheduled as soon as possible after the decision is made to 
permanently discontinue study treatment.
3.1.3.
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 
electronic case report form (eCRF).
3.2.
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 and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study completion for an individual subject is defined as reaching the Week 52 Visit.  Subjects not 
meeting this definition will be considered early termination subjects.  Subjects who discontinue 
from the study at Week 12 (either because they meet the early escape criteria or for any other 
reason) will complete the Week 12 Visit. Subjects who prematurely discontinue from the study 
at any other time prior to the Week 52 Visit, including subjects who early escape into the Long-
term Active-treatment Study, will complete the Early Termination (ET) Visit (Section 6.3). The 
ET Visit should be scheduled as soon as possible after the last dose of IP. 
Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from 
the study and do not enter into the Long-term Active-treatment Study, will have a 4-week 
Follow-up Visit. If the ET Visit occurs 28 days or more after the last dose of IP, then the Follow-
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
34
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
up Visit is not required. Subjects entering the Long-term Extension Study will not have the 
Follow-up Visit. 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
35
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 1064 subjects with active CD will be enrolled worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is a male or female ≥ 18 years at the time of signing the informed consent form 
(ICF).
2. Subject must understand and voluntarily sign an ICF prior to conducting any study-
related assessments/procedures. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject must have a diagnosis of CD with a duration of at least 3 months prior to the 
Screening Visit.
5. Subject must have ileitis, ileocolitis or colitis, as determined by ileocolonoscopy during
screening.
6. Subject must have active CD disease, defined as a CDAI score ≥ 220 and ≤ 450 at 
screening.
7. Subject must have a 7-day average stool frequency ≥3.5 or abdominal pain ≥ 1.5 at 
screening.
8. Subject must have a total SES-CD ≥ 6 at screening, or the ileum segmental SES-CD ≥ 4 
at screening.
9. Subject must have failed or experienced intolerance to at least one of the following: 
budesonide; systemic corticosteroids; immunosuppressants (eg, AZA, 6-MP, or MTX); or 
biologics for the treatment of CD (ie, infliximab, adalimumab, certolizumab or 
vedolizumab). (See Appendix H for details.)
10. Subject must meet the following laboratory criteria
a.
White blood cell count ≥ 3000/mm3 (≥3.0 x 109/L)
b. Platelet count ≥100,000/mm3 (≥100 x 109/L)
c.
Serum creatinine ≤1.5 mg/dL (≤132.6 μmol/L)
d. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT) ≤2.5 x upper limit of normal (ULN)
e.
Total bilirubin ≤ 2 mg/dL (34 μmol/L), unless the subject has a confirmed 
diagnosis of Gilbert’s Disease
f.
Hemoglobin ≥ 8 g/dL (≥ 4.97 mmol/L)
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
36
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
g. Activated partial thromboplastin time (APTT) ∀1.5 x ULN
11. Females of childbearing potential (FCBP)1 must have a negative pregnancy test at the 
Screening and Baseline Visits.  While on IP and for at least 28 days after taking the last 
dose of IP, FCBP who engage in activity in which conception is possible must use one of 
the approved contraceptive options described below: 
Option 1:  Any one of the following highly effective methods:  hormonal 
contraception (oral2, 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
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a diagnosis of ulcerative colitis (UC), indeterminate colitis, ischemic colitis, 
microscopic colitis, radiation colitis or diverticular disease-associated colitis.
2. Subject has local manifestations of CD such as abscesses, short bowel syndrome, or 
other disease complications for which surgery might be indicated or could confound the 
evaluation of efficacy.
3. Subject had any intestinal resection within 6 months or any intra-abdominal surgery 
within 3 months prior to the Screening Visit.
4. Subject has an ileostomy or a colostomy.
5. Subject had prior treatment with mycophenolic acid, tacrolimus, sirolimus, cyclosporine, 
thalidomide or apheresis (eg, Adacolumn®) within 8 weeks prior to the Screening Visit.
6. Subject has received IV corticosteroids within 2 weeks prior to the Screening Visit.
7. Subject has changed or discontinued the dose of oral aminosalicylates within 2 weeks 
prior to the Screening Visit.
8. Subject has changed or discontinued the dose of oral corticosteroids (prednisone ≤ 20 
mg/day or equivalent, budesonide ≤ 9 mg/day) within 3 weeks prior to the Screening 
Visit.
                                               
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 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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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
37
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
9. Subject has initiated immunosuppressants (eg, AZA, 6-MP, or MTX) within 12 weeks 
prior to the Screening Visit and has changed or discontinued the dose of 
immunosuppressants within 8 weeks prior to the Screening Visit.
10. Subject has received topical GI treatments, such as, 5-aminosalicylic acid (5-ASA) or 
corticosteroid enemas or suppositories within 2 weeks prior to the Screening Visit.
11. Subject has received bile acid sequestrants (eg, cholestyramine) within 3 weeks prior to 
the Screening Visit.
12. Subject has changed or discontinued antibiotics used for the treatment of CD (eg, 
ciprofloxacin, metronidazole), within 2 weeks prior to the Screening Visit.
13. Subject had prior treatment with more than 3 biologics for the treatment of CD (ie, 
infliximab, adalimumab, certolizumab or vedolizumab).
14. Subject had treatment with a biologic within 8 weeks or 5 elimination half lives,
whichever is longer, prior to the Screening Visit. (See Table 8 for elimination half-life 
timeframes of biologics.)
15. Subject has received total parenteral nutrition within 4 weeks prior to the Screening
Visit.
16. Subject has evidence of enteric infection or Clostridium (C.) difficile toxin at the 
Screening Visit.
17. Subject has a history of any clinically significant neurological, renal, hepatic, 
gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, 
hematological disorder or disease, or any other medical condition that, in the 
Investigator's opinion, would prevent the subject from participating in the study.
18. Subject has any condition, including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she was to participate in the study or 
confounds the ability to interpret data from the study.
19. Subject is pregnant or breastfeeding. 
20. Subject has a history of any of the following cardiac conditions within 6 months prior to 
the Screening Visit and at any time during the Screening Period, up through the first 
dose of IP:  myocardial infarction, acute coronary syndrome, unstable angina, new onset 
atrial fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, 
ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, 
interventional cardiac catheterization (with or without a stent placement), interventional 
electrophysiology procedure, or presence of implanted defibrillator.
21. Subject has a known active current or history of clinically significant bacterial, viral, 
fungal, or other infections, or any major episode of infection requiring hospitalization or 
treatment with IV antibiotics within 4 weeks prior to the Screening Visit and at any time 
during the Screening Period, up through the first dose of IP.
22. Subject has a history of congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency disease).
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
38
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
23. Subject has a history of colorectal cancer or a confirmed diagnosis of colorectal 
dysplasia (with the exception of adenomatous colonic polyps that have been completely 
resected).
24. Subject has a history of malignancy, except for:
a.
Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas
b. Treated (ie, cured) carcinoma in situ of the cervix that has been treated at least 5 
years prior to the Screening Visit
Note: History of treated (ie, cured) cancer >10 years before the Screening Visit and 
without recurrence can be considered based on the nature of the cancer and must be 
discussed with the sponsor on a case-by-case basis.
25. Subject has received any investigational drug or device within 1 month or 5 elimination 
half-lives, whichever is longer, prior to the Screening Visit.
26. Subject has a history of alcohol, drug, or chemical abuse within the 6 months prior to the 
Screening Visit.
27. Subject has a known hypersensitivity to oligonucleotides or any ingredient in the IP.
28. Subject has received prior treatment with GED-0301, or participated in a clinical study 
involving GED-0301.
29. Subject has strictures with prestenotic dilatation, requiring procedural intervention, or 
with obstructive symptoms. In addition, subjects with colonic strictures that are not 
passable with an adult colonoscope, or strictures in the ileum or ileocecal valve that are 
fibrotic in nature, will be excluded.
30. Subject had prior treatment with biologics for the treatment of CD (approved or 
investigational), other than infliximab, adalimumab, certolizumab or vedolizumab.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
39
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
5.
TABLE OF EVENTS
Table 3:
Table of Events
Screeni
ng 
Period
Double-blind Treatment Period
Follow-
up 
Period
Visit Number
1
Screeni
ng
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
a
16b
Week
-4
0
4
8
12c
16
20
24
28
32
36
40
44
48
52d
NA
Follow-
up
(Visit Window)
28 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)
(± 3 
days)
NA
4 weeks
after the 
last dose 
of IP (± 
3 days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion Criteria
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior / Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior / Concomitant Procedures
X
X
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
X
X
Pregnancy Teste
X
X
-
-
X
-
-
-
-
-
-
-
-
-
X
X
X
Contraception Educationf
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Vital Signs / Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Complete Physical Exam
X
-
-
-
X
-
-
-
-
-
-
-
-
-
X
X
-
Limited Physical Exam
-
X
-
-
-
-
-
X
-
-
X
-
-
-
-
-
X
12-lead ECG
X
-
-
-
X
-
-
-
-
-
-
-
-
-
X
X
-
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
40
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 3:
Table of Events (Continued)
Screening 
Period
Double-blind Treatment Period
Follow
-up 
Period
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
a
16b
Week
-4
0
4
8
12c
16
20
24
28
32
36
40
44
48
52d
NA
Follow
-up
(Visit Window)
28 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)
(± 3 
days)
NA
4 weeks 
after 
the last 
dose of 
IP (± 3 
days)
Stool Assessment 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Clinical Lab (Hematology) g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Lab (Coagulation) g
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
X
X
Clinical Lab (Chemistry) g
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
X
X
Clinical Lab (Urinalysis)g
X
X
-
-
X
-
X
-
X
-
X
-
X
-
X
X
X
Efficacy Assessments
Subject Diaryh
Instruct use of electronic 
device/assess compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDAIi
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ileocolonoscopyj
X
-
-
-
X
-
-
-
-
-
-
-
-
-
X
X
-
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 3:
Table of Events (Continued)
Screening 
Period
Double-blind Treatment Period
Follow
-up 
Period
Visit Number
1
Screening
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
a
16b
Week
-4
0
4
8
12c
16
20
24
28
32
36
40
44
48
52d
NA
Follow
-up
(Visit Window)
28 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)
(± 3 
days)
NA
4 weeks 
after 
the last 
dose of 
IP (± 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
X 
CDAI = Crohn’s Disease Activity Index; ECG = Electrocardiogram; ET = Early Termination Visit; 
; FCBP = 
females of childbearing potential; 
 
; IP = investigational product; NA = not applicable; 
; Sc= Screening; 
 
;  V1 = Visit 1; 
a Subjects who prematurely discontinue from the study at any time other than the Week 12 Visit and prior to the last scheduled study visit, including subjects who enter the Long-
term Active-treatment Study (GED-0301-CD-004), will complete the Early Termination (ET) Visit (Section 6.3). The ET Visit should be completed as soon as possible after the 
decision is made to permanently discontinue the study treatment. Subjects who discontinue from the study at Week 12 will complete the Week 12 Visit.
b Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from the study, will have a 4-week Follow-up Visit (Section 6.4). If the ET Visit 
occurs ≥28 days after the last dose of IP, then the Follow-up Visit is not required. Subjects entering the Long-term Extension Study will not have the Follow-up Visit. 
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EDMS Doc. Number: 
GED-0301
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Celgene Corporation
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
c At the Week 12 Visit and thereafter, until the Week 52 Visit, subjects 
 
, will be eligible to early escape into the Long-term Active-treatment Study (GED-0301-CD-
004), or may discontinue from the study.  In order to be considered for the early escape at
. Due to the delay 
in receiving the hematocrit sample results, beginning at the Week 12 Visit, and throughout the remainder of the study, the CDAI score will be evaluated by the site using the 
hematocrit results from the previous visit.
d Subjects who complete the GED-0301-CD-002 study at the Week 52 Visit, will have the option to enter the Long-term Active-treatment Study. Subjects entering the Long-term 
Extension Study will not have the Follow-up Visit.
e Pregnancy testing will be performed for FCBPs. Serum pregnancy tests will be performed at screening and urine pregnancy will be done at the remaining visits as described in 
Table 3.
f Contraception education is for Females of Child Bearing Potential (FCBP).  The Investigator will educate all FCBP about the different options of contraceptive methods and 
their correct use at Screening and Baseline Visits.  The subject will be re-educated every time her contraceptive measures/methods or ability to become pregnant changes.  The 
female subject's chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be 
initiated at least 28 days before baseline).
g Details pertaining to clinical labs are provided in Section 6.5.3.
h The electronic Subject Daily Diary (Section 6.6.1) will be provided to subjects at the Screening Visit.  Subject compliance with the completion of diary data should be assessed 
at each study visit during the Screening and Double-blind Treatment Period.
i The screening CDAI (Section 6.6.2) will be based on the Subject Daily Diary data collected during the Screening Period. Note that an abdominal exam is needed for CDAI 
assessment.
 
j The screening ileocolonoscopy should be performed following confirmation of the subject’s eligibility, based on the CDAI score.  Follow-up ileocolonoscopies will be done at 
Week 12 and Week 52 (Section 6.6.5).  The ET ileocolonoscopy will not be repeated if performed within 8 weeks of the previous ileocolonoscopy.
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EDMS Doc. Number: 
GED-0301
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
6.
PROCEDURES
The following procedures/assessments will be conducted according to the schedule indicated in 
the Table of Events (Table 3).
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 
randomization) unless noted otherwise below. Subjects may be allowed to re-screen with 
approval from the sponsor or designee.
6.1.1.
Screening Visit
The following assessments will be performed at the Screening Visit as specified in Table 3, after 
informed consent has been obtained: 
!
Demographics including initials, date of birth, sex, race, and ethnicity-if allowed by 
local regulations
!
Complete medical history including all relevant medical conditions diagnosed, and 
occurring prior to the Screening Visit, should be recorded.
!
Prior and concomitant procedures including all procedures occurring ≤ 30 days before 
the Screening Visit
!
Prior and concomitant medication evaluation including all medications (prescription 
and nonprescription, including vitamins) taken by the subject up to ≤ 30 days prior to 
the Screening Visit should be recorded. All medications taken by the subject at any 
time during the study must also be recorded. Other key medications and therapies, 
such as previous treatment for tuberculosis or relevant diseases, should also be 
recorded.
!
Prior and concomitant CD medications taken by the subject and CD-related 
procedures performed, at any time prior to and during the study, should be recorded, 
including the stop dates for medications prohibited in the study.
!
Adverse event 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. Refer to Section 10 for details pertaining to AEs.
!
Pregnancy test is required for all female subjects of childbearing potential.  Serum 
beta human chorionic gonadotropin β-hCG pregnancy test will be performed at the 
Screening Visit. 
!
Contraception education (Section 6.5.6)
!
Vital signs including blood pressure, temperature, and heart rate
!
Height and weight will be measured and recorded at screening; weight is to be done 
in street clothes, no shoes
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
!
Complete physical examination (Section 6.5.1)
!
12-lead electrocardiogram (ECG) (Section 6.5.2)
!
Stool culture analysis and assessment of Clostridium (C.) difficile toxin will be 
performed at the Screening Visit. Subjects with stool that is positive for any enteric 
pathogen or C. difficile toxin at the Screening Visit will be excluded from the 
study. Subjects who are initially positive for C. difficile toxin may re-screen for the 
study 8 weeks after the start of therapy, provided that the toxin results for C. difficile
are negative (Section 6.5.4).
!
Clinical laboratory evaluations will be performed by a central laboratory and are 
described below.  Subject eligibility and clinical laboratory criteria are provided in 
Section 4.2.  One laboratory re-test is allowed after obtaining Medical Monitor
approval during the Screening Period. Details pertaining to the central laboratory 
assessments and panels are included in Section 6.5.3:
#
Hematology panel 
#
Chemistry panel 
#
Coagulation: prothrombin time (PT), activated partial thromboplastin time 
(APTT) 
#
Urinalysis (dipstick)
o
Microscopic urinalysis (epithelial cells, red blood cells [RBC], white blood 
cells [WBC], crystals, bacteria, and casts) will be performed only if the 
dipstick urinalysis is abnormal.
!
Subject Daily Diary (Section 6.6.1)
#
The electronic device to record the Subject Daily Diary 
 will be provided 
to subjects at the Screening Visit.  Subjects should enter diary data continuously 
throughout the study.  
!
Subjects will receive instructions pertaining to the use of the electronic device and the 
importance of diary compliance throughout the study.
#
Diary compliance must be assessed throughout the study.
During the Screening Period, the following assessments and procedures will be performed 
following the Screening Visit and prior to study randomization as specified in the Table of 
Events (Table 3):
!
To be eligible for the study, the subject must have a 7-day average stool frequency 
score ≥3.5 or a 7-day average an abdominal pain score ≥ 1.5 extracted from the 
subject daily diary, during the Screening Period.
!
CDAI score (Section 6.6.2)
#
The CDAI score is a key efficacy assessment in this study and will also be used to 
determine study eligibility. The subject self-assessment questionnaire items that 
are included in the CDAI scoring will be extracted from the Subject Daily Diary.
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sco


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
#
The screening CDAI score will be based on subject diaries collected during the 
Screening Period.  If the screening CDAI score is ≥220 and ≤ 450, the subject will 
proceed with the screening endoscopy.
!
Ileocolonoscopy is the type of endoscopy being performed during this study
(Section 6.6.5) and the SES-CD is the instrument being used to assess endoscopy 
(Section 6.6.6).
#
The screening endoscopy should be performed after confirmation of a qualifying 
CDAI score and a qualifying 7-day average of stool frequency or abdominal pain. 
#
The SES-CD is a key efficacy assessment based on endoscopic evaluation.
During the study, the SES-CD will be evaluated by both the Investigator and by a 
central reader blinded to study treatment. The SES-CD score from the central 
reader will be used to determine study eligibility:

Subjects with a SES-CD ≥6 at screening, or the ileum segmental SES-CD 
≥ 4 at screening, will be eligible for study randomization;

Subjects will be randomized upon notification of the qualifying SES-CD.
-
For subjects who will be re-screened, endoscopies performed as part of the 
original screening period, within 30 days prior to the re-screen date, and reviewed 
by a central reader, may be used to determine eligibility.
6.2.
Double-blind Treatment Period
The subject will begin study treatment upon confirmation of eligibility. For all subsequent visits
in the Double-blind Treatment Period, an administrative window of ± 3 days is permitted.  The
following evaluations will be performed at the frequency specified in Table 3. The evaluations 
should be performed prior to dosing on the visit day, unless otherwise specified.
!
Prior and concomitant procedures
!
Prior and concomitant medications
!
AE evaluation (continuously assessed)
!
Electrocardiogram at the Week 12 and Week 52 Visits
!
Contraception education (Section 6.5.6) at the Baseline Visit (Visit 2)
!
A local urine pregnancy test will be performed on all FCBP. 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.
!
Vital signs and weight
!
Complete physical examination (Section 6.5.1) at the Week 12 and Week 52 Visits 
!
Limited physical examination (Section 6.5.1) at the Baseline Visit, Week 24, and 
Week 36 Visits
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
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46
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
!
An abdominal examination to assess for the presence of an abdominal mass for the 
CDAI calculation will be performed at every visit. (Section 6.5.1)
!
Clinical laboratory evaluations
!
Subject Daily Diary Assessment 
!
CDAI assessment
#
Due to the delay in receiving the hematocrit sample results, beginning at the
Week 12 Visit and thereafter until the Week 52 Visit, the CDAI score will be 
evaluated by the site using the hematocrit results from the previous visit.
!
Ileocolonoscopy for SES-CD should be performed within the Visit window at Week 
12 and Week 52.
 
!
Dispense IP: The Principal Investigator (PI), Sub-investigator (Sub-I), or Study 
Coordinator (SC) should make an effort to witness subjects taking their first dose and 
record the date and time in the source document record.  The IP (four tablets) should 
be taken QD by the subjects.  Subjects will be instructed to take the IP 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.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
47
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
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 3 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
An Early Termination (ET) evaluation will be performed for subjects who are withdrawn from 
study treatment for any reason at any time other than the Week 12 Visit, including subjects who 
early escape into the Long-term Active-treatment Study, as soon as possible after the decision to 
permanently discontinue study treatment has been made. (Subjects who discontinue from study 
treatment at Week 12 will complete the Week 12 Visit.)
The following evaluations will be performed as specified in Table 3:
!
Prior and concomitant procedures
!
Prior and concomitant medications
!
AE evaluation (continuously assessed)
!
12-lead ECG
!
A urine pregnancy test will be performed on all FCBP 
!
Vital signs and weight
!
Complete physical examination 
!
Clinical laboratory evaluations 
!
Subject Daily Diary Assessment 
!
CDAI assessment 
!
Ileocolonoscopy (if not already done within 8 weeks of the previous colonoscopy)
!
Return and count IP 
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EDMS Doc. Number: 
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Celgene Corporation
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6.4.
Follow-up Period 
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as 
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 complete the Week 52 Visit, as well as subjects who prematurely discontinue from 
the study, will have a 4-week Follow-up Visit. If the ET Visit occurs 28 days or more after the 
last dose of IP, then the Follow-up Visit is not required. 
Subjects entering the Long-term Extension Study will not have the Follow-up Visit. 
The following evaluations will be performed at Follow-up Visit:
!
Prior and concomitant procedures
!
Prior and concomitant medications
!
AE evaluation  
!
Vital signs and weight
!
A urine pregnancy test will be performed on all FCBP  
!
Limited physical examination
!
Clinical laboratory evaluations
!
Subject Daily Diary assessment
!
CDAI assessment
6.5.
Safety Assessments
6.5.1.
Physical Examination
A complete physical examination will include evaluation of the skin, nasal cavities, eyes, ears, 
abdomen, and respiratory, cardiovascular, 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, abdomen, and respiratory, 
cardiovascular, 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 
 calculations.
6.5.2.
Electrocardiogram
Subjects will have a 12-lead electrocardiogram (ECG) at the frequency specified in Table 3. 
Sites are to use 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. 
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EDMS Doc. Number: 
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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 3:
!
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, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, 
lactic dehydrogenase (LDH), magnesium, and complement activation (Bb, C3a and 
C5a).
!
Coagulation assessment will include: prothrombin time (PT) and activated partial 
thromboplastin time (APTT)
!
Urinalysis will be done at the central lab and will include specific gravity, pH, 
glucose, ketones, protein, blood, bilirubin, leukocyte esterase, nitrite, and 
urobilinogen. 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 lab requisition form.
In subjects who develop new changes in liver function tests (eg, ALT or AST > 2 x the upper 
limit of normal [ULN], or Total Bilirubin [TBL] > 1.5 x ULN with normal baseline values, or    
≥ 2 x the baseline values in subjects with abnormal baseline values), repeat testing should be 
performed within 48 to 72 hours. If abnormalities persist, subjects should be evaluated for causes 
of new elevations in ALT/AST or TBL (including but not limited to tests for hepatitis, liver 
imaging, history of Gilbert’s syndrome). If there are persistent elevations in ALT or AST and/or 
TBL then close observation (including laboratory testing as appropriate) should be initiated and 
treatment could be temporarily interrupted or discontinued. Discontinuation or temporary 
interruption of study treatment should occur when criteria delineated in Appendix O are met. 
After treatment discontinuation or interruption, assessments should continue until a return of 
aminotransferases and/or TBL to normal or baseline levels, or until alternative explanation for 
the abnormal liver function tests (LFTs) is found.  
6.5.4.
Stool Assessment
Stool culture analysis and assessment of Clostridium (C.) difficile toxin will be performed at the 
Screening Visit. Subjects who are stool positive for any enteric pathogen or 
C. difficile toxin at the Screening Visit, will be excluded from the study. Subjects who are 
initially positive for C. difficile toxin may re-screen for the study 8 weeks after the start of
therapy, provided that the toxin results for C. difficile are negative.
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creen
creen


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
50
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
6.5.5.
Clinically Significant Abnormal Findings
Clinically significant abnormal findings (clinical laboratory assessments, physical examination, 
ECG), with exception to the disease under study (CD), identified prior to first dose of IP will be 
recorded on the eCRF as medical history; clinically significant findings after the first dose of IP 
will be recorded as AEs.
6.5.6.
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 
contraceptive methods and their correct use at the Screening and Baseline Visits.  The subject 
will be re-educated every time her contraceptive measures/methods or ability to become pregnant 
changes. The female subject's chosen form of contraception must be effective by the time the 
female subject is randomized into the study (for example, hormonal contraception should be 
initiated at least 28 days before baseline). 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.
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 1 
of the approved contraceptive options as described in the eligibility criteria 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 a subject’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. 
6.6.
Efficacy Assessments 
6.6.1.
Subject Daily Diary
During the Screening Visit, an electronic subject diary device will be given to each subject. The 
subject 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 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 should enter diary data, each day, 
continuously throughout the study.  Site personnel must also assess the subject’s compliance 
with reporting of the daily diary data entries throughout the study.
The daily diary data will be extracted from the electronic devices and used for calculation of the 
CDAI 
 efficacy parameters.  
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: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
51
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
!
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 D) 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, and severe disease is defined as a CDAI score > 450.  
Remission is defined as a CDAI score < 150.
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 arthralgias
!
Iritis/uveitis
!
Erythema nodosum, pyoderma gangrenosum, or aphthous ulcers 
!
Anal fissures, fistulae, 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 kg] / [standard weight in kg]) x 100%
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
52
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
  
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
53
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
 
 
 
 
6.6.5.
Ileocolonoscopy 
All eligible subjects are required to have ileocolonoscopies performed during the Screening 
Period, Week 12, and Week 52. The screening ileocolonoscopy should be performed if the 
subject’s screening CDAI score is ≥ 220 and ≤ 450.  
Subjects who discontinue from the study prior to the Week 52 Visit, will have the 
ileocolonoscopy done at the ET Visit, if an ileocolonoscopy has not been performed within 8
weeks of the previous ileocolonoscopy.  
Video images of all endoscopic procedures will be captured and sent to a qualified centralized 
reader for calculation of the SES-CD to assess subject eligibility at screening, and to assess 
efficacy at Weeks 12 and 52.  Additionally, the local SES-CD will be collected from the 
investigational sites.  The site will receive a central reader SES-CD report during the Screening 
Period to determine if the SES-CD inclusion criterion is met.
For subjects at increased risk for colorectal cancer, pan-colonic surveillance with colonoscopy 
and biopsies should be done according to local guidelines.
6.6.6.
Simple Endoscopic Score for CD
The SES-CD (Appendix E) is a validated endoscopic index that closely correlates with the
Crohn’s Disease Endoscopic Index of Severity 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).
6.7.
Corticosteroid Tapering Procedure
Subjects are eligible to start corticosteroid tapering beginning at the Week 12 Visit, 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.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
54
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
55
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
56
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
57
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
 
 
 
 


EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
58
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
GED-0301 will be provided as 40-mg film coated tablets. Placebo will be provided as identically 
appearing tablets.
7.2.
Treatment Administration and Schedule
Subjects will receive GED-0301(160 mg QD) or placebo during the first 12 weeks of the study, 
followed by one of 3 dose regimens of GED-0301 (40 mg QD or 160 mg QD) or placebo QD, 
until the end of the study (Week 52 Visit).  All subjects will receive 4 tablets daily during the 
Double-blind Treatment Period.  Matched placebo tablets will also be provided.  Subjects will be 
instructed to take the IP in the morning, 30 minutes before breakfast, with a glass of water. 
Treatment and administration schedule are described in Table 4.
Subjects who consent to participate in the PK substudy will be instructed to bring their IP to the 
study site where it must be administered after the collection of the predose PK blood 
sample. When the subject is providing a predose blood draw on the day of a PK substudy visit, 
the subject must be reminded to provide the date and time of his/her last dose from the day 
before the visit. 
7.2.1.
Dose Modification or Interruption 
Dose modification is not permitted.  Subjects will take their IP as determined by treatment arm. 
If a subject inadvertently does not take his or her medication for 4 or more consecutive days,
Celgene or a Celgene designee must be contacted to decide whether the subject may remain in 
the study.  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.  If a 
subject is unable or unwilling to restart IP at the prior dose and/or dose interval, then the subject 
will be evaluated by the Investigator for discontinuation from the Double-blind Treatment Period
of the study, and enter the Follow-up Period.
7.2.2.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP (GED-0301). 
Overdose for this protocol, on a per-dose basis, is defined as ingestion of more than 4 tablets of 
GED-0301 (or matching placebo) 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.
7.3.
Method of Treatment Assignment
Approximately 1064 subjects will be randomized in a 1:1:1:1 ratio (266 subjects per GED-0301 
arm [total 798]; 266 subjects in the placebo arm) to receive double-blind, oral GED-0301 or 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
59
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
identically appearing placebo QD for 52 weeks. The total number of subjects with a total SES-
CD score ≥ 6 is targeted to comprise approximately 80% of the study population.
Subjects will receive double-blind, oral GED-0301 or identically appearing placebo daily (QD) 
as follows (Table 4):
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
the Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit;
!
Placebo QD until the Week 52 Visit.
Treatment assignment at baseline (Week 0/Visit 2) will be stratified via an IWRS based on 
concomitant use of corticosteroids (yes/no); concomitant use of immunosuppressants (eg, AZA, 
6-MP, or MTX) (yes/no); and previous exposure to biologics (ie, infliximab, adalimumab, 
certolizumab or vedolizumab) (yes/no).  The total number of subjects with previous exposure to 
biologics is targeted to comprise approximately 35% of the study population.
At the Week 12 Visit and thereafter, until the Week 52 Visit, subjects who meet the criteria for 
early escape (Table 7) may (a) continue in the study at the discretion of the Investigator based on 
the totality of clinical data, (b) enter the Long-term Active-treatment Study (GED-0301-CD-
004), or (c) discontinue the study. Subjects who complete the GED-0301-CD-002 Study at the 
Week 52 Visit will have the option to enter the Long-term Active-treatment Study.
Designated study personnel at the investigational sites will be assigned password-protected, 
coded identification numbers, which give them authorization to access the IWRS to randomize 
subjects.  The system will present a menu of questions by which the study personnel will identify 
the subject and confirm eligibility.  When all questions have been answered, the IWRS will 
assign a randomization identification number. Confirmation of the randomization will be sent via 
fax to the investigational site, Celgene and/or its representative.
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the randomization number assigned by the IWRS.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
60
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Table 4:
IP Dispensing Schedule: Double-blind Treatment Period
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
GED-0301
160 mg QD
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Placebo
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160 mg QD
Placebo
QD
GED-0301  
160 mg QD
Placebo
QD
GED-0301  
160 mg QD
Placebo
QD
GED-0301  
160 mg QD
Placebo
QD
GED-0301  
40 mg QD
Placebo
QD
GED-0301  
40 mg QD
Placebo
QD
GED-0301  
40 mg QD
Placebo
QD
GED-0301  
40 mg QD
Placebo
QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
GED-0301  
40 mg QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
Placebo
QD
IP = investigational product; QD= once daily.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
61
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
7.4.
Packaging and Labeling
GED-0301 tablets will be packaged in blister cards and or opaque high density polyethylene 
(HDPE) bottles fitted with induction seals and tamper evident child resistant caps. The label(s) 
for IP will include Sponsor name, address and telephone number, the protocol number, IP name, 
dosage form and strength (where applicable), amount of IP per container, lot number, expiry date 
(where applicable), medication identification/kit number, dosing instructions, storage conditions, 
and required caution statements and/or regulatory statements as applicable. Additional 
information may be included on the label as applicable per local regulations.
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 3). 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: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
62
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All medications (prescription and non-prescription), treatments, and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated 
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the eCRF.  The dose, unit, frequency, route, indication, date the medication 
was started, and date the medication was stopped (if not ongoing) must be recorded.
8.1.
Permitted Concomitant Medications and Procedures
The following medications are allowed during the study:
!
Oral aminosalicylates (SSZ or 5-ASA compounds), provided that treatment has been 
given at a stable dose for at least 2 weeks prior to the Screening Visit. The dose of 
oral aminosalicylates must remain stable through the duration of the study or early 
termination from the study.  If oral aminosalicylates have been recently discontinued, 
treatment must have been stopped at least 2 weeks prior to the Screening Visit.
!
Oral corticosteroids, provided that the dose (prednisone ≤ 20 mg/day or equivalent, 
budesonide ≤ 9 mg/day) has been stable for 3 weeks prior to the Screening Visit, and 
the dose must remain stable until the subject is eligible to start corticosteroids 
tapering (Section 6.7).  If oral corticosteroids have been recently discontinued, 
discontinuation must have been completed at least 3 weeks prior to the Screening
Visit.
!
Immunosuppressants, such as AZA, 6-MP, or MTX, provided that treatment was 
initiated ≥ 12 weeks prior to the Screening Visit, must be at a stable dose for ≥ 8 
weeks prior to the Screening Visit and remain stable for the duration of the study. If 
immunosuppressants have been recently discontinued, discontinuation must have 
been completed at least 8 weeks prior to the Screening Visit.
!
Antibiotics used for the treatment of CD (eg, ciprofloxacin, metronidazole), provided 
that the dose has been stable for at least 2 weeks prior to the Screening Visit. If 
antibiotics have been recently discontinued, discontinuation must have been 
completed at least 2 weeks prior to the Screening Visit.
!
Acetaminophen and low-dose aspirin for cardiovascular prophylaxis are allowed.
Note:  The dose of concomitant CD medications noted above may not be increased during the 
study. No new CD therapy can be prescribed once the subject has been screened in the study. 
8.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are prohibited during the Double-blind Treatment Period 
of the study, Screening Visit (Visit 1) through the Week 52 Visit, or the ET Visit for subjects 
who discontinue prematurely during the study:
!
Use of any biologics are prohibited during the study and must be discontinued at least
8 weeks or 5 elimination half lives of the biologic, whichever is longer, prior to the 
Screening Visit. (See Table 8 for elimination half-life timeframes for biologics.)
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EDMS Doc. Number: 
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!
Use of bile acid sequestrants (eg, cholestyramine) is prohibited during the study and 
must be discontinued at least 3 weeks prior to the Screening Visit.
!
Use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine, thalidomide or 
apheresis (eg, Adacolumn®) is prohibited during the study and must be discontinued 
at least 8 weeks prior to the Screening Visit. 
!
Use of topical treatments with 5-ASA or corticosteroid enemas or suppositories is
prohibited during the study and must be discontinued at least 2 weeks prior to the 
Screening Visit.
!
Use of IV corticosteroids is prohibited during the study and must be discontinued at 
least 2 weeks prior to the Screening Visit.
!
Administration of total parenteral nutrition (TPN) is prohibited and must be 
discontinued at least 4 weeks prior to the Screening Visit.
!
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) is prohibited.
In addition, subjects who require ileostomy, colostomy, any intestinal resection, or intra-
abdominal surgery (related to CD) during the study will be discontinued from treatment. 
8.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications.
Required procedures include ileocolonoscopy.
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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 Biostatistics department of the sponsor or its designee.
This study will be conducted as a double-blind study with in-house blinding procedures. For the 
purpose of the final data analysis, the official, final Week 52 database will not be unblinded until 
medical/scientific review has been conducted, protocol violations have been identified, the data
have been declared final and complete, and a SAP has been written and approved. The 
randomization schedule will be generated and implemented by the external vendor of the study 
interactive web response system (IWRS).
9.2.
Study Population Definitions
The intent-to-treat (ITT) population will be the primary population for the efficacy analysis. The 
ITT population will consist of all subjects who are randomized and receive at least 1 dose of IP.
 
 
Subjects will be included in the treatment group to which they were randomized for the efficacy 
analysis using the ITT 
 populations.
The analysis of safety data in this study will be based on the safety population, which will consist 
of all subjects who are randomized and receive at least 1 dose of IP.  Subjects will be included in 
the treatment group corresponding to the IP they actually received for the analysis using the 
safety population.
9.3.
Sample Size and Power Considerations
With a total of approximately 1064 subjects and a randomization ratio of 1:1:1:1, this study will 
randomize approximately 266 subjects into each of the three GED-0301 treatment groups and the 
placebo group.  For the efficacy analyses of the first 12 weeks of the study, the three GED-0301 
treatment groups will be pooled, due to the same treatment of GED-0301 160 mg QD received 
during the first 12 weeks, and the treatment comparisons will be made between GED-0301 160 
mg QD (approximately 798 subjects) and placebo.  For the efficacy analyses beyond Week 12, 
the treatment comparisons will be made between each of the three GED-0301 treatment groups 
and placebo.  The study sample size is driven by the comparison of each of the three GED-0301 
treatment groups with placebo with respect to the proportion of subjects with ER-50 at Week 52.  
The sample size and power calculations (not accounting for multiplicity adjustment) at a 2-sided 
significance level of 0.05 are given in Table 5.
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EDMS Doc. Number: 
GED-0301
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Table 5:
Sample Size and Power Calculations
Endpoint
Assumptions
Sample Size per 
Group
Powera
Clinical remission 
(CDAI score < 150) at 
Week 12
Placebo = 22%
GED-0301 160 mg QD 
= 36%
Placebo = 266
GED-0301 160 mg QD 
= 798
99%
Clinical remission 
(CDAI score < 150) at 
Week 52
Placebo = 22%
GED-0301 160 mg QD 
= 36%
Placebo = 266
Any GED-0301 group = 
266
95%
ER-50 at Week 52
Placebo = 10%
Any GED-0301 group = 
20%
Placebo = 266
Any GED-0301 group = 
266
90%
CDAI = Crohn’s Disease Activity Index; ER-50 = endoscopic response defined as a reduction of at least 50% in the 
SES-CD; QD = once daily; SES-CD = Simple Endoscopic Score for Crohn’s Disease.
a All power calculations do not account for multiplicity adjustment and are based on a 2-group chi-square test at a 2-
sided significance level of 0.05, using EastTM 6.3.
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and other continuous variables will be summarized using 
descriptive statistics, while sex, race and other categorical variables will be provided using 
frequency tabulations.  Medical history data will be summarized using frequency 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.  A 
summary of subjects enrolled by site will be provided. Protocol deviations/violations will be 
summarized using frequency tabulations.
9.6.
Efficacy Analysis
For the efficacy analyses of the first 12 weeks of the study, the three GED-0301 treatment groups 
will be pooled, due to the same treatment of GED-0301 160 mg QD received during the first 12 
weeks, and the treatment comparisons will be made between GED-0301 160 mg QD and 
placebo.  For the efficacy analyses beyond Week 12, the treatment comparisons will be made 
between each of the three GED-0301 treatment groups and placebo.
9.6.1.
Statistical Methods
Binary endpoints will be analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors.  Subjects who have insufficient data for response 
determination for the time point under consideration will be considered nonresponders for that 
time point.
 
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
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9.6.2.
Multiplicity
Formal statistical tests are planned for the primary and secondary efficacy endpoints.  In order to 
control the family-wise Type I error rate at the 0.05 level, formal statistical tests will be carried 
out using a gatekeeping closed testing procedure; details of this procedure, including the 
endpoints subjected to this procedure and their hierarchy, will be specified in the SAP.
For formal statistical tests that are planned but not performed as a result of the multiplicity 
adjustment procedure, as well as for any other comparisons that are not subjected to multiplicity 
adjustment, nominal 2-sided p-values (without adjustment for multiplicity) will be provided as a 
measure of the strength of association between the endpoint and the treatment effect rather than 
formal tests of hypotheses.
 
 
9.7.
Safety Analysis
Safety and tolerability 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.
TEAEs will be classified using the MedDRA classification system.  All TEAEs will be 
summarized by system organ class, preferred term, severity, and relationship to IP.  TEAEs
leading to death or to 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 postbaseline will be provided for laboratory 
tests.
9.8.
Interim Analysis
No interim analysis is planned for this study.
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EDMS Doc. Number:
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Protocol GED-0301-CD-002
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9.9.
Other Topics
 
 
9.9.3.
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 will follow 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. 
9.9.4.
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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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 investigational product should be reported as an 
AE on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. 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.  AEs 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 adverse events 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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!
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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Mild
!
Asymptomatic or mild symptoms; clinical or diagnostic observations only
!
Intervention not indicated
!
Activities of daily life (ADLs) minimally or not affected
!
No or minimal intervention/therapy may be required 
Moderate 
!
Symptom(s) cause moderate discomfort
!
Local or noninvasive intervention indicated
!
More than minimal interference with ADLs but able to carry out daily social and 
functional activities.
!
Drug therapy may be required
Severe (could be non-serious or serious) 
!
Symptoms causing severe discomfort/pain
!
Symptoms requiring medical/surgical attention/intervention
!
Interference with ADLs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)
!
Drug therapy is required
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
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EDMS Doc. Number: 
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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 a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the 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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10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 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 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 
SAE made known to the Investigator at anytime 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/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
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initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
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 Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.  
Celgene or its authorized representative shall notify the Investigator of the following information 
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 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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11.
DISCONTINUATIONS
Subjects can discontinue at any time at their own request or at the discretion of the investigator. 
Reasons for discontinuation of a subject from treatment include but are not limited to:
!
Any safety reason (eg, adverse event, laboratory abnormality) which in the opinion of 
the Investigator or the sponsor (or designee) places the subject at significant risk 
should he/she continue participating in the study. Please refer to Appendix O for 
discontinuation criteria related to liver function test abnormalities.
!
Surgical procedures related to Crohn’s disease (eg, intestinal resection, ileostomy, 
colostomy, intra-abdominal surgery related to CD)
!
Initiation of a biologic medication (eg, TNF-α blockers, natalizumab, vedolizumab, 
ustekinumab)
!
Initiation of immunomodulatory agents for the treatment of CD, such as
mycophenolic acid, tacrolimus, sirolimus, cyclosporine, thalidomide or apheresis (eg, 
Adacolumn®).
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
!
Lack of efficacy
!
Adverse Event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Other (to be specified in the eCRF)
!
Pregnancy
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
!
Lack of efficacy
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Protocol GED-0301-CD-002
Celgene Corporation
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!
Adverse event
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Withdrawal by subject
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Death
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Lost to follow-up
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Other (to be specified on the eCRF)
!
Pregnancy
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
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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
The blind must not be broken during the course of the study unless, in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. The Investigator should ensure that the code is broken only in accordance 
with the protocol. The Investigator should promptly notify the Medical Monitor of the 
emergency unblinding and the reason for breaking the blind, which should be clearly 
documented by the Investigator in the subject’s source documentation. Emergency unblinding 
should only be performed by the Investigator through the IWRS by using an emergency 
unblinding personal identification number (PIN), and the Investigator should call IWRS for 
unblinded dose information.
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EDMS Doc. Number: 
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Protocol GED-0301-CD-002
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
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 informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number: 
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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/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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sought. 
ought
al


EDMS Doc. Number: 
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Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
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/EC, regulatory authorities, etc).  In addition, the 
Investigator or Celgene has the right to discontinue a single site at any time during the study for 
medical or administrative reasons such as: 
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
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/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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EDMS Doc. Number: 
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Protocol GED-0301-CD-002
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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ruction of 
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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 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 Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, Federal Drug Administration 
[FDA], European Medicines Agency [EMA]), Health Canada and company authorized 
representatives.  The Investigator should make every effort to be available for the audits and/or 
inspections.  If the Investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Celgene immediately.
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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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17.
REFERENCES
 
Baumgart DC, Sandborn WJ. Crohn’s disease.  Lancet 2012;380:1590-1605.
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.
Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease-a true paradigm of 
success? Gastroenterol Hepatol 2012 Jan;8(1):29-38
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.
 
 
 
  
 
 
 
 
 
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Levesque BG, Sandborn WJ, Ruel J, Feagan BG, Sands BE, Colombel JF. Converging goals of 
treatment for inflammatory bowel disease from clinical trials and practice. Gastroenterology 
2015;148(1):37-51.e1.
Lewis SJ, Heaton KW.  Stool form scale as a useful guide to intestinal transit time.  Scand J 
Gastroenterol. 1997;32(9):920–4.
Liang K, Zeger, S. Longitudinal data analysis of continuous and discrete responses for pre-post 
designs. Sankhyā: The Indian Journal of Statistics (Series B) 2000;62:134-148.
Lichtenstein GR, Hanauer SB, Sandborn WJ, The Practice Parameters Committee of the 
American College of Gastroenterology.  Management of Crohn's disease in adults. Am J
Gastroenterol 2009 Feb;104(2):465-83.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent 
variable in analyses of change from baseline in clinical trials? Statist Med 2009;28:2509-2530.
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;126:1504-17.
MacDonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 
2005;307:1920-5.
Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trial with missing data using 
multiple imputation in conjunction with robust regression. Biometrics 2012;68:1250-1259.
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: 601-9.  
Monteleone G, Caruso R, Pallone F. Role of Smad7 in inflammatory bowel diseases. World J 
Gastroenterol 2012;18(40):5664-8.
 
 
 
 
 
 
 
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.
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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 2011; Jan;106(1):110-9.
 
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18.
APPENDICES
APPENDIX A: TABLE OF ABBREVIATIONS
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADL
Activity of daily life
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
APTT
Activated partial thromboplastin time
ASA
Aminosalicylic acid
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
AZA
Azathioprine
β-hCG
β-subunit of human chorionic gonadotropin
BUN
Blood urea nitrogen
CD
Crohn’s disease
C. difficile
Clostridium difficile
CDAI
Crohn’s Disease Activity Index
CI
Confidence interval
Cmax
Maximum plasma concentration of drug
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
CT
Computed tomography
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EFD
Embryo-fetal development
 
ER-25
Endoscopic response-25
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ER-50
Endoscopic response-50
ET
Early Termination
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed consent form
ICH
International Council for Harmonisation
IFN-γ
Interferon-gamma
IND
Investigational New Drug
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IV
Intravenous
IWRS
Interactive Web Response System
LDA
Longitudinal data analysis
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
6-MP
6-mercaptopurine
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MTX
Methotrexate
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PBO
Placebo
PK
Pharmacokinetics
PT
Prothrombin time
QD
Once daily
RBC
Red blood cell 
ROW
Rest of World
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
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
SSZ
Sulfasalazine
SUSAR
Suspected unexpected serious adverse reaction
TBL 
Total bilirubin
TEAE
Treatment-emergent adverse event
TGF-β1
Transforming growth factor- beta 1
TNF-α
Tumor necrosis factor-alpha
UC
Ulcerative colitis
ULN
Upper limit of normal
US
United States
VAS
Visual Analogue Scale
WBC
White blood cell count
 
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APPENDIX B:
DEFINITIONS FOR EFFICACY OUTCOMES
Table 7:
Definitions for Efficacy Outcomes
Efficacy Outcome
Definition
Clinical Remission
CDAI score < 150 
Clinical Response
Decrease from baseline in CDAI ≥ 100 points  
Endoscopic Response-50 
(ER-50)
A reduction of at least 50% in SES-CD compared with baseline
Endoscopic Response-25 
(ER-25)
A reduction of at least 25% in SES-CD compared with baseline
Endoscopic remission
SES-CD ≤ 2 
Early Escape Criteria 
Beginning at the Week 12 Visit and thereafter, until the Week 52 Visit, 
subjects 
 
 will have the option to 
enter the Long-term Active-treatment Study (GED-0301-CD-004).
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APPENDIX C: SUBJECT DAILY DIARY
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APPENDIX D. CROHN’S DISEASE ACTIVITY INDEX (CDAI) SCORE
Source:  Best, 1976
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APPENDIX E. 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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APPENDIX H. DEFINITION OF CD TREATMENT FAILURE AND 
INTOLERANCE
Budesonide
!
Failure is defined as having signs and symptoms of active disease despite a history of 
receiving ≥8 weeks of treatment with budesonide at doses ≥9 grams
!
Intolerance: similar to systemic corticosteroids
Systemic corticosteroids
!
Failure is defined as having signs and symptoms of active disease despite a history of 
receiving at least one 4-week course regimen with prednisone ≥ 0.75 mg/kg mg daily 
orally or equivalent, or 1 week of intravenous corticosteroids. Where regional or local 
practice standards for the use of steroids in CD differ from this definition of failure, the 
local or regional standard should be used.
!
Intolerance includes, but is not limited to Cushing’s syndrome, osteopenia/osteoporosis, 
hyperglycemia, insomnia and infection.
Immunosuppressants
!
Failure is defined as signs and symptoms of active CD despite a history of ≥8 weeks of 
treatment with azathioprine (≥1.5 mg/kg), or 6-mercaptopurine (≥0.75 mg/kg), or 
methotrexate (≥12.5 mg/week)
!
Intolerance includes, but is not limited to nausea, vomiting, abdominal pain, pancreatitis, 
liver function test abnormalities, lymphopenia and infection
Biologics
!
Failure is defined by:
o
an inadequate initial response (primary nonresponder) after at least 2 doses of 
induction therapy to: infliximab (doses of ≥5 mg/kg); adalimumab (doses of 160 mg 
followed by 80 mg); certolizumab (doses of 400 mg) or vedolizumab (doses of 300 
mg) at least 2 weeks apart, or
o
recurrence of signs and symptoms, such as worsening of diarrhea, abdominal pain, 
rectal bleeding, or initiation or increased use of antidiarrheals (secondary 
nonresponders) after at least 2 doses of maintenance therapy to infliximab (doses of 
≥5 mg/kg), adalimumab (doses of 40 mg), certolizumab (doses of 400 mg); or 
vedolizumab (doses of 300 mg).
!
Intolerance to biologics may include fever, chills, rash, flush, itching, hypotension, 
urticaria, myalgia, arthralgias; which were related to the treatment.
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
118
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
7,21
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EDMS Doc. Number:
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
119
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
$7,21
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
120
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
APPENDIX M.HALF LIVES OF BIOLOGICS
Table 8:
Elimination Half Lives of Biologics
Biologic
1 Elimination Half Life
5 Elimination HalfLives
Infliximab
10 days
50 days
Adalimumab
20 days
100 days
Certolizumab
14 days
70 days
Vedolizumab
25 days
125 days
* Note: The half-life information was obtained from the package insert of each above-mentioned biologics.
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EDMS Doc. Number: 
GED-0301
Protocol GED-0301-CD-002
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GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
APPENDIX O: CRITERIA FOR TEMPORARY INTERRUPTION OF IP 
OR STUDY DISCONTINUATION BASED ON LIVER FUNCTION 
TEST ABNORMALITIES
Criteria for discontinuing or temporarily interrupting study treatment:
!
When the baseline values were < 2 x upper limit of normal (ULN), discontinue if alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) increases to > 5 x baseline 
values.
!
When the baseline values were ≥2 x ULN but < 5 x ULN, discontinue if ALT or AST 
increases to > 3 x baseline values.
!
When ALT or AST increase > 2 x baseline values AND the increase is accompanied by a 
concomitant total bilirubin (TBL) increase to > 2 x baseline values.
!
All patients who develop symptoms consistent with hepatic injury (eg, appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia [>
5%]) in combination with elevations in liver enzymes.
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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-002
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Subject
Section(s) Affected
Change / Justification
Endpoint 
Harmonization  
Protocol Summary, 
(Endpoints, Statistical 
Methods); Table 2
(Study Endpoints); 
Section 9.3 (Statistical 
Considerations, Sample 
Size and Power 
Considerations, Table 5
[previously Table 7])
The primary purpose of this protocol amendment is to 
harmonize and reprioritize the order of endpoints 
based on regulatory agency feedback. There is now 
one set of endpoints for all regions. The primary 
efficacy measure will be clinical remission (defined as 
a Crohn’s Disease Activity Index [CDAI] score < 
150) at Week 12.  Key secondary efficacy measures 
will include: clinical remission at Week 52; 
endoscopic response-50 (ER-50, defined as a 
reduction of at least 50% compared with baseline in 
the Simple Endoscopic Score for Crohn’s Disease 
[SES-CD]) at Week 52; clinical response (defined as 
a decrease from baseline in CDAI ≥ 100 points) at 
Week 12;
 
 steroid-free clinical remission at 
Week 52; sustained clinical remission at both Week 
12 and Week 52; endoscopic response-25 (ER-25, 
defined as a reduction of at least 25% compared with
baseline in SES-CD) at Week 12; and the evaluation 
of endoscopic remission (defined as SES-CD ≤ 2) at 
Week 52.  
 
 
 
 
 
The statistical sections were revised to support the 
hierarchy of endpoints as listed above.
Monitoring of liver 
function tests
Clinical Laboratory 
Assessments (Section 
6.5.3); Criteria for 
Temporary Interruption 
of IP or Study 
Discontinuation Based 
on Liver Function Test 
Abnormalities 
(Appendix O) 
Additional guidance has been added for subjects who 
develop new changes in liver function tests, including 
but not limited to repeat testing, evaluation for cause, 
and close observation. Criteria have also been 
provided to consider IP interruption or study 
discontinuation.
 
 
Discontinuation 
Criteria
Discontinuations 
(Section 11)
Text was updated to specify potential reasons for 
discontinuation, including but not limited to patient 
safety (eg, liver function test abnormalities), CD-
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
5
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Subject
Section(s) Affected
Change / Justification
related surgeries, initiation of biologics, and initiation
of specific CD-related medications.
The reasons for treatment and study discontinuation 
were updated to include lack of efficacy.
The amendment also includes several other minor clarifications and corrections:
Subject
Section(s) Affected
Change / Justification
Medical Monitor
contacts
Medical Monitor 
Contact Information
Contact information now includes details for 
QuintilesIMS medical monitors by region.
 
 
 
Efficacy 
Measurements and 
Outcomes
Section 1.3.2 
(Rationale for the Study 
Design); Appendix B 
(Definitions for
Efficacy Outcomes,
Table 7 [previously 
Table 9])
For simplification purposes, the definition of clinical 
remission is CDAI < 150 only. While clinical 
symptoms of stool frequency ≤3 and abdominal pain
score ≤1 are still important endpoints to consider, the 
term “clinical remission” is now specific to CDAI.
The title of Appendix B was changed to match the 
table title.
Exclusion Criteria
Section 4.3 (Exclusion 
Criteria)
Exclusion Criterion 24 was revised to further specify 
exceptions to the malignancy exclusion.
Ileocolonoscopy at 
Early Termination
Section 5 (Table of 
Events, Table 3 
[previously Table 5]); 
Section 6.6.5 
(Ileocolonoscopy)
Text was revised such that an ileocolonoscopy does 
not need to be performed at Early Termination if done 
within 8 weeks of the previous ileocolonoscopy.
Visit Windows 
Section 5 (Table of 
Events, Table 3 
[previously Table 5])
A 3-day visit window was added for the follow up 
visit, and the 3-day visit window was removed for the 
baseline visit. These updates were made to reflect the 
intended variance for visit scheduling.
 
 
 
Rescreening 
requests
Section 6.1 (Screening 
period)
Text was clarified to indicate that subjects may be 
allowed to rescreen with approval by the sponsor or 
designee.
Clostridium 
difficile testing
Section 6.1.1 
(Screening Visit); 
Section 6.5.4 (Stool 
Assessment)
The process for C. difficile treatment and testing was
revised as 2 months of consecutive negative toxin 
results are not necessary before rescreening. Subjects 
who test positive for the C. difficile toxin may
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
6
GED-0301-CD-002 Amendment 3 Final: 15 Aug 2017
Subject
Section(s) Affected
Change / Justification
undergo a rescreen 8 weeks after the start of 
treatment, provided that the toxin results for C. 
difficile are negative. 
 
 
 
 
 
 
 
 
 
Abbreviations
Appendix A 
(Abbreviations and 
Specialist Terms, Table 
6)
Abbreviations were added for total bilirubin 
 
Criteria for Steroid 
Failure
Appendix H (Definition 
of CD Treatment 
Failure and Intolerance)
Based on feedback from sites, a note was added to 
clarify that where local or regional practice standards 
differ from protocol defined steroid failure criteria, 
local or regional standards should be used. 
Typographical 
Section 2 
Section 6.3 (Early 
Termination)
 
 
 
 
 
 
 
 
Ileocolonoscopy was added to the list of assessments 
as it was inadvertently omitted.
 
 
Throughout
Minor editorial corrections were made throughout the 
document.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
3
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Subject
Section(s) Affected
Change / Justification
Endpoint Hierarchy  Protocol Summary, 
(Endpoints, Statistical 
Methods); Tables 2-4 
(Study Endpoints); 
Section 9.3 (Statistical 
Considerations, Sample 
Size and Power 
Considerations, Table 
7)
The primary purpose of this protocol amendment is to prioritize the evaluation of clinical 
remission and endoscopic outcomes as primary and key secondary endpoints. Endpoints are now 
listed by two regions (United States [US] and Rest of World [ROW]) based on feedback from 
regulatory authorities. The primary efficacy measure will be clinical remission (defined as an 
average daily liquid or soft stool frequency ≤ 3 AND abdominal pain score ≤ 1 [US] or a Crohn’s 
Disease Activity Index (CDAI) score < 150 [ROW]) at Week 12.  The key secondary efficacy 
measures will include: the evaluation of endoscopic remission (defined as SES-CD ≤ 2) at Week 
52; clinical remission based on CDAI score at Week 12 (US only); clinical remission (based on 
stool frequency/ abdominal pain and CDAI score for US, and CDAI score for ROW) at Week 52; 
clinical response (defined as a decrease from baseline in CDAI ≥ 100 points) at Week 12; 
endoscopic response-50 ([ER-50], defined as a reduction of at least 50% compared with baseline
in SES-CD) at Week 52; sustained clinical remission at both Week 12 and Week 52; steroid-free 
clinical remission at Week 52; endoscopic response-25 ([ER-25], defined as a reduction of at 
least 25% compared with baseline in SES-CD) at Week 12;
 
 
  
 
 
 
The statistical sections were revised to support the hierarchy of endpoints as listed above.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
Inclusion Criteria
Protocol Summary 
(Study Population);
Section 1.3.1 (Study 
Rationale and Purpose);
Section 4.2 (Inclusion 
Criteria); Section 6.5.6
(Contraception 
Education); Section 
6.6.4 Ilecolonoscopy; 
Appendix H (Definition 
of CD Treatment 
Failure and Intolerance)
Aminosalicylates were removed as one of the therapies that subjects may have failed to allow for 
study eligibility. Treatment with aminosalicylates is (a) often insufficient therapy for patients 
with CD, (b) generally not first-line therapy for patients with CD, and (c) usually prescribed in 
conjunction with other CD therapy. In addition, failed treatment with biologics was further 
specified to include infliximab, adalimumab, certolizumab or vedolizumab.   
Inclusion criteria were updated to clarify that the presence of active CD must be determined by 
ileocolonoscopy at screening (exclusive of other imaging procedures). 
Pan-colonic screening surveillance was removed as a requirement for inclusion for subjects with 
increased risk of colorectal cancer in CD, as there is no clear, global guidance with respect to
screening programs for colorectal cancer. However, Section 6.6.4 now includes a statement 
indicating that subjects with increased risk of colorectal cancer should have undergone a 
colonoscopy with pan-colonic surveillance biopsies according to local guidelines.
Clarification was added to the contraception options for inclusion, as follows:
-
The inclusion criterion requiring male subjects to use barrier contraception when engaging in 
sexual activity was removed. Based on additional PK results, there is minimal concern for
GED-0301 entering blood at such high concentrations that it could get into semen.
-
Subjects taking an oral contraceptive may need a backup or alternative method of birth 
control based on Investigator judgment. 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 CD, which may affect gastrointestinal absorption or transit of oral contraceptives. 
These details were also added to Section 6.5.6 (Contraception Education).
Exclusion Criteria
Protocol Summary 
(Study Population), 
Section 4.3 (Exclusion 
Criteria); Section 6.6.4 
(Efficacy Assessments, 
Ileocolonoscopy);
Exclusion criteria were revised to clarify the protocol requirements with respect to strictures. 
Strictures with prestenotic dilatation, requiring procedural intervention, or with obstructive 
symptoms, will be excluded. In addition, subjects with colonic strictures not passable with an 
adult colonoscope, or strictures in the ileum or ileocecal valve that are fibrotic in nature, will be 
excluded.
Prior use of biologics is now specific to infliximab, adalimumab, certolizumab or vedolizumab.  
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
5
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
Section 8.2 (Prohibited 
Concomitant 
Medications and 
Procedures); Appendix 
M (Half Lives of 
Biologics, Table 10)
These specifics were added to exclusion criteria related to prior exposure with > 3 biologics. In 
addition, an exclusion criterion was added to prohibit subjects with prior exposure to biologics 
for the treatment of CD, approved or investigational, other than infliximab, adalimumab, 
certolizumab or vedolizumab. The exclusion of subjects with  prior exposure to natalizumab was 
removed, as it is subsumed under the new exclusion criterion.
Exclusion criteria now consider the duration of 5 elimination half-lives for biologics, in addition 
to the 8 week and 1 month wash-out periods for biologics and investigational drugs, respectively. 
Appendix M (Table 10) was added to provide the half-lives for biologics, ie, infliximab, 
adalimumab, certolizumab or vedolizumab. This additional detail accounts for the variance in 
half-lives for different biologics and the need, in these cases, for a longer wash-out period. 
All bile acid sequestrants are now excluded within 3 weeks prior to screening (previously limited 
to cholestyramine). This change is reflected in the exclusion criteria and in Section 8.2 
(Prohibited Concomitant Medications and Procedures).
It is now specified that subjects with a confirmed diagnosis of colorectal dysplasia are excluded 
from the study (with the exception of adenomatous colonic polyps that have been completely 
resected), in addition to subjects with a history of colorectal cancer.
Clarification was added such that known serious infections are excluded without actively 
screening for exclusion of specific diseases (eg, tuberculosis, atypical mycobacterial disease, 
herpes zoster, or HIV). 
The amendment also includes several other minor clarifications and corrections:
Subject
Section(s) Affected
Change / Justification
Medical Monitor
contact
Medical Monitor Contact 
Information
Address for sponsor contact was updated.
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
6
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
Disease/ 
Compound 
Background 
Protocol Summary 
(Indication); Section 1.2 
(Compound Background)
Information was copied from the compound background section to the indication section to 
better describe the relationship between transforming growth factor – beta 1 (TGF-β1), Smads, 
and inflammatory bowel disease (IBD). Other edits were also made achieve consistency across 
the GED-0301 protocols.
Efficacy 
Measurements 
and Outcomes
Protocol Summary 
(Objectives); Section 
1.3.2 (Rationale for the 
Study Design); Table 2 
(Study Objectives); 
Appendix B (Table of 
Definitions, Table 9)
Clinical activity is now measured by average daily liquid or soft stool frequency and abdominal 
pain (as well as CDAI, as previously stated).  The definition of clinical remission now includes 
an average daily liquid or soft stool frequency ≤ 3 AND abdominal pain score ≤ 1 (or CDAI < 
150, as previously stated). Definitions for endoscopic response-25 (ER-25) and endoscopic 
response-50 (ER-50) were added. The terminology of mucosal healing was changed to 
endoscopic remission based on regulatory agency feedback.
For simplification purposes, the definitions for clinical activity and endoscopic outcomes were 
removed from the primary and secondary objectives. The Week 12 time point was added to the 
primary objective. The secondary objectives were re-ordered to coincide with the order of the 
endpoints. Time points were removed from Appendix B (Table 9) as these are no longer part of 
the definitions for efficacy outcomes. In addition, the early escape definition in Table 9 was 
updated to indicate eligibility beginning at Week 12.
 
 
 
 
SES-CD scores
Protocol Summary (Study 
Design); Section 3.1 
(Study Design); Section 
7.3 (Method of Treatment 
Assignment)
To ensure a broad distribution of Crohn’s Disease subjects, including those with more extensive 
and/or significant mucosal disease activity, the total number of subjects with a total SES-CD 
score ≥6 is targeted to comprise approximately 80% of the study population.
Options for 
completers and 
Protocol Summary (Study 
Design), Section 3.1 
Clarification was added to outline the treatment options for subjects at critical time points in the 
study. Subjects who complete the Week 52 Visit may enter the Long-term Active-treatment 
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
7
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
subjects who meet 
early escape 
criteria
(Study Design); Figure 1 
(footnote); Section 7.3 
(Method of Treatment 
Assignment)
Study (GED-0301-CD-004). Subjects who meet the criteria for early escape beginning at the 
Week 12 Visit and thereafter until the Week 52 Visit, may (a) continue in the study at the 
discretion of the investigator based on the totality of clinical data, (b) enter the Long-term 
Active-treatment Study (GED-0301-CD-004), or (c) discontinue the study. 
Discontinuation 
Instructions
Protocol Summary (Study 
Design); Section 3.1 
(Study Design); Figure 1; 
Section 3.1.2 (Early 
Termination Visit); 
Section 3.2 (End of 
Study); Table 5 (Table of 
Events); Section 6.3 
(Early Termination) 
Text was updated to indicate that subjects who discontinue at Week 12 (either because they meet 
early escape criteria or for any other reason) should complete the Week 12 Visit (instead of the 
Early Termination Visit).
Clarification was also added to emphasize that subjects who prematurely discontinue from the 
study and do not enter into the Long-term Active-treatment study will have a 4-week Follow-up 
Visit.
Study Design 
Schematic
Figure 1
The figure was updated to remove the Week 2 time point and to indicate that no IP treatment is 
given during the Follow-Up period.
Contact Before 
Considering 
Subjects Lost to 
Follow up
Section 3.1.3 (Lost to 
Follow-up)
Language was revised such that the subject should be contacted through multiple (previously 3) 
telephone calls and/or emails and one registered letter before considering the subject lost to 
follow up. 
Abdominal 
examination
Table 5 (Table of Events)
footnote; Section 6.2
(Double Blind Treatment 
Period); Section 6.5.1 
(Physical examination)
Language was added to clarify that an abdominal examination will be performed at every visit
(including those visits in which a complete or limited physical exam is not being done) to assess 
the presence of an abdominal mass for the CDAI
 calculations. As a result, the statement 
regarding recording results for complete and physical examinations in source documents only 
was removed.  
Screening 
procedures
Section 6.1 (Screening 
Period); Section 6.1.1 
Additional provisions were made for screening procedures, including the ability to re-screen 
upon approval from the sponsor. In addition, for subjects who will be re-screened, endoscopies 
performed (a) as part of the original screening period, (b) within 30 days prior to the re-screen 
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
8
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
(Screening visit)
date, and (c) reviewed by a central reader, may be used to determine eligibility.
Microscopic urinalysis also includes crystals and bacteria. These analytes were added to the 
screening urinalysis be consistent with information in Section 6.5.3 (Clinical Laboratory 
Assessments).
Clostridium(C.) 
difficile toxin
Section 6.1.1 (Screening 
visit), Section 6.5.4 
(Stool assessment)
Additional clarity was provided regarding the need for negative C. difficile toxin results in order 
to be eligible for the study.
Hematocrit results
Section 6.2 (Double 
Blind Treatment Period), 
Table 5 (Table of Events)
Text was clarified to explain that due to the delay in receiving the hematocrit sample results, the 
CDAI score will be evaluated using the hematocrit results from the previous visit, beginning at 
the Week 12 Visit and thereafter until the remainder of the study. 
CDAI 
components
Section 6.6.2 (Crohn’s 
Disease Activity Index)
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 apthous ulcers 
(previously in the same category with iritis/uveitis). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
9
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
 
 
 
 
 
Compliance with 
Investigational 
Product (IP)
Section 7.2.1 (Dose 
modification or 
interruption)
Text was revised to state that if a subject inadvertently does not take his or her medication for 4 
or more consecutive days, Celgene must be contacted to decide whether the subject may remain 
in the study.  
Overdose
Section 7.2.2 (Overdose)
The timeframe for overdose was revised to be within the same calendar day (instead of a 24 hour 
time period). Text was added to indicate that overdose also includes more than 4 tablets of 
matching placebo (in addition to GED-0301).
Concomitant 
Medications and 
Procedures
Sections 8.1 & 8.2 
(Permitted/Prohibited 
Concomitant Medications 
and Procedures)
Timeframes for discontinuation of immunosuppressants (8 weeks) and antibiotics (2 weeks) were 
added to Section 8.1. A correction was also made to the text so that no new CD therapy can be 
prescribed once the subject has been screened (instead of randomized) in the study. Text was 
added to Section 8.2 to indicate that subjects who require ileostomy, colostomy, any intestinal 
resection, or intra-abdominal surgery (related to CD) during the study, will be discontinued from 
treatment.
Analysis model
Protocol Summary 
(Statistical Methods); 
Section 9.6.1 (Statistical 
Methods)
Revisions were made to indicate that a longitudinal data analysis (LDA) model will be used to 
analyze continuous endpoints. In this model, time is treated as a categorical value so that no 
restriction is imposed on the trajectory of the means over time. In addition, the model adjusts for 
stratification factors.
 
 
 
 
 
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EDMS Doc. Number: 
GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
10
GED-0301-CD-002 Amendment # 2 Global Final:  25 Oct 2016
Subject
Section(s) Affected
Change / Justification
Male 
contraception
Section 10.4 
(Pregnancy) ; Table 5 
(Table of Events) ; 
Section 6.5.6 
(Contraception 
Education)
Language was removed regarding male contraception, male contraception education, and 
partners of male subjects who become pregnant. These changes are based on the removal of the 
inclusion criterion requiring male subjects to use barrier contraception when engaging in sexual 
activity. Based on additional PK results, there is minimal concern for GED-0301 entering blood 
at such high concentrations that it could get into semen.
Removal of IVRS 
Section 12.2 (Emergency 
Identification of 
Investigational Products)
Interactive Voice Response System (IVRS) was removed as an option as Interactive Web 
Response System (IWRS) is now the only method through which emergency unblinding is 
performed.
References and 
Appendices
Section 17 (References); 
Section 18 (Appendices)
References 
 Boirivant, 2006; 
; Liang, 2000; Lewis, 1997; Liu, 
2009; Mehrotra, 2012) and appendices (Appendix A, Appendix B, Appendix H, Appendix M, 
 were updated or added as appropriate.
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GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
3
GED-0301-CD-002 Amendment 1 Final: 23 Sep 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Addition of Inclusion Criteria 
The primary purpose of this protocol amendment is to add inclusion criteria 
 
The rationale for this amendment is to align with 
 
  
Revised Sections: 
!
Protocol Summary, Study Population
!
Section 4.2, Inclusion Criterion # 7
!
Section 6.1.1, Screening Procedures
Update of Exclusion Criterion #12
Exclusion Criterion #12 was updated to allow stable doses of antibiotics for the treatment of 
Crohn's disease (CD), provided that the dose has been stable for at least 2 weeks prior to the 
Screening Visit. In earlier GED-0301 studies; the use of antibiotics for the treatment of CD was 
prohibited. Following discussions with clinical investigators, the use of antibiotics may be
commonly used as background therapy in subjects with CD and there is no reason to suspect a 
diminished effect of GED-0301 with its different mechanism of action. This change will support
a broader subject population to be studied in this phase 3 trial.
Revised Sections: 
!
Protocol Summary, Study Population
!
Section 4.3, Exclusion Criterion # 12
!
Section 8.1, Permitted Concomitant Medications and Procedures
!
Section 8.2, Prohibited Concomitant Medications and Procedures
Revision of Exclusion Criterion #13
Exclusion Criterion #13 was revised to exclude subjects with prior treatment with 3 biologics as 
opposed to 2 biologics.
The rationale is based on the expectation of responsiveness to GED 0301 (with a different 
mechanism of action then biologic therapy) in terms of clinical and endoscopic benefit, which is 
expected to be substantively similar in patients having been exposed to either 2 or 3 biologics. 
The intention, therefore, is to study a broader group of patients with prior biologic exposure. The 
target of 65% of the subjects in this trial to be naive to prior biologic therapy is unchanged.
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GED-0301
Summary of Changes GED-0301-CD-002
Celgene Corporation
Confidential and Proprietary
4
GED-0301-CD-002 Amendment 1 Final: 23 Sep 2015
Revised Sections: 
!
Protocol Summary, Study Population
!
Section 4.3, Exclusion Criterion # 13
The amendment also includes several other minor clarifications and corrections:
!
Update of Inclusion Criterion #9 to allow subjects who are at risk for colorectal 
cancer to have a colonoscopy within 2 years of the Baseline Visit. 
!
Update of Exclusion Criterion #22 to clarify that subjects treated with intravenous 
antibiotics for clinically significant infection prior to the Screening Visit, are 
excluded from the study. Subjects are permitted oral antibiotics to treat infection prior 
to the study.
!
Update of Exclusion Criterion #24 to clarify that subjects with colonic polyps are 
permitted in the study. 
!
Clarification of subjects who require a Follow-up Visit. Subjects who escape into the 
Long-term Active-treatment Study will have the Early Termination Visit but not the 
Follow-up Visit.
!
Correction of footnotes in Table 3.
!
Correction to Table 3 (Week 52 Visit). Investigational product is not dispensed at 
Week 52.
!
Correction to Table 3 (Early Termination Visit). Visit Number is Visit 16.
!
Correction to Section 6.6.4, Ileocolonoscopy. Biopsies are not being done in this 
study. The word “biopsies” is deleted from this section. 
!
Correction of formatting in Section 6.2.(dispensing of IP).
!
Correction to 
!
Correction to Appendix H, Definition of CD Treatment Failure and Intolerance
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
MONGERSEN (GED-0301) FOR THE TREATMENT OF SUBJECTS WITH ACTIVE 
CROHN’S DISEASE
STUDY DRUG:
GED-0301
PROTOCOL NUMBER:
GED-0301-CD-002
DATE FINAL:
20 Mar 2018
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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ummit, NJ 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................11
3.
STUDY OBJECTIVES...........................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................14
4.3.
Stratification, Randomization, and Blinding............................................................18
4.4.
Sample Size Determination and Power Considerations ...........................................19
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................21
5.1.
Reporting Conventions ...........................................................................................21
5.2.
Time Points ............................................................................................................22
5.2.2.
Screening and Baseline Definitions.........................................................................22
5.3.
Analysis Populations ..............................................................................................23
5.3.1.
Intent-to-treat Population........................................................................................23
5.3.3.
Safety Population....................................................................................................23
6.
SUBJECT DISPOSITION......................................................................................24
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................25
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................26
8.1.
Demographics and Baseline Characteristics ............................................................26
8.2.
Baseline Disease Characteristics.............................................................................26
8.3.
Medical History......................................................................................................28
8.4.
Prior Medications/Procedures .................................................................................28
9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT.........................29
9.1.
Treatment Duration.................................................................................................29
9.2.
Treatment Compliance............................................................................................29
9.3.
Overdose ................................................................................................................30
10.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................31
10.1.
Concomitant Medications .......................................................................................31
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
3
10.2.
Concomitant Procedures.........................................................................................31
11.
EFFICACY ANALYSIS ........................................................................................32
11.1.
Multiplicity.............................................................................................................32
11.2.
Missing Data Handling ...........................................................................................32
11.2.2.
Binary Efficacy Endpoints......................................................................................32
11.2.2.1.
Primary Approach for Analysis...............................................................................32
11.3.
Analysis of Primary Endpoint.................................................................................34
11.3.1.
Primary Analysis of Primary Endpoint....................................................................34
11.4.
Analyses of Secondary Efficacy Endpoints.............................................................35
11.4.1.
Primary Analyses of Secondary Efficacy Endpoints................................................35
11.7.
Assessing Study Center Effect and Treatment-by-center Interaction .......................37
12.
SAFETY ANALYSIS ............................................................................................38
12.2.
Adverse Events.......................................................................................................39
12.2.1.
Overall Summary of TEAEs ...................................................................................39
12.2.2.
All TEAEs..............................................................................................................40
12.2.3.
Drug-related TEAEs...............................................................................................40
12.2.4.
TEAEs by Maximum Severity................................................................................40
12.2.5.
Serious TEAEs.......................................................................................................40
12.2.6.
TEAEs Leading to Drug Withdrawal ......................................................................40
12.2.7.
Deaths ....................................................................................................................40
12.3.
Clinical Laboratory Evaluations..............................................................................40
12.4.
Vital Signs and Body Weight..................................................................................41
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TEAEs
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
4
12.5.
Electrocardiogram ..................................................................................................41
15.
INTERIM ANALYSIS...........................................................................................44
16.
CHANGES TO THE STATISTICAL CONSIDERATIONS SECTION OF 
THE PROTOCOL ..................................................................................................45
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Study Objectives.....................................................................................................12
Table 3:
Protocol-specified Endpoints ..................................................................................14
Table 5:
Sample Size and Power Calculations ......................................................................19
Table 7:
Laboratory Marked Abnormalities Criteria .............................................................52
LIST OF FIGURES
Figure 1
Overall Study Design..............................................................................................14
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
7
Celgene Lead Product Safety Physician
Signature
Printed Name
Date
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Meaning
AE
Adverse event
ALT
Alternating
ANCOVA
Analysis of covariance
APTT
Activated partial thromboplastin time 
ATC
Anatomical Therapeutic Chemical
ATC2
Anatomical Therapeutic Chemical: Therapeutic (Level 2)
AZA
Azathioprine
BMI
Body mass index
BUN
Blood urea nitrogen
CBC
Complete blood count
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
DAO
Data as observed
 
ECG
Electrocardiograms
eCRF
Electronic case report form
ET
Early Termination
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
9
Abbreviation
Meaning
IP
Investigational product
ITT
Intent-to-treat
IWRS
Interactive Web Response System
LDH
Lactic dehydrogenase 
LOCF
Last observation carried forward
LS
Least-squares
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
Missing not at random
6-MP
6-mercaptopurine
MTX
Methotrexate
NRI
Nonresponder imputation
 
PP
Per-protocol
PT
Preferred term
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
10
Abbreviation
Meaning
Q1
25th percentile
Q3
75th percentile
QD
Once Daily
RBC
Red blood cell
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
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
TNF- α
Tumor necrosis factor-alpha
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-002
Celgene 
Confidential and Proprietary
11
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol GED-0301-CD-002 “A Phase 3, Randomized, Double-blind, Placebo-controlled, 
Multicenter Study to Investigate the Efficacy and Safety of Mongersen (GED-0301) for the 
Treatment of Subjects with Active Crohn’s Disease” as amended on 15 Aug 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) and GED-0301 40 mg QD are referred to as 
GED 160 and GED 40, respectively. Subjects will be randomized to receive 1 of 3 GED-0301 
treatment regimens or placebo during the study. For the first 12 weeks of the study, each 
GED-0301 treatment regimen will consist of GED 160. These 12 weeks will be followed by 
either 1) placebo QD for 4 weeks followed by alternating (ALT) GED 160 for 4 weeks and 
placebo QD for 4 weeks until the end of the study; 2) placebo QD for 4 weeks followed by 
alternating GED 40 for 4 weeks and placebo QD for 4 weeks until the end of the study; or 3) 
continuous GED 40 until the end of the study. These 3 GED-0301 treatment regimens will be 
referred to as GED 160/GED 160 4 WK ALT, GED 160/GED 40 4 WK ALT, and GED 
160/GED 40, respectively. Investigational product (IP) refers to placebo, GED 160, or GED 40.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
12
3.
STUDY OBJECTIVES
Table 2:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of GED-0301 compared with placebo on 
clinical activity at Week 12 in subjects with active Crohn’s disease (CD).
Secondary Objectives
The secondary objectives are: 
!
To evaluate the efficacy of GED-0301 compared with placebo on endoscopic outcomes in 
subjects with active CD;
!
To evaluate the long-term efficacy of GED-0301 compared with placebo on clinical activity in 
subjects with active CD;
!
To evaluate the efficacy of GED-0301 compared with placebo on corticosteroid-free clinical 
remission in subjects with active CD;
!
To evaluate the safety and tolerability of GED-0301 in subjects with active CD.
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of 3 treatment regimens of oral GED-0301 versus placebo in subjects 
with active CD (defined by a CDAI score ≥ 220 and ≤ 450 and a total SES-CD ≥ 6 at screening, 
or the ileum segmental SES-CD ≥ 4 at screening).  Approximately 1064 subjects will be 
randomized in a 1:1:1:1 ratio (266 subjects per GED-0301 arm [total 798]; 266 subjects in the 
placebo arm) to receive 1 of 3 double-blind, oral GED-0301 treatment regimens, or identically 
appearing placebo once daily (QD) for 52 weeks. The total number of subjects with a total SES-
CD score ≥ 6 is targeted to comprise approximately 80% of the study population.
Treatment assignment at baseline (Week 0/Visit 2) will be stratified via an Interactive Web 
Response System (IWRS) based on concomitant use of corticosteroids (yes/no); concomitant use 
of immunosuppressants (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate 
[MTX]) (yes/no), and previous exposure to biologics (ie, infliximab, adalimumab, certolizumab 
or vedolizumab) (yes/no).  The total number of subjects with previous exposure to biologics is 
targeted to comprise approximately 35% of the study population.
Subjects will receive double-blind, oral GED-0301 or identically appearing placebo QD as 
follows:
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
the Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit;
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit;
!
Placebo QD until the Week 52 Visit.
Subjects who complete the GED-0301-CD-002 study at the Week 52 Visit may enter the Long-
term Active-treatment Study (GED-0301-CD-004). Subjects who meet the criteria for early 
escape beginning at the Week 12 Visit and thereafter until the Week 52 Visit, may (a) continue 
in the study at the discretion of the Investigator based on the totality of clinical data, (b) enter the 
Long-term Active-treatment Study (GED-0301-CD-004), or (c) discontinue the study. 
The criteria for early escape are defined as 
Subjects may discontinue the study at any time. Subjects who discontinue from the study at 
Week 12 (either because they meet the early escape criteria or for any other reason), will 
complete the Week 12 Visit. Subjects who prematurely discontinue from the study at any other 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
14
time prior to the Week 52 Visit, including subjects who early escape into the Long-term Active-
treatment Study, will complete the Early Termination (ET) Visit. The ET Visit should be 
scheduled as soon as possible after the last dose of IP. 
Subjects who complete the Week 52 Visit, as well as subjects who prematurely discontinue from 
the study, will have a 4-week Follow-up Visit. If the ET Visit occurs 28 days or more after the 
last dose of IP, then the Follow-up Visit is not required. 
Subjects entering the Long-term Extension Study will not have the Follow-up Visit.
A schematic of the study design is in Figure 1.
Figure 1
Overall Study Design
4.2.
Study Endpoints
Table 3:
Protocol-specified Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Efficacy
(Clinical 
remission)
The proportion of subjects achieving clinical remission, 
defined as a CDAI score < 150, at Week 12
Week 12
Secondary
Efficacy
The proportion of subjects achieving clinical remission, 
defined as a CDAI score < 150, at Week 52 
Week 52
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
15
Table 3:
Protocol-specified Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Efficacy
The proportion of subjects with endoscopic response-
50 (ER-50), defined as a reduction of at least 50% in 
the SES-CD compared with baseline, at Week 52
Week 52
Efficacy
The proportion of subjects who have a clinical response, 
defined as a decrease from baseline in CDAI ≥ 100 points, 
at Week 12
Week 12
 
 
Efficacy
The proportion of subjects who achieve corticosteroid-free 
clinical remission (CDAI <150) at Week 52 among 
subjects receiving oral corticosteroids for CD at baseline 
Week 52
Efficacy
The proportion of subjects achieving sustained clinical 
remission, defined as a CDAI score < 150 at both Week 
12 and Week 52 
Week 12 and 
Week 52
Efficacy
The proportion of subjects with endoscopic response-25 
(ER-25), defined as a reduction of at least 25% from 
baseline in SES-CD, at Week 12 
Week 12
Efficacy
The proportion of subjects with endoscopic remission, 
defined as SES-CD ≤ 2, at Week 52
Week 52
Safety
Type, frequency, severity, seriousness, and relationship of 
AEs to IP
Through 
Week 52
Safety
Number of subjects who discontinue IP due to any AE
Through 
Week 52
Safety
Clinically significant changes in vital signs, ECGs, and/or 
laboratory findings
Through 
Week 52
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
16
Table 3:
Protocol-specified Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
17
Table 3:
Protocol-specified Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; CD = Crohn’s disease; CDAI = Crohn's Disease Activity Index; ECG = electrocardiogram; 
; IP = investigational product;
 
SES-CD = Simple Endoscopic Score for Crohn's disease
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
18
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
Approximately 1064 eligible subjects will be randomized via an IWRS in a 1:1:1:1 ratio to 
receive 1 of 3 double-blind, oral GED-0301 treatment regimens, or identically appearing placebo 
QD for 52 weeks, as follows:
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
19
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed                   
by alternating GED-0301 160 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit
!
GED-0301 160 mg QD for 12 weeks; followed by placebo QD for 4 weeks; followed by 
alternating GED-0301 40 mg QD for 4 weeks and placebo QD for 4 weeks, until the 
Week 52 Visit
!
GED-0301 160 mg QD for 12 weeks; followed by continuous GED-0301 40 mg QD, 
until the Week 52 Visit
!
Placebo QD until the Week 52 Visit.
Treatment assignment at baseline (Week 0/Visit 2) will be stratified via an IWRS based on 
concomitant use of corticosteroids (yes/no); concomitant use of immunosuppressants (eg, 
azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) (yes/no), and previous 
exposure to biologics (ie, infliximab, adalimumab, certolizumab or vedolizumab) (yes/no). The 
total number of subjects with previous exposure to biologics is targeted to comprise 
approximately 35% of the study population.
4.4.
Sample Size Determination and Power Considerations
With a total of approximately 1064 subjects and a randomization ratio of 1:1:1:1, this study will 
randomize approximately 266 subjects into each of the three GED-0301 treatment groups and the 
placebo group. For the efficacy analyses of the first 12 weeks of the study, the three GED-0301 
treatment groups will be pooled, due to the same treatment of GED-0301 160 mg QD received 
during the first 12 weeks, and the treatment comparisons will be made between GED-0301 160 
mg QD (approximately 798 subjects) and placebo. For the efficacy analyses beyond Week 12, 
the treatment comparisons will be made between each of the three GED-0301 treatment groups 
and placebo. The study sample size is driven by the comparison of each of the three GED-0301 
treatment groups with placebo with respect to the proportion of subjects with ER-50 at Week 52.  
The sample size and power calculations (not accounting for multiplicity adjustment) at a 2-sided 
significance level of 0.05 are given in Table 5.
Table 5:
Sample Size and Power Calculations
Endpoint
Assumptions
Sample Size per 
Group
Powera
Clinical remission 
(CDAI score < 150) at 
Week 12
Placebo = 22%
GED-0301 160 mg QD 
= 36%
Placebo = 266
GED-0301 160 mg QD 
= 798
99%
Clinical remission 
(CDAI score < 150) at 
Week 52
Placebo = 22%
GED-0301 160 mg QD 
= 36%
Placebo = 266
Any GED-0301 group = 
266
95%
ER-50 at Week 52
Placebo = 10%
Any GED-0301 group = 
20%
Placebo = 266
Any GED-0301 group = 
266
90%
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
20
CDAI = Crohn’s Disease Activity Index; ER-50 = endoscopic response defined as a reduction of at least 50% in the 
SES-CD; QD = once daily; SES-CD = Simple Endoscopic Score for Crohn’s Disease.
a All power calculations do not account for multiplicity adjustment and are based on a 2-group chi-square test at a 2-
sided significance level of 0.05, using EastTM 6.3.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
21
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
The following reporting conventions apply generally to tables, listings, and figures:
!
Stratified analyses will use the randomization stratification factors (concomitant use 
of corticosteroids, concomitant use of immunosuppressants, and previous exposure to 
biologics), unless otherwise specified.
 
!
Efficacy analyses will be presented by GED-0301 treatment regimen and placebo (the 
efficacy analyses of the first 12 weeks will additionally include a total group 
combining all 3 GED-0301 treatment regimens), and safety analyses will be presented 
by GED-0301 treatment regimen, placebo, and a total group combining all 3 GED-
0301 treatment regimens.
 
 
 
!
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.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
22
!
All laboratory data will be reported using standard international units.
5.2.
Time Points
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.2.
Screening and Baseline Definitions
 
 
 
 
 
Unless otherwise specified, the baseline value is defined as the last assessment on or before the 
date of the first dose of IP in the study. 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
23
 
5.3.
Analysis Populations
5.3.1.
Intent-to-treat Population
The intent-to-treat (ITT) population will be the primary population for the efficacy analysis. The
ITT population is defined to include all subjects who are randomized and receive at least 1 dose 
of IP.
Due to the early termination of the study, for binary efficacy endpoints, the denominator at the 
time point under consideration will include subjects who have either completed that time point 
 
or discontinued at any time due to reasons other than “study terminated by sponsor”, 
instead of all subjects included in the ITT population (Section 11.2.2.1).
 
Subjects will be included in the treatment group to which they were randomized for the efficacy 
analysis using the ITT population.
 
5.3.3.
Safety Population
The analysis of safety data in this study will be based on the safety population, which will consist
of all subjects who are randomized and receive at least 1 dose of IP.
At least 1 post-baseline assessment is required for inclusion in the analysis of each specific 
laboratory, vital sign, weight, or ECG parameter. To assess the change from baseline, a baseline 
assessment is also required.
Subjects will be included in the treatment group corresponding to the IP they actually received 
for the analysis using the safety population. 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
24
6.
SUBJECT DISPOSITION
The number of subjects screened, the numbers and percentages of subjects randomized and not 
randomized, 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 populations will be summarized 
based on all subjects randomized.
Subject disposition (entered, completed, discontinued, along with the primary reason for 
discontinuation) will be summarized for
!
Double-blind Treatment Period (based on all subjects randomized): Weeks 0-12, Weeks 
12-52, and Weeks 0-52
!
Follow-up Period (based on all subjects who enter the Follow-up Period): Weeks 0-12, 
Weeks 12-52, and Weeks 0-52
 
 
 
 
 
 
 
 
 
 
 
 
A listing of discontinued subjects with reason for discontinuation will be provided.
The number and percentage of subjects by region, country, and site will be provided based on all 
subjects randomized.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
25
7.
PROTOCOL DEVIATIONS/VIOLATIONS
Protocol violations and deviations will be summarized for the screening period, Weeks 0-12 and 
the entire study using the ITT population, and for Weeks 12-52 for subjects who complete Week 
12/Visit 5. 
A listing of all protocol violations and deviations in the study will be provided.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
26
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized descriptively based on the ITT 
population. The comparability of the treatment groups for each relevant characteristic will be 
assessed descriptively in table format; no statistical hypothesis tests will be performed on these 
characteristics. Subject data listings will be provided.
8.1.
Demographics and Baseline Characteristics
The following characteristics will be summarized as continuous variables:
!
Age (years)
!
Baseline body weight (kg)
!
Baseline body mass index (BMI = 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) 
Age will be calculated as (date of informed consent – date of birth + 1) / 365.25 when the full
date of birth is collected; otherwise, the age recorded will be used.
8.2.
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized as continuous variables:
!
Baseline CDAI score
!
Baseline SES-CD score (central read)
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
27
 
 
 
 
 
 
 
 
!
Baseline CDAI score (≤ 300, > 300; < 220, 220 – < 270, 270 – < 330, 330 – < 390, 390 –
≤ 450, > 450)
!
Baseline SES-CD (central read; < 6, 6 – 12, > 12)
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
28
8.3.
Medical History
Medical history will be coded according to the Medical Dictionary for Regulatory Activities
(MedDRA), and summarized based on the ITT population by system organ class (SOC) and
preferred term (PT), with SOCs sorted in alphabetical order and PTs within each SOC in 
descending order of frequency, and by PT only in descending order of frequency.
8.4.
Prior Medications/Procedures
Prior medications are defined as medications with a start date before the date of the first dose of 
IP in the study (whether or not the end date is before the date of the first dose of IP). Prior 
medications that continue on or after the date of the first dose of IP will be also reported as 
concomitant medications. The Anatomical Therapeutic Chemical (ATC) coding scheme of the 
World Health Organization Drug Dictionary (WHODD) will be used to group medications into 
relevant categories. Prior medications will be summarized based on the ITT population by ATC2
level and standardized medication name, with ATC2 levels and standardized medication names 
within each ATC2 level sorted in descending order of frequency.
Prior procedures are similarly defined. Prior procedures will be coded according to the 
MedDRA, and summarized based on the ITT population by SOC and PT, with SOCs sorted in 
alphabetical order and PTs within each SOC in descending order of frequency.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
29
9.
EXTENT OF EXPOSURE TO INVESTIGATIONAL PRODUCT
9.1.
Treatment Duration
Treatment duration will be summarized for Weeks 0-12 and Weeks 0-52 using the safety 
population, and for Weeks 12-52 for subjects who receive at least 1 dose of IP after Week 
12/Visit 5
 
 
 
 
Treatment 
duration will be summarized as a continuous variable, and as a categorical variable with the 
following exposure intervals:
!
Weeks 0-12: ≤ 4, > 4 – 8, > 8 weeks
!
Weeks 12-52: ≤ 8, > 8 – 16, > 16 – 24, > 24 – 32, > 32 weeks (intervals denote the 
number of weeks relative to the date of the first dose of IP in Weeks 12-52 as defined 
above)
!
Weeks 0-52: ≤ 4, > 4 – 8, > 8 – 12, > 12 – 20, > 20 – 28, > 28 – 36, > 36 – 44, > 44 
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 0-12 and Weeks 0-52 using the ITT population, and for Weeks 12-52 for 
subjects who receive at least 1 dose of IP after Week 12/Visit 5
 
 
 
 
 
 
Treatment compliance rate will be summarized as a continuous variable, and as a categorical 
variable with the following categories: < 75%, 75% – 120%, and > 120%.
A subject data listing of drug accountability records will be provided.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
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30
9.3.
Overdose
A subject data listing of overdose records will be provided.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
31
10.
CONCOMITANT MEDICATIONS AND PROCEDURES
Concomitant medications and procedures will be summarized for Weeks 0-52 using the safety 
population.
10.1.
Concomitant Medications
 
 
 
 
 
The ATC coding scheme of the WHODD will be used to group medications into relevant 
categories. Concomitant medications will be summarized by ATC2 level and standardized 
medication name, with ATC2 levels and standardized medication names within each ATC2 level 
sorted in descending order of frequency.
10.2.
Concomitant Procedures
Concomitant procedures are defined similarly to concomitant medications. Concomitant 
procedures will be coded according to the MedDRA, and summarized by SOC and PT, with 
SOCs sorted in alphabetical order and PTs within each SOC in descending order of frequency.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
32
11.
EFFICACY ANALYSIS
All efficacy analysis tables will be presented by GED-0301 treatment regimen, placebo, and a 
total group combining all 3 GED-0301 treatment regimens. The 3 GED-0301 treatment regimens 
will be labeled as GED 160/GED 160 4 WK ALT, GED 160/GED 40 4 WK ALT, and GED 
160/GED 40, and the total group combining all 3 GED-0301 treatment regimens will be labeled 
as GED Total. Formal treatment comparisons will be made between GED Total (ie, GED 160) 
and placebo for the efficacy analyses of the first 12 weeks, and between each of the 3 GED-0301 
treatment regimens and placebo for the efficacy analyses beyond Week 12.
 
11.1.
Multiplicity
The protocol specifies that a gatekeeping closed testing procedure will be used to control the 
family-wise Type I error rate at the 2-sided significance level of 0.05 for the primary and 
secondary efficacy endpoints. Due to the early termination of the study, however, no multiplicity 
adjustment will be performed.
11.2.
Missing Data Handling
 
 
 
 
 
11.2.2.
Binary Efficacy Endpoints
11.2.2.1.
Primary Approach for Analysis
For binary efficacy endpoints, the primary approach to handling missing data will be 
nonresponder imputation (NRI), where subjects who are included in the denominator at the time 
point under consideration but have insufficient data for response determination at that time point
will be considered nonresponders for that time point.
 
 
To eliminate the downward bias to the estimate of a binary endpoint due to the inclusion of
subjects (as nonresponders due to NRI) who have not had a chance to reach the time point under 
consideration but have discontinued due to “study terminated by sponsor”, the denominator at 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
33
the time point under consideration will include subjects who have either completed that time 
point
 
or discontinued at any time due to reasons other than “study terminated by
sponsor”, instead of all subjects in the ITT population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
34
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.3.
Analysis of Primary Endpoint
11.3.1.
Primary Analysis of Primary Endpoint
The primary analysis of the primary endpoint, the proportion of subjects achieving clinical 
remission at Week 12, will be based on the ITT population. Missing data will be handled by the 
NRI method.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
35
The within-group proportion, standard error (SE), and 2-sided 95% CI
 
 for the within-group proportion will be provided for placebo, GED-0301 
treatment regimens, and GED 160 (combining all 3 GED-0301 treatment regimens). The 
treatment comparison will be made between GED 160 and placebo. The unstratified treatment 
difference in proportions, stratified treatment difference in proportions using the weighted 
average of the treatment differences across the strata with the Cochran-Mantel-Haenszel (CMH) 
weights, stratified 2-sided 95% CI 
 for 
the treatment difference in proportions, and the 2-sided p-value from the CMH test stratified by 
the randomization stratification factors, will be provided for the comparison of GED 160 and 
placebo.
 
 
 
11.4.
Analyses of Secondary Efficacy Endpoints
11.4.1.
Primary Analyses of Secondary Efficacy Endpoints
The primary analysis of each secondary efficacy endpoint will be performed similarly to the 
primary analysis of the primary endpoint. The treatment comparisons will be made between 
GED 160 (combining all 3 GED-0301 treatment regimens) and placebo for the endpoints at 
Weeks 4 and 12 and between each of the 3 GED-0301 treatment regimens and placebo for the 
endpoints at Week 52.
The analysis of the proportion of subjects who achieve corticosteroid-free clinical remission at 
Week 52 among subjects receiving oral corticosteroids at baseline will be based on the subjects 
included in the ITT population who receive oral corticosteroids for CD at baseline.
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
36
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
37
 
 
 
 
 
 
 
 
 
 
 
11.7.
Assessing Study Center Effect and Treatment-by-center Interaction
This study is a multicenter study and has hundreds of study sites planned. The limited number of 
subjects expected at many sites does not allow for a meaningful assessment of study center 
effect.
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
38
12.
SAFETY ANALYSIS
Safety will be evaluated via descriptive statistics and point estimates. No inferential testing for 
statistical significance will be performed.
The safety analyses will be based on the safety population. All safety analysis tables will be 
presented by GED-0301 treatment regimen, placebo, and a total group combining all 3 GED-
0301 treatment regimens. The 3 GED-0301 treatment regimens will be labeled as GED 160/GED 
160 4 WK ALT, GED 160/GED 40 4 WK ALT, and GED 160/GED 40, and the total group 
combining all 3 GED-0301 treatment regimens will be labeled as GED Total.
 
 
 
 
 
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
39
 
12.2.
Adverse Events
Adverse events 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 total group combining all 3 GED-0301 
treatment regimens.
For the analyses 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.
!
 
 
 
 
 
 
 
 
 
All AE summaries will be provided for Weeks 0-52. Where so indicated, select AE summaries 
will also be provided for Weeks 0-12 and/or Weeks 12-52.
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 0-12, Weeks 
12-52, and Weeks 0-52:
!
Any TEAE
!
Any drug-related TEAE
!
Any severe TEAE 
!
Any serious TEAE
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
40
!
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 total group combining all 3 GED-0301 treatment regimens) for Weeks 0-
12, Weeks 12-52, and Weeks 0-52.
12.2.3.
Drug-related TEAEs
Drug-related TEAEs will be summarized for Weeks 0-12, Weeks 12-52, and Weeks 0-52.
12.2.4.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, and severe) for Weeks 0-
52. 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 0-12, Weeks 12-52, and Weeks 0-52. 
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 0-12, Weeks 12-52, and 
Weeks 0-52.
A subject data listing of AEs leading to drug withdrawal will be provided.
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), 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
41
alanine aminotransferase/serum glutamic pyruvic transaminase (SGPT), sodium, 
potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, lactic 
dehydrogenase (LDH), magnesium.
!
Complement activation (Bb, C3a and C5a). 
!
Coagulation assessment will include: prothrombin time and activated partial 
thromboplastin time (APTT).
!
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, the end of Weeks 0-12, the 
end of Weeks 12-52, and the end of Weeks 0-52).
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 0-12, the end of Weeks 12-52, the 
end of Weeks 0-52, and the worst value of Weeks 0-52) 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 18.4 will be provided for 
Weeks 0-52.
 
 
 
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.
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, the end 
of Weeks 0-12, the end of Weeks 12-52, and the end of Weeks 0-52).
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 0-52 in
investigator clinical interpretation of ECG (normal; abnormal, not clinically significant; and 
abnormal, clinically significant) will be provided. 
 
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Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
42
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
43
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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GED-0301
Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
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44
15.
INTERIM ANALYSIS
There will be no interim analysis for this study.
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45
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.
!
For binary efficacy endpoints, the denominator at the time point under consideration will 
include subjects who have either completed that time point
 
or discontinued at 
any time due to reasons other than “study terminated by sponsor”, instead of all subjects 
included in the ITT population (Sections 5.3.1 and 11.2.2.1).
 
 
!
The protocol specifies that a gatekeeping closed testing procedure will be used to control 
the family-wise Type I error rate at the 2-sided significance level of 0.05 for the primary 
and secondary efficacy endpoints. This SAP specifies no multiplicity adjustment will be 
performed (Section 11.1).
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Statistical Analysis Plan. Protocol GED-0301-CD-002
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Statistical Analysis Plan. Protocol GED-0301-CD-002
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Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
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Statistical Analysis Plan. Protocol GED-0301-CD-002
Celgene 
Confidential and Proprietary
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