A Non-Interventional Long-term Post-Marketing Registry of Patients Treated With Certolizumab Pegol (Cimzia ®) for Crohn's Disease
Conditions: Crohn's Disease
Sponsor: UCB BIOSCIENCES, Inc.

UCB
08 Sep 2017
Clinical Study Protocol
Certolizumab pegol
C87075
Confidential
Page 1 of 115
Study C87075
Protocol Amendment 5
SECURE
A Non-Interventional Long-term Post-Marketing Registry of Patients Treated with 
Certolizumab Pegol (Cimzia®) for Crohn's Disease
IND Number: 011197
UCB Biosciences, Inc.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Hereafter “UCB”
Protocol/Amendment Number
Date
Type of amendment
Protocol
06-Jan-2009
Not applicable
Protocol Amendment 1
24-Jun-2009
Substantial
Protocol Amendment 2
05-Dec-2011
Substantial
Protocol Amendment 3
03-Dec-2013
Substantial
Protocol Amendment 4
10-Feb-2015
Substantial
Protocol Amendment 5
08-Sep-2017
Nonsubstantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.
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08 Sep 2017
Clinical Study Protocol
Certolizumab pegol
C87075
Confidential
Page 2 of 115
STUDY CONTACT INFORMATION
Sponsor
UCB Biosciences, Inc., 8010 Arco Corporate Drive, Raleigh, NC  27617, USA
Clinical Program Director
Name:
Phone:
Fax:
Not Applicable
Senior Clinical Project Manager
Name:
Phone:
Fax:
Not Applicable
Senior Biostatistician
Name:
Phone:
Fax:
Not Applicable
Sponsor Study Investigator
Name:
, MD
Phone:
Fax:
Sponsor Study Epidemiologist
Name
, PhD
Phone:
Fax:
Not Applicable
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08 Sep 2017
Clinical Study Protocol
Certolizumab pegol
C87075
Confidential
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SERIOUS ADVERSE EVENT REPORTING
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www. secure-cimziadata.com
Fax:
+1 (888) 772 6919 (PRA number to be used if site is unable to access 
the electronic data capture [EDC] system)
Phone:
+1 (800) 772 3125 Study code 707501 (PRA number for EDC 
questions)
Phone:
+1 (866) 822 0068 (UCB number for questions related to adverse event 
reporting)
Email:
chosafety@praintl.com (PRA contact)
Site Support
Phone:
+1 (800) 772 3125 (reference number: 707501)
Patient Interview Service
Phone:
+1 (877) 580 7246
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08 Sep 2017
Clinical Study Protocol
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C87075
Confidential
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TABLE OF CONTENTS
1
INTRODUCTION .............................................................................................................8
2
REGISTRY RATIONALE ................................................................................................8
3
REGISTRY OBJECTIVE..................................................................................................8
4
REGISTRY STUDY PLAN ..............................................................................................9
4.1
Investigator Selection Criteria .................................................................................9
4.2
Selection of Study Population..................................................................................9
4.3
Subject Inclusion/Exclusion Criteria .......................................................................9
4.4
Study Procedures ...................................................................................................10
4.5
Schedule of Assessments.......................................................................................10
4.6
Informed Consent...................................................................................................12
4.7
Participation and Retention Strategies...................................................................13
4.8
Data Collection Strategies......................................................................................14
4.8.1
Enrollment Visit...........................................................................................14
4.8.2
Follow-Up Period ........................................................................................15
5
ADVERSE EVENTS OF INTEREST, SERIOUS ADVERSE EVENTS, CASE 
AND EXPOSURE DEFINITIONS .................................................................................15
5.1
Definitions..............................................................................................................16
5.2
Adverse Events of Interest.....................................................................................16
5.2.1
Autoimmune disorders.................................................................................18
5.2.2
Demyelinating disorders..............................................................................18
5.2.3
Serious and Opportunistic Infections...........................................................18
5.2.4
Lymphoma and Other Malignancies............................................................19
5.2.5
Hypersensitivity Reaction............................................................................19
5.2.6
Congestive heart failure...............................................................................19
5.2.7
Aplastic anemia............................................................................................20
5.2.8
Serious bleeding events ...............................................................................20
5.2.9
Serious skin reactions ..................................................................................20
5.3
Anticipated Serious Adverse Events......................................................................20
5.4
Adverse Event Reporting to the Registry ..............................................................20
5.5
Pregnancy and Breastfeeding.................................................................................21
5.6
UCB Pharmacovigilance Reporting.......................................................................21
6
STATISTICAL CONSIDERATIONS.............................................................................23
6.1
Endpoints ...............................................................................................................23
6.1.1
Primary Endpoints .......................................................................................23
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6.1.2
Secondary Endpoints ...................................................................................23
6.2
Comparator Group .................................................................................................23
6.3
Determination of Sample Size ...............................................................................24
6.4
Statistical Analyses ................................................................................................24
6.4.1
Primary Analyses.........................................................................................25
6.4.1.1
Malignancy Events.............................................................................25
6.4.1.2
Acute Events ......................................................................................26
6.4.1.3
Propensity Scores...............................................................................27
6.4.1.4
Event Rate Comparisons....................................................................29
6.4.2
Secondary Analyses.....................................................................................29
6.5
Interim Analyses ....................................................................................................30
7
ETHICS REQUIREMENTS............................................................................................30
7.1
Institutional Review Board ....................................................................................30
8
COMPLETION OF THE STUDY...................................................................................30
9
USE OF INFORMATION AND PUBLICATION..........................................................30
10
DISCLOSURE OF TRIAL INFORMATION.................................................................31
11
REFERENCES ................................................................................................................31
12
APPENDICES .................................................................................................................32
12.1
Appendix A: Harvey-Bradshaw Index (HBI)........................................................32
13
DECLARATION AND SIGNATURE OF INVESTIGATOR .......................................33
14
AMENDMENTS .............................................................................................................34
14.1
Protocol amendment 1 ...........................................................................................34
14.2
Protocol amendment 2 ...........................................................................................55
14.3
Protocol amendment 3 ...........................................................................................75
14.4
Protocol amendment 4 .........................................................................................100
14.5
Protocol amendment 5 .........................................................................................110
LIST OF FIGURES
Figure 5‒1: Event reporting process ........................................................................................22
Figure 6‒1: Example person-time at risk for malignancy events.............................................26
Figure 6‒2: Example person-time at risk for acute events.......................................................27
LIST OF TABLES
Table 5‒1: Standardized MedDRA Queries for select adverse events of interest..................17
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C87075
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LIST OF ABBREVIATIONS
AE
adverse event
anti-TNFα
anti-tumor necrosis factor alpha
CD
Crohn’s disease
CI
confidence interval
CPM
Clinical Project Manager
CRO
Contract Research Organization
CSE
cross-section echocardiography
eCRF
electronic case report form
EDC
electronic data capture
EEG
Electroencephalogram
EMG
Electromyogram
FDA
Food and Drug Administration
HBI
Harvey-Bradshaw Index
IRB
Institutional Review Board
MedDRA®
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
p-y
patient years
RR
Rate ratio
SAE
serious adverse event
SAP
statistical analysis plan
TNF
tumor necrosis factor
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08 Sep 2017
Clinical Study Protocol
Certolizumab pegol
C87075
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USA
United States of America
WHO Drug
World Health Organization Drug
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08 Sep 2017
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Certolizumab pegol
C87075
Confidential
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1
INTRODUCTION
Following the Food and Drug Administration (FDA) approval of certolizumab pegol 
(Cimzia®) for Crohn’s disease (CD), UCB has committed to collect additional long-term, 
post-marketing safety data on patients exposed to the product in a real-life setting. To achieve 
this goal, a pharmacoepidemiologic study entitled SECURE was designed. The study began 
in January 2009 with the goal of collecting prospective data on 2000 patients prescribed 
Cimzia and a 2000 patient comparator group prescribed other treatments (including biologics) 
for CD. 
The protocol has been amended (Amendment 5) to cease enrolling patients into the SECURE 
registry (protocol C87075). The decision was based on the results of a current interim 
analysis that indicated that no new safety issues had emerged from the currently known safety 
profile of Cimzia. Patients who already enrolled in C87075 at the time of discontinuation will 
continue to be followed.
The SECURE registry represents a significant addition to post-marketing safety assessments 
based on spontaneous reports. The study is anticipated to continue monitoring all enrolled 
patients for approximately 8 years after enrollment. Section 14 provides detailed information 
on protocol history since Final Version.
2
REGISTRY RATIONALE
This study is a post-approval commitment study designed to monitor the long-term safety of 
Cimzia compared to other CD treatments when used in customary clinical practice in patients 
with CD. Enrolled patients will be followed for approximately 8 years during normal 
Investigator visits and through direct patient follow-up in the form of web, mail surveys 
and/or phone follow-up calls. All patients will receive and use their medications according to 
their normal course of medical treatment per Investigator clinical judgment.
The treating Investigator is requested to report all serious adverse events (SAEs) and 
nonserious adverse events (AEs) of interest to the registry. These events will be collected and 
summarized in aggregate.
3
REGISTRY OBJECTIVE
The objective of this registry is to measure the safety outcomes among Cimzia patients 
compared to those that occur while on a different CD treatment regimen.
All SAEs and AEs of interest will be collected and summarized (see Section 5). The AEs of 
interest are: selected autoimmune disorders and demyelinating disorders, serious infections 
including opportunistic infections, hypersensitivity reactions, lymphoma and other 
malignancies. In addition, UCB plans to evaluate aplastic anemia and serious cardiac events
(specifically, CHF). All these events represent serious risks known to the class of tumor 
necrosis factor (TNF) blocking agents. During the development program for CD and 
rheumatoid arthritis consisting of over 6,000 subjects, reported events were consistent with 
the class.
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4
REGISTRY STUDY PLAN
4.1
Investigator Selection Criteria
Selected gastroenterologists and internal medicine Investigators from both community-based 
and academic practice settings (75% and 25% respectively) will be approached to participate 
in this registry. Investigators will be asked to provide a confidentiality agreement, recruitment 
questionnaire, signed protocol signature page, signed study contract, Form FDA 1572, 
Financial Disclosure Form, current CV, and receive Institutional Review Board (IRB) 
approval prior to study activation. Once activated, Investigators will be able to consent 
patients using their IRB approved template and enroll patients into the study. Each
Investigator should be able to recruit a minimum of 5 patients prescribed Cimzia and/or 
5 patients prescribed other treatments.
4.2
Selection of Study Population
This is a long-term observational study in the USA that includes a total of 3045 CD patients
(1371 in the Cimzia Cohort and 1674 in the Comparison Cohort) as of Mar 2017. To ensure a 
sufficient number of Cimzia-treated patients in the registry, approximately half of enrolled 
patients will be receiving Cimzia for ≤12 months or about to receive Cimzia at the time of 
enrollment. The study will be conducted in all regions in the USA at approximately 280
enrolling investigative sites.
Recruitment of Cimzia-treated and comparator patients will be monitored and controlled as 
needed in order to ensure balanced enrollment over time.
Quarterly progress reports will be sent to the FDA during the patient recruitment period.
4.3
Subject Inclusion/Exclusion Criteria
Patients who meet all of the following criteria will be eligible for inclusion into the SECURE 
Registry:

Patient (or his/her legally acceptable representative) is able to provide written informed 
consent to permit collection of data.

Patient must be 18 years of age or older.

Patient must have medically documented CD.

The decision to prescribe Cimzia or other medications has been made by the Investigator
independently of the decision to include the patient in the study.

Patients participating in randomized, blinded clinical trials for CD or other conditions are 
not eligible for inclusion into the SECURE registry. Involvement in other registries, 
where patients follow routine clinical practice, is permitted, however.
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Cimzia-treated patients
For a patient to qualify as being treated with Cimzia, they must meet one of the following 
criteria:

Patient is receiving treatment with Cimzia for the first time. Patient must receive Cimzia 
treatment within 2 months of enrollment into the registry.

Patient is currently receiving treatment with Cimzia for ≤12 months. Patients must also
receive a Cimzia dose within 2 months following enrollment into the registry.
Comparator patients
Patients enrolled in the comparator group are eligible to participate in the registry if one of 
the following criteria is fulfilled:

Patient is switching CD treatments or beginning CD treatment for the first time. Previous 
Cimzia treatment is prohibited in the comparator group.

Patient must receive new CD treatment within 2 months of enrollment into the registry.
Patients must fit into at least ONE of the following 3 criteria:

Patient is currently receiving for CD anti-TNF treatment (or other approved biologics) for 
≤12 months. Patient must receive anti-TNF treatment (or other biologics) within 2 months 
following enrollment into the registry.

Patient is currently receiving immunosuppressant therapy for ≤12 months. Patient must 
receive immunosuppressant therapy within 2 months following enrollment into the 
registry.

Patient is currently receiving systemic steroid therapy for ≤12 months. Patient must 
receive systemic steroid therapy within 2 months following enrollment into the registry.
4.4
Study Procedures
Patient care will follow current clinical practice for CD at the respective site. No additional 
diagnostic or monitoring procedures will be applied. The choice of medical treatment will be 
made independently by the Investigator in the regular course of practice and will not be 
influenced by participation in the study protocol.
The Investigator will treat the patient according to standard medical practice for CD at the 
respective site. Investigators are free to add or withdraw any medication, or to withdraw the 
patient from the study at their own discretion. Patients are likely to receive other treatments 
for CD as part of their treatment plan in the regular course of practice.
Cimzia or other medications will not be provided nor paid for by the Sponsor.
4.5
Schedule of Assessments
No mandatory visits are required as part of this protocol. All visits will be scheduled and 
conducted per sites standard of care. Standard of care is defined as: A diagnostic and 
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Clinical Study Protocol
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customary clinical treatment/practice process that a clinician should follow for a Crohn’s 
disease patient, a certain type of illness, or clinical circumstance.
Investigators will complete the baseline data for each patient after enrollment into the study
and includes the signing of the Informed Consent Form (ICF). Follow-up data for patient 
visits will be reported in accordance to sites standard of care or clinical judgment 
appointments. Telephone contacts are permitted. All data, as described in Section 4.8.2, are to 
be collected as available during the telephone contacts.
In an effort to minimize missing data and unreported events over the 8-year Follow-Up 
Period, patients will directly report data in parallel to the Investigator reported data. Direct 
patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12, etc) via a 
web-based system, by mail or by phone - as preferred by the patient. If a patient does not 
provide the information via the web, mail or by phone within approximately 1 week after the 
3 month due date, the study patient interview service will call the patient to obtain the 
required information over the phone. Safety information collected directly from the patient 
will be available for the study investigative site to review. If 8 consecutive quarterly patient 
surveys have not been at least partially completed, further attempts at patient contact are not 
required.  The Investigator will be requested to confirm whether the patient status should be 
changed to ‘Lost to Follow-up’. 
Study Entry 
(Baseline)
Investigator-
Reported Follow-
upb
Direct Patient 
Follow-up 
Year 1-8
ENROLLMENT
PER STANDARD 
OF CARE
EVERY 
3 MONTHS
Written informed consent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or other 
medication
X
Planned Cimzia or other medication 
treatment period 
X
X
CD treatment medication changes and 
reason 
X
X
Concomitant medications 
X
X
X
All SAEs and AEs of interest since time 
of last completed follow-upa
X
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C87075
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Study Entry 
(Baseline)
Investigator-
Reported Follow-
upb
Direct Patient 
Follow-up 
Year 1-8
ENROLLMENT
PER STANDARD 
OF CARE
EVERY 
3 MONTHS
Major changes in health status since last 
completed follow-up
X
Investigator’s assessment of disease 
severity
X
X
Investigator’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease severity
X
X
Reasons for discontinuation from 
registry (early termination or end of 
Year 8)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey-Bradshaw Index; SAE=serious adverse event
aAll SAEs and AEs of interest are to be reported through the registry. 
b Telephone contacts are permitted.
c.This may also be completed by qualified site personnel as designated by the Investigator.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the Investigator telephone contact instead of the full HBI. 
4.6
Informed Consent
The patient (or his/her legally acceptable representative) must be able to provide written 
informed consent for participation in this registry and release of their data to UCB (sponsor) 
and the Contract Research Organization (CRO) for analysis. Prior to obtaining informed 
consent, the Investigator or designee will explain to the patient the nature and purpose of the 
study. After informed consent is obtained, the patient will complete a “Patient Contact Form”, 
which will request contact information (phone number, email address, and physical address). 
This form will be submitted to an independent patient interview service by the Investigator.
Information and instructions informing patients about the Follow-Up Period and how to 
report AEs is included in the Informed Consent Form. The original document will be placed 
in the patient’s medical record and a signed copy given to the patient.
Medication guides will be provided per standard of care.
Upon enrollment, patients will receive an enrollment kit that includes general registry 
information, including a patient card that identifies them as a participant in the SECURE 
Registry. The card informs the treating Investigator that the patient is participating in a 
registry study, and provides instructions for the treating Investigator on how to report AE or 
other treatment information to the Investigator.
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4.7
Participation and Retention Strategies
Individual patient follow-up is approximately 8 years after enrollment, regardless of 
discontinuation of Cimzia or other medications.
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if preferred, by mail (including a prepaid self-addressed return envelope) or by the 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey. “Lost to follow-up” is defined as a 
patient who goes 2 years with no data being collected/reported (2 years without Investigator
visit/telephone contact or failure to at least partially complete 8 consecutive quarterly patient 
surveys; further attempts at patient contact are not required). The patients will receive emails 
or postal mail reminding them to complete the survey. If they have not completed the survey 
one week after the due date, they will be called by the independent patient interview service 
to complete the survey via phone. Patients completing the quarterly surveys will receive a 
nominal appreciation gift (if approved by the site’s IRB).
In the event an Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients. The 
Informed Consent Form include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and the name and contact information of the closest participating study 
Investigator that they can contact during the remainder of their participation in the registry. 
The new Investigator and the patient should document re-consent of the transition. The 
registry can continue to collect the direct patient-reported data without the need for re-
consent. If the patient is unable or unwilling to be followed by a new Investigator, the patient 
must be discontinued from the study. 
In the event a patient moves to a new location or chooses to leave their current Investigator, 
patients are provided with information upon enrollment as to how to locate a participating 
Investigator in their area or how to provide the registry information to a new Investigator that 
may not yet be participating. Participating patients will have access to all of this information 
on the study specific web portal.
The goal of these strategies is to enhance patient retention activity, potentially resulting in a 
lower drop-out rate and improved quality of data.
Over the course of a long-term study, patient death may occur. Additionally, patients may 
develop serious co-morbidities that cause them to become “lost to follow-up” in the Registry. 
Periodically throughout the study, and in case of “lost to follow-up”, searches of appropriate 
databases, such as the national death index and state cancer registries, death or cancer 
registries will be performed for any matches. In addition, the sponsor may utilize patient-
centric data warehouse organization(s), to extract de-identified data from healthcare channels 
in the US. Data sources include, but are not limited to, medical claims, pharmacy claims, 
hospital charge master records, behavioral and demographic information, oncology electronic 
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medical records (EMR), long-term care pharmacy, and laboratory data. The output from this 
activity will not be used to solicit additional events from Investigators.
4.8
Data Collection Strategies
All investigator-reported data must be retained as source data in the patient’s medical record. 
Data will be collected for this registry study from both the Investigators and patients using 
electronic data capture (EDC) system. Participating Investigators and enrolled patients (web-
based participants) will enter the applicable data for each collection interval into a specific 
electronic case report form (eCRF). Enrolled patients requesting mail surveys will return the 
completed paper survey in the prepaid self-addressed return envelope and the applicable data 
will be entered in the specific eCRF by the independent patient interview service. Data 
collected from enrolled patients by phone will be entered in the eCRF by the independent 
patient interview service.
A study-specific web portal will be created and used as a centralized location for prospective 
Investigators and patients to find basic registry study information. For participating 
Investigators, a restricted area of the web portal may be accessed via SECURE username and 
password. The restricted area of the web portal will contain study-related material such as the 
protocol, trainings, study communications, as well as the link for the eCRF for data entry.
As this is an 8-year follow up registry study, the technologies used for this registry such as 
EDC will be 21 CFR Part 11 compliant and evaluated on an on-going basis throughout the 
registry study to ensure upgrades are made when necessary.
4.8.1
Enrollment Visit
For each patient enrolled in this registry, the Investigator will document the following 
information into the corresponding eCRFs within the registry study EDC system:

Demographic information such as gender, age, race, ethnicity, household income, 
occupation and smoking status

Crohn’s disease history, including length of time since initial presentation of symptoms, 
date of diagnosis, all past treatment and surgeries for CD (with special focus on 
anti-TNFα and other biologics), and reason for switch to Cimzia or other medications 
since diagnosis and within the past 3 months

Investigator’s assessment of CD severity 

Investigator’s completion of the Harvey-Bradshaw Index (HBI) – See Section 12.1
APPENDIX A. This may also be completed by qualified site personnel as designated by 
the Investigator

Patient’s assessment of CD severity

Patient’s completion of the modified HBI. The modified HBI does not include the 
abdominal mass question contained in the full HBI
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
Other medical history including current medical status, concomitant medications, and 
planned treatment period (if known) with special focus on previous occurrence of each 
AE of interest and related risk factors (eg, history of serious infections, conditions that 
might place a patient at higher risk of serious infection)
4.8.2
Follow-Up Period
Each study Investigator or patient will be contacted by the CRO at regular intervals 
throughout the study to ensure they are entering data in the eCRF at the following 
frequencies:

Every six months for Investigator-reported information. Telephone contacts are permitted.

Every three months for patient-reported information (web, mail survey or phone) 
The following data will be collected as available by the Investigator in EDC at each follow-up 
interval:

All SAEs and AEs of interest that have been reported since last follow-up

Investigator’s HBI completed at clinic visits or modified HBI completed during telephone 
contacts. This may also be completed by qualified site personnel as designated by the 
Investigator

Investigator’s assessment of disease severity

Full details on exposure (eg, dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for CD
The following data will be collected from the patient at each quarterly interval: 

Any major changes in health status that may have occurred since last follow-up

Patient’s Modified HBI

Patient’s assessment of disease severity

Full details on exposure to Cimzia or other medications

Any changes in medication

Any administrative changes such as change in contact information
5
ADVERSE EVENTS OF INTEREST, SERIOUS ADVERSE 
EVENTS, CASE AND EXPOSURE DEFINITIONS
Serious adverse events and AEs of interest are the focus of this registry; Investigators are not 
expected to enter nonserious AEs in the eCRF except for AEs of interest regardless of 
seriousness.
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5.1
Definitions
Adverse Event (AE): Any untoward medical occurrence in a patient administered a 
pharmaceutical product or device and that does not necessarily have a causal relationship 
between the product and event. An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom temporally associated with a medicinal 
product, whether or not related to the medicinal product.
Serious Adverse Event (SAE): Any untoward medical occurrence which results in:

Death

Is life-threatening

Requires inpatient hospitalization, or prolongs hospitalization

Results in persistent or permanent disability or incapacitation

Results in a congenital anomaly, or birth defect

Any important medical event that may not be immediately life-threatening or result in 
death or hospitalization but, based upon appropriate medical judgment, may jeopardize 
the patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition above should also be reported as an SAE. These events 
include but are not limited to peripheral or pulmonary edema which requires diuresis in an 
emergency room or out-patient setting, aplastic anemia/pancytopenia, serious cardiac 
event or an infection requiring treatment with parenteral antibiotics, etc.
All SAEs must be reported within 24 hours of being acknowledged by the Investigator.
5.2
Adverse Events of Interest

Autoimmune disorders, such as:

systemic lupus erythematous

rheumatoid arthritis 

Demyelinating disorders, such as:

multiple sclerosis

Guillain-Barre syndrome

chronic inflammatory demyelinating polyneuropathy 

Serious infections including opportunistic infections, such as:

tuberculosis

pneumonia

Lymphoma and other malignancies, such as:
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
hepatosplenic T-cell lymphoma

non-Hodgkin’s lymphoma

solid malignancies

Acute hypersensitivity reactions occurring within 2 hours of drug administration, such as:

urticaria, rash, pruritus, flushing, swollen lips/tongue/pharynx, wheezing, dyspnea, 
hypotonia, cramping, abdominal pain, and vomiting

Other events: 

congestive heart failure 

aplastic anemia, pancytopenia, thrombocytopenia, neutropenia and leucopenia

serious bleeding events

serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme)
When available, narrow scope SMQs (Standardized MedDRA Queries) from the Medical 
Dictionary for Regulatory Activities (MedDRA®) version 17.0 will be used to define the AEs
of interest (Section 5.2).  Adverse events of interest that are the clinical endpoints for the 
SECURE registry will be confirmed by review of  the results of diagnostic tests and 
diagnostic criteria used by the Investigator which are further explained within each section 
below.
Table 5‒1:
Standardized MedDRA Queries for select adverse events of 
interest
Event
SMQ Title
SMQ Code
SMQ Scope
Malignancy
Malignant tumours
20000194
Narrow PTs
Congestive Heart Failure 
Cardiac failure 
20000004
Narrow PTs
Serious skin reactions 
Severe cutaneous adverse 
reactions
20000020
Selected Narrow PTs
Hypersensitivity 
reactions
Anaphylactic reaction
20000021
Narrow/Broad PTs
Serious bleeding events
Haemorrhage 
20000038 
Narrow PTs
Aplastic anemia 
Haematopoietic 
cytopenias affecting more 
than one type of blood cell 
20000028
Narrow PTs
Aplastic anemia 
Haematopoietic 
erythropenia
20000029
Narrow PTs
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Table 5‒1:
Standardized MedDRA Queries for select adverse events of 
interest
Event
SMQ Title
SMQ Code
SMQ Scope
Aplastic anemia
Haematopoietic 
leukopenia
20000030
Narrow PTs
Aplastic anemia 
Haematopoietic 
thrombocytopenia 
20000031
Narrow PTs
For events in which SMQs are not available, MedDRA v 17.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. For AEs of interest, where no SMQ is available, medical review will occur to 
select AEs (eg demyelinating disorders, autoimmune disorders and serious infections). 
Additional detail on the clinical validation of the primary endpoints is presented below 
although all safety events that meet the definition of AEs of interest will be collected and 
summarized as part of the study.
5.2.1
Autoimmune disorders
For this category, the primary events are Systemic Lupus Erythematous and Rheumatoid 
Arthritis.
The diagnosis has to be supported with medical history and physical findings, serologic 
evidence and other evidence from biopsy, laboratory results, imaging results, or other 
specialized testing, where appropriate, and the exclusion of other disorders which might cause 
a similar pattern of findings.
5.2.2
Demyelinating disorders
For this category, the primary event is Multiple Sclerosis. Guillain-Barre syndrome and 
chronic inflammatory demyelinating polyneuropathy will be analyzed as autoimmune 
disorders.  
Medical history and physical findings, laboratory results, imaging results (eg, MRI) and any 
other specialized test (EEG, EMG, CSF analysis) results have to be considered in determining 
the final diagnosis.
5.2.3
Serious and Opportunistic Infections
Serious infections are defined as all infections meeting the definition of an SAE, and/or an 
infection requiring parenteral administration of antibiotics.
For the opportunistic infection category, the primary events are tuberculosis and pneumonia. 
The definitive diagnosis of pneumonia and tuberculosis may be confirmed by obtaining 
sputum smears or relevant biopsies and verifying by cultures. Infections not usually seen in 
immunocompetent patients or infections that have an accelerated pathogenesis or a more 
severe outcome in a given setting will also be considered opportunistic infections.
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5.2.4
Lymphoma and Other Malignancies
For this category, the primary events are lymphoma, including hepatosplenic T cell 
lymphoma and non-Hodgkin lymphoma, and solid malignant tumors which are captured on 
malignancy forms.
Diagnosis has to be confirmed by tissue biopsy for histopathology (sources of tissue samples 
for review may include those obtained from an excisional biopsy) -a tissue sample from the 
affected nodes or organ, a needle aspiration, or a bone marrow biopsy. Pathohistological 
results have to correlate clinically with imaging results and/or any other pertinent information 
prior to determining the final diagnosis.
5.2.5
Hypersensitivity Reaction
Primary endpoints for hypersensitivity reaction are events meeting the criteria of an 
anaphylactic reaction and acute hypersensitivity reaction occurring within 2 hours of drug 
administration. As described in the case definition below, anaphylactic events include all 
terms listed in Category A, which consists of the narrow terms Type I hypersensitivity, 
anaphylactic shock and anaphylactoid reaction. In addition, combinations of the AE terms 
listed in Categories B, C and D will also be defined as anaphylactic events. 
Category A: anaphylactic reaction, Type I hypersensitivity, anaphylactic shock,
anaphylactoid reaction
Category B: dyspnoea, chest discomfort, cough, swollen tongue, oedema mouth, throat 
tightness, wheezing, laryngeal oedema, respiratory distress, sensation of foreign body,
asthma, sneezing
Category C: swelling face, urticaria, pruritus, rash, eye swelling, pruritus generalized, rash, 
generalized, flushing, erythema, swelling, eye pruritus, lip swelling, rash pruritic, rash,
erythematous, eyelid oedema, ocular hyperaemia, injection site urticaria, angioedema
Category D: hypotension, blood pressure decreased
To meet the definition of an anaphylactic event, a case has to meet one of the following 
criteria:
1. A narrow term or a term from Category A;
2. A term from Category B (Upper Airway/Respiratory) AND a term from Category C
(Angioedema/Urticaria/Pruritus/Flush);
3. A term from Category D (Cardiovascular/Hypotension) AND either a term from 
Category B (Upper Airway/Respiratory) or a term from Category C 
(Angioedema/Urticaria/Pruritus/Flush)
5.2.6
Congestive heart failure
Congestive heart failure (CHF) is the primary endpoint for cardiac events of interest. CHF 
will be defined by Framingham criteria. The diagnostic criteria include physical findings of 
low cardiac output or increased cardiac workload and radiographic evidence (chest X-ray, 
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ECG, Echocardiogram, CT, MRI, angiogram) and laboratory findings, ECG and imaging 
results and any other specialized test results have to be considered for final diagnosis. CHF 
present at baseline and worsening during the study (worsening of New York Heart 
Association (NYHA) functional classification) will be captured, as well as new onset CHF.
5.2.7
Aplastic anemia
Aplastic anemia is a primary endpoint. Diagnosis must be confirmed by complete blood count 
(CBC) with peripheral smear, and bone marrow biopsy. Findings of pancytopenia 
(neutropenia, thrombocytopenia, and anemia), a reduction in the absolute number of 
reticulocytes, and a hypocellular bone marrow could be used to confirm the diagnosis.
5.2.8
Serious bleeding events
For this category, bleeding events meeting the criteria of an SAE are primary endpoints.
5.2.9
Serious skin reactions
For this category, primary endpoints are Erythema multiforme, Stevens Johnson’s syndrome, 
and Toxic epidermal necrolysis.
5.3
Anticipated Serious Adverse Events
The following list of Anticipated SAEs has been identified as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure. This original list will remain in effect for the duration of the protocol.
This list does not change the Investigator’s obligation to report all serious AEs (including 
Anticipated SAEs) as detailed in Section 5.4.
Crohn’s disease
perianal abscess
abdominal pain
5.4
Adverse Event Reporting to the Registry
Serious adverse events and AEs of interest are the focus of this registry; Investigators are 
expected to enter all SAEs and AEs of interest in the eCRF.
All SAEs and all AEs of interest will be entered in the EDC system within 24 hours of site 
notification and will be automatically forwarded to PRA, International for assessment and 
further processing as per regulatory requirements and UCB procedures (see Figure 5‒1, Event 
Reporting Process for flow of activity).
Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the Investigator for medical confirmation. Once medical 
confirmation is obtained, the Investigator will report the event through the EDC system. 
To ensure the capture of any events that might occur between patient or Investigator data 
entry intervals, each patient will be provided a safety reporting process patient card that they 
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can present to an Investigator if they have an event. The card will contain instructions for the 
Investigator on how to report event information.
Information and instructions informing patients about the Follow-Up Period and how to 
report AEs is included in the Informed Consent Form. More detailed instructions to sites 
regarding reporting of SAEs and AEs of interest are provided in the UCB safety Guidance 
booklet. 
5.5
Pregnancy and Breastfeeding
Investigators are required to report pregnancy and breastfeeding of study participants; and 
pregnancy of study participant partners. An informed consent form will be provided to a 
study participant’s partner who becomes pregnant during the study; and who will be willing 
to provide information on pregnancy course and outcome. More detailed instructions to sites 
regarding reporting of pregnancy and breastfeeding are provided in the UCB safety Guidance 
booklet. 
5.6
UCB Pharmacovigilance Reporting
Adverse events collected from the registry that occur within 70 days of last Cimzia dose will 
be included in UCB’s safety database and reported to the FDA as per regulatory reporting 
guidelines. Registry cases of malignancy, death, and pregnancy will be included in UCB’s 
safety database and reviewed and evaluated for FDA reporting even if the event occurs after 
70 days of last Cimzia dose. Any reports received prior to start of the registry and after 
completion of the study will be evaluated and reported as per standard UCB 
pharmacovigilance plans for spontaneous reporting.
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Figure 5‒1: Event reporting process
AE=adverse event; EDC=electronic data capture; SAE=serious adverse event
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6
STATISTICAL CONSIDERATIONS 
6.1
Endpoints
The objective of this registry is to measure the safety outcomes among Cimzia patients 
compared to those that occur while on a different CD treatment.
6.1.1
Primary Endpoints
The primary outcome of this observational study is malignancy. Additionally, the following 
safety events will be investigated: 

Autoimmune disorders 

Demyelinating disorders 

Serious infections or opportunistic infections

Hypersensitivity reactions

Other events: 

congestive heart failure 

aplastic anemia

serious bleeding events

serious skin reactions
MedDRA coding version 17.0 will be used to identify and define AEs of interest. The
specific MedDRA codes used to determine AEs of interest will be provided in the SAP.
Narrow scope SMQs and clinical validation of primary endpoints are provided in Section 5.2
of the protocol.
6.1.2
Secondary Endpoints
Secondary endpoints include the following:

Changes in HBI rating scale from baseline to each post-baseline assessment 

Changes in Investigator’s assessment of disease from baseline to each post-Baseline 
assessment

Changes in the patient’s disease assessment of disease from Baseline to each 
post-Baseline assessment
6.2
Comparator Group
Given that patients will be followed for 8 years, it is anticipated that patients will switch CD 
medications while enrolled in the registry. Therefore, an individual’s treatment at baseline 
will most likely not reflect their exposure throughout the study. Two comparisons may be 
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used to reflect these treatment changes over time and provide context for events reported to 
the registry: (1) a comparison of Cimzia event rates compared to all other CD treatment event 
rates across patients, and (2) case-crossover comparison or a within patient comparison.

Cimzia event rates versus all other CD treatment event rates
Incidence and recurrence rates may be calculated for Cimzia and compared to all other CD 
treatment event rates across patients. Class-specific and product-specific event rates may also 
be calculated, if appropriate. 

Case-crossover comparisons
Case-crossover studies are useful for investigating the effect of transitory exposures on acute 
events. By having patients act as their own controls, this design eliminates between-person 
confounding on non-time varying characteristics, such as baseline disease and treatment 
characteristics and gender. However, there is still the potential for within-person confounding 
due to changes in the patient’s profile over time (eg, changes in prescribing or in disease 
severity).
The incidence of safety events with short-term latency may also be compared within patients
for patients that switch treatments at the time of enrollment into the registry and/or while 
participating in the registry. For this type of comparison, if applicable, the incidence of events 
of short-term latency within the first 6 months of receiving a new treatment may be compared 
to the incidence of the same events when beginning another new treatment.
6.3
Determination of Sample Size
Prior to Amendment 5, the study planned for a total of 4000 patients (2000 patients per arm). 
A total of 3045 patients (1371 in the Cimzia Cohort and 1674 in the Comparison Cohort) 
were enrolled as of Mar 2017. The total duration of participation (treatment and follow-up) of 
8 years is planned for each patient. Assuming an 8% annual drop-out rate (1) (withdrawal, 
lost-to-follow-up or death), approximately 25,000 (12,500 per arm) total patient years (p-y) 
post-enrollment is expected in this registry. With a two-sided significance level of 0.05, the 
study is designed to have at least 80% power to detect incidence rate ratios (calculated based 
on observed rates in the control group) of 1.5 for serious infections, 3.3 for lymphoma, and 
1.56 for solid malignancies after 8 years. Event rate estimates for this study were calculated 
using corresponding event rates observed in a CD anti-TNFα registry study control group (1, 
2).
6.4
Statistical Analyses
All analyses will be performed on the eligible population, defined as all patients enrolled in 
this non-interventional study that meet eligibility requirements. All data captured from 
enrollment to last completed follow-up (Investigator or direct-to-patient) will be included. 
Specifics to the primary and secondary analyses are outlined below and described in more 
detail in the SAP. All statistical analyses will be conducted using SAS version 9.1.3 or 
higher.
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6.4.1
Primary Analyses
Safety events will be categorized based on event types (eg, malignancies, infections, 
demyelinating disorders, hypersensitivity reactions, and autoimmune disorders) with analyses 
conducted for each category. Analysis of specific outcomes may be conducted if appropriate.
Event rates will be calculated by dividing the number of reported safety events by the 
person-years at risk. Cimzia-specific rates will be calculated and compared to all other CD 
treatment rates. Incidence rates will be calculated by dividing the number of subjects who had 
reported safety events by the appropriate person-years at risk. 
For incidence rate and event rate calculations, the number of events will be determined for 
Cimzia and for all other CD treatments based on the date of the last dose received before 
event onset and treatment class-specific half-life exposure of the medication. The exposure 
half-lives used for rate calculations for each treatment class are as follows: 

Corticosteroids: 7 days

Immunosuppressants: 28 days

Biologic agents (including Cimzia): 70 days
Propensity scores will be used to assess the comparability of patients who are receiving 
Cimzia at baseline and those who are receiving another CD medication and will be 
incorporated into the primary analysis. Two-sided 95% confidence intervals (CIs) will be 
calculated for all rates.
Appropriate analytical methodologies will be used to investigate the effect of time varying 
confounders.
Cancer progresses in several stages before reaching a detectable, malignant state. While this 
latency period may differ by cancer type, it is generally believed to occur over a long time 
period (Ecsedy and Hunter, 2002). Thus, a treatment-related event may not be seen until years 
after the initial exposure. In contrast, acute events typically have very short latency periods; 
therefore, it is unlikely that a treatment-related event will occur after exposure to the product 
has ended. For this reason, 2 different methods of person-time at risk calculations will be 
used, one for malignancy events (Section 6.4.1.1) and one for acute events (Section 6.4.1.2).
6.4.1.1
Malignancy Events
The following analyses will be conducted to better elucidate treatment patterns and treatment 
attribution in malignancy events:

The number of malignancy events and number of patients experiencing malignancy 
events will be tabulated by the number of CD treatments received during the study. Also, 
the mean number of treatments received per patient in the Cimzia and comparator groups 
(based on baseline assignment) will be calculated, as well as for both groups combined.

The number of malignancy events and number of patients experiencing malignancy 
events will be tabulated by treatment patterns for biologics observed in the study. The 
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name and order of the biologic treatment will be specified in the summary table (eg, “A-
B” implies that patients received two different biologics, “A” followed by “B”; “C” 
implies that patients received one biologic “C” throughout the study; “A-C-D” implies 
that patients received three different biologics, in the order of “A”, “C”, then “D”, etc.).
•
The number of malignancy events and the number of patients experiencing malignancy
events will be tabulated by the type of CD therapy received (monotherapy versus 
combination therapy). If a patient received combination therapy (TNF-α antagonist plus 
immunosuppressant) at least once during the study, then this patient will be included in 
the combination therapy category.
Due to the long latency of malignancy, gaps in exposure will not be factored into person-time 
calculations for malignancies. Any patient exposed to Cimzia during the study will only
contribute person time to the Cimzia cohort from that point onward Figure 6‒1.
As an example, if a malignancy should occur any time after Cimzia exposure, it will be 
attributed to Cimzia. If a malignancy occurred in a patient prior to Cimzia exposure or in a 
patient with no Cimzia exposure, then it would be attributed to comparator. Thus, a patient 
may have exposure to multiple biologics, but any malignancies diagnosed after treatment 
with Cimzia would be systematically attributed to Cimzia.
Figure 6‒1: Example person-time at risk for malignancy events
6.4.1.2
Acute Events
The primary analysis for acute events will be time-to-event analyses using Cox proportional 
hazard modeling. A Kaplan-Meier analysis will be performed censoring patients at the time 
of their first treatment switch during the study period, including patients who switch from one 
non-Cimzia treatment to another non-Cimzia treatment, as a secondary analysis.
Exposure person-time at risk will be calculated for each CD treatment using the following 
equation:
ܮܽݏݐܦܽݐ݁െܨ݅ݎݏݐܦܽݐ݁൅1
First date is defined as the latest enrollment date or first dose date. Last date is defined as the 
earliest of the following:
•
Date of safety event of interest (for incidence rate calculations only)
•
Last dose date + treatment class-specific half-life exposure for product
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
Date of discontinuation, withdrawal, or data cut-off
Any gaps in exposure, as illustrated in the figure below, will be excluded from person-time at 
risk calculations for acute events. Class-specific and product-specific person-time at risk may 
also be calculated if appropriate.
Figure 6‒2: Example person-time at risk for acute events
Figure 6‒2 presents an example of a patient’s exposure history. For this example, exposure 
person-time at risk would be calculated as follows:
Exposure person-time = (Last treatment date + Treatment class-specific half-life) – First 
treatment date + 1) + (earliest of End treatment date + treatment class-specific half-life 
exposure, last date in study, data cutoff date) – Resume treatment date + 1).
Further details on all person-time calculations will be provided in the SAP.
6.4.1.3
Propensity Scores
Treatment selection in an observational study is not random; instead, the decision to start, 
stop, or remain on treatment is complex, factoring disease severity, past response to 
treatment, socio-economic status, and Investigator/patient preference. Therefore, patients in 
an observational study may vary substantially by demographics and disease characteristics 
based on treatment selection. These differences in baseline characteristics may influence the 
number, type, and severity of outcomes reported. Propensity score analysis assesses the 
impact of differences in baseline characteristic on treatment selection, so that comparability 
between treatment populations may be evaluated and quantified. 
6.4.1.3.1
Propensity score variables
Propensity scores will be calculated for each patient using all collected, potential confounding 
variables. These variables include (but are not limited to) the following Baseline 
characteristics:

Age

Gender

Race
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
Smoking status

Other biologic treatment use in the year prior to Baseline

Immunosuppressant use in the year prior to Baseline

Corticosteroid use in the year prior to Baseline

Disease location 

Diagnosed with fistulas 

Duration of disease

Investigator assessment of disease severity

Number of Crohn’s related hospitalizations in the year prior to Baseline

Number of surgical resections in the year prior to Baseline

Disease extent
6.4.1.3.2
Propensity score estimation and analysis
The propensity score represents the probability that a specific patient receives Cimzia 
conditional on the included confounding factors. Patients will be classified based on 
propensity score quintiles. The distribution of the propensity scores will be summarized by 
treatment selection and by quintiles. The variables to be included in the propensity score 
analysis were selected a priori using a directed acyclic graph (DAG). This approach has the 
advantage of improving the statistical efficiency of a model. It also minimizes the 
introduction of bias which may result from more traditional confounder identification and 
adjustment approaches (Shrier and Platt, 2008).
It is possible that some of the strata may contain only patients from either the Cimzia cohort 
or from the comparator cohort, which could lead to invalid comparisons. To ensure adequate 
performance of the propensity score stratification, a common support region or a sufficient 
overlap of the distribution of the variables in Cimzia and comparator cohorts are needed prior 
to creating the quintiles. The common support ensures that any combination of Baseline 
prognostic factors in the Cimzia cohort would also be observed in the comparator cohort. To 
evaluate adequate overlap of the propensity scores, 2 methods will be used:

Graphical method. A visual inspection of the density distribution of the propensity 
scores in both Cimzia and comparator cohorts will be performed (Lechner, 2000). The 
extent of overlap should be evident from simple histograms or density distribution 
plots of the propensity scores from Cimzia and comparator cohorts. A more formal
analysis using the Kolmogorov-Smirnov test for the equality of the propensity score 
distributions in the 2 groups will also be conducted to confirm the results of the visual 
assessment (Massey, 1951).

Minima-Maxima Rule. The lower bound of the propensity scores will be determined 
as the larger of the minima of the scores in the 2 treatment groups while the upper 
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bound will be computed as the smaller of the maxima. As an example, if Cimzia and 
the comparator propensity scores range from 0.01 to 0.8 and from 0.03 to 0.8, 
respectively, then the common region will be defined as [0.03, 0.8].
Given that the determination of a common region/overlap may result in the exclusion of 
patients outside the distribution common to both groups, the number of patients kept in the 
analysis will be maximized by not discarding observations that are close to the upper and 
lower bounds. To evaluate the effect of patients treated contrary to prediction, propensity 
score quintiles will be determined using 2 different criteria for inclusion in the score:

Unrestricted, where only patients inside the distribution common to both groups are 
included

Restricted using a 0.01 caliper, where only patients within the 1 to 99 percentiles are 
included
The calculation of the quintiles using 2 different methods provides a natural way of 
evaluating the robustness of study findings. Once a common support region is found, only 
non-discarded patients will be used in further propensity score analyses aimed at estimating 
treatment effects.
Sensitivity analyses will be conducted to evaluate the potential effect of different levels of 
hypothetical confounding on registry findings (Lash et al, 2009). Appropriate analytical 
methodologies will also be used to investigate the effect of time varying confounders.
6.4.1.4
Event Rate Comparisons
In addition to the propensity score analysis, comparisons between Cimzia event rates and all 
other CD treatment rates for comparator products will be examined using RRs and 
corresponding 95% CIs from conventional multivariate regression analyses. The same vector 
of covariates that are included in the propensity score analysis will be also used as 
confounders in the conventional multivariate regression analyses. This will allow for an 
assessment of the robustness of study findings. It is important to note, however, that the 
interpretation of any rate ratios using conventional modeling may be hindered if there are 
substantial differences in the characteristics of patients in the Cimzia and comparator cohorts.
Rate ratios comparing Cimzia event rates to other frequently used CD treatments or treatment 
classes will also be calculated as appropriate.
6.4.2
Secondary Analyses
Descriptive statistics on the Investigator’s assessment of disease at study entry will be 
presented. Disease severity, measured by Investigator’s and patient’s assessment, will be used 
to quantify the potential influence of disease severity on the safety profile. Demographics and 
baseline patient characteristics, including medical history, CD history, physical examination 
findings (if available), vital signs (if available), the HBI score, patient’s assessment, and 
reasons for treatment and study discontinuation will be summarized. Concomitant 
medications will be presented following the World Health Organisation Drug (WHO Drug) 
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classification. Characteristics of treatment with Cimzia or other medication such as planned 
treatment duration and actual duration of therapy will be tabulated. A stratified analysis by 
cumulative Cimzia exposure may also be performed for malignancy events to identify 
potential patterns in long-term use of Cimzia. 
All AEs will be summarized descriptively by MedDRA Primary System Organ Class and 
Preferred Term (latest version at each interim analysis). Each interim analysis will indicate 
the MedDRA version that was utilized. Additional tables will summarize those AEs by 
severity and relationship to study drug as well as separate tables for AEs leading to 
withdrawal from the study, SAEs and deaths. 
Further details on all analyses will be provided in the SAP.
6.5
Interim Analyses
Data captured for the study will be analyzed periodically, and at the end of the study.
Supplemental data analyses may be performed throughout the study in addition to the 
periodic and final analyses.
7
ETHICS REQUIREMENTS
7.1
Institutional Review Board
Institution requirements of an institutional review board approval or notification of this 
protocol, related informed consent and/or participant materials shall be the Investigator’s 
responsibility to secure such approval prior to initiating study procedures.
8
COMPLETION OF THE STUDY
The Investigator will conduct this study in compliance with the protocol and all applicable 
regulatory and legal requirements. UCB reserves the right to terminate this study at any time, 
either in its entirety or at an individual Investigator’s site, for reasonable cause provided that 
notification in writing is provided at a reasonable time in advance of the intended termination. 
The Investigator may terminate the study at their site for reasonable cause, after providing 
written notification to UCB within a reasonable time in advance of the intended termination.
9
USE OF INFORMATION AND PUBLICATION
Authorship of planned manuscripts for submission to medical journals shall be determined in 
accordance with the International Committee of Medical Journal Editors (ICMJE) Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals. 
The Investigator agrees that if the Investigator is part of a multi-center study, the Investigator
shall coordinate in advance any intended disclosure of the results of the trial with UCB to 
ensure that the results of individual Investigators are not published or presented before those 
of the multi-center study, unless otherwise agreed by in writing by UCB.
Subject to the following paragraph, the authors have the final responsibility for the content of 
their own publication(s) and the decision to submit it/them for publication.
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Any planned manuscript, presentation, abstract, or other intended disclosure of the results of 
the trial or otherwise originating from the study shall be made available for review to UCB at 
least thirty (30) days before submission for publication or any other means of disclosure in 
order to allow UCB to protect its intellectual property.
In the rare event that such disclosure would affect the patentability of any invention to which 
UCB has rights, UCB shall have the right to request an additional delay to the proposed 
disclosure of no more than ninety (90) days so as to allow UCB to preserve its intellectual 
property.
10
DISCLOSURE OF TRIAL INFORMATION
UCB alone shall be responsible for the registration of clinical trials in a public trials registry 
and for the disclosure of trials results on a publicly accessible web site.
11
REFERENCES
Ecsedy J, Hunter D. Textbook of Cancer Epidemiology. Eds, Hans-Olov Adami, David 
Hunger, and Dimitrios Trichopoulos. New York, NY: Oxford University Press, Inc; 2002.
Lash TL, Fox MP, Fink AK. Applying Quantitative Bias Analysis to Epidemiologic Data. 
Springer. 2009.
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, et al. 
Serious infections and mortality in associate with therapies for Crohn’s disease: TREAT 
registry. Clin Gastroenterol Hepatol 2006;4:621-30.
Lichtenstein GR, Cohen RD, Feagan BGG, Sandborn WJ, Salzberg BA, Chen DM, et al. 
Safety of infliximab and other Crohn’s disease therapies – TREAT Registry data with nearly 
15,000 patient-years of follow-up. Gastroenterology 2006;130 (4 Suppl 2):A71.
Massey, FJ. The Kolmogorov-Smirnov Test for Goodness of Fit. Journal of the American 
Statistical Association. Vol. 46, No. 253, 1951, pp. 68–78.
Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 
2008 Oct 30;8:70
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12
APPENDICES
12.1
Appendix A: Harvey-Bradshaw Index (HBI)
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13
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and 
local laws and requirements.
I will ensure that all subInvestigators and other staff members read and understand all aspects 
of this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be 
treated confidentially, and will not be made available to third parties without prior 
authorization by UCB.
All rights of publication of the results reside with UCB, unless other agreements were made 
in a separate contract.
Investigator:
__________________________________
Printed Name
__________________________________
Date/Signature
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14
AMENDMENTS 
14.1
Protocol amendment 1
Rationale for the amendment
The protocol has been amended to address feedback from the FDA, update administrative 
changes, and correct minor typographical and wording errors.  In addition, the eligibility 
criteria for the Cimzia cohort has been broadened to permit start of anti-TNF treatment based 
entirely on the Investigator’s discretion and text to ensure balanced enrollment in the 
non-Cimzia and the Cimzia cohorts has been included.  Furthermore, reporting of partner 
pregnancy and breastfeeding has been added as per current UCB procedures and AE reporting 
information has been updated.
Modifications and changes
Global changes
The following changes were made throughout the protocol:

Internet address for SAE, pregnancy, and breastfeeding reporting has been added.

Toll-free numbers for site support and patient interview service have been included.

Contact information for the Clinical Program Director has been updated.

Text regarding balanced enrollment of subjects in the non-Cimzia and Cimzia cohorts was 
added.

Restriction of eligibility criteria for the Cimzia cohort to medical documentation of 
>3 months duration has been removed.

An eligibility criterion for the non-Cimzia cohort was added.

As an alternative to the web-based survey and if requested by the patient, the patient 
survey will also be sent by mail (including a postage prepaid self-addressed return 
envelope).

Acute hypersensitivity reactions and solid malignancies have been added to the list of 
AEs of special interest to be evaluated.

Text on SAE and AE of interest reporting has been updated.

Partner pregnancy and breastfeeding reporting requirements have been included.

Hypersensitivity reactions have been added as a primary endpoint.
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Specific changes
Change #1
The following was added to the title page:
Protocol/Amendment Number
Date
Protocol
06-Jan-2009
Protocol Amendment 1
24-Jun-2009
Change #2
2
CONTACT INFORMATION
UCB Contributors:
Clinical Program Director (Study related questions)
Name:
Phone:
Fax:
Has been changed to:
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UCB Contributors:
Clinical Program Director (Study related questions)
Name:
Phone:
Fax:
Change #3
2
CONTACT INFORMATION
SAEs Reporting (24h/7d)
Fax:
+1 800 880-6949
Phone:
+1 (678) 799-4007
Has been changed to:
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www.secure-cimziadata.com
Alternative
Fax:
+1 (800) 880 6949
Site Support
Phone:
+1 (800) 772 3125 (reference number: 707501)
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SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Patient Interview Service
Phone:
+1 (877) 580 7246
Change #4
6.
REGISTRY RATIONALE
Patients will be followed for approximately 10 years during normal Investigator visits and 
through direct patient follow-up in the form of web surveys and follow-up calls, during which 
the counts and frequency of serious adverse events (SAEs) and adverse events (AEs) will be 
collected.  All patients will receive and use their medications according to their normal course 
of medical treatment per Investigator clinical judgment.
Has been changed to:
Patients will be followed for approximately 10 years during normal Investigator visits and 
through direct patient follow-up in the form of web, mail surveys and/or phone follow-up 
calls, during which the counts and frequency of all serious adverse events (SAEs) and 
nonserious adverse events (AEs) of interest will be collected.  All patients will receive and 
use their medications according to their normal course of medical treatment per Investigator
clinical judgment.
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Change #5
7.
REGISTRY OBJECTIVE
All SAEs and AEs will be collected and summarized (see Section 9).  The AEs of primary 
interest are: autoimmune disorders, demyelinating disorders, serious and opportunistic 
infections, lymphoma and other malignancies.
Has been changed to:
All SAEs and nonserious AEs of interest will be collected and summarized (see Section 9).  
The AEs of primary interest are: autoimmune disorders, demyelinating disorders, serious 
infections including opportunistic infections, hypersensitivity reactions, lymphoma and other 
malignancies.
Change #6
8.1
Investigator Selection Criteria
The following last sentence in the paragraph has been deleted:
Normal distribution of Crohn severity disease needs to be reflected in the patients recruited.
Change #7
8.2
Selection of Study Population
This is a long-term observational study in the USA that will include 2000 Cimzia-treated 
Crohn’s disease patients and 2000 patients treated with other Crohn’s disease medications.  
The study will be conducted in all regions in the USA at approximately 300 enrolling 
investigative sites. In order to allow appropriate matching, recruitment will be stratified by 
disease severity (mild/moderate/severe), use of other anti-TNFα, age and gender. . 
Stratification strategy will be outlined in the SAP.
Has been changed to:
This is a long-term observational study in the USA that will include 2000 Cimzia-treated 
Crohn’s disease patients and 2000 patients treated with other Crohn’s disease medications.  
The study will be conducted in all regions in the USA at approximately 300 enrolling 
investigative sites.
Recruitment into both cohorts will be monitored and controlled as needed in order to ensure 
balanced enrollment over time.  In order to ensure reasonable balance between both cohorts, 
recruitment will be frequency matched for disease severity (mild/moderate/severe), age 
categories and gender.
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Change #8
8.3 
Subject Inclusion/Exclusion Criteria
Patients who meet all of the following criteria will be eligible for inclusion into the SECURE 
Registry:

Patient (or his/her legally acceptable representative) is able to provide written informed 
consent (patients under the age of consent must provide assent) to permit collection of 
data.  Patients who join the registry prior to legal age of consent will provide written 
informed consent as an adult upon reaching the legal age of consent.

Patient must have medically documented Crohn’s disease > 3 months duration prior to 
study entry.

The decision to prescribe Cimzia or other medications has been made by the Investigator
independently of the decision to include the patient in the study.

Cimzia cohort - Patient must be about to receive treatment with Cimzia as part of a pre-
existing management plan for Crohn’s disease or has already been receiving treatment 
with Cimzia for < 6 months.

Comparison cohort – Patient must be about to receive treatment with any other 
medication as part of a pre-existing management plan for Crohn’s disease or has already 
been receiving treatment.  Previous Cimzia treatment is prohibited for the control arm.
Has been changed to:
Patients who meet all of the following criteria will be eligible for inclusion into the SECURE 
Registry:

Patient (or his/her legally acceptable representative) is able to provide written informed 
consent (patients under the age of consent must provide assent) to permit collection of 
data.  Patients who join the registry prior to legal age of consent will provide written 
informed consent as an adult upon reaching the legal age of consent.

Patient must have medically documented Crohn’s disease.

The decision to prescribe Cimzia or other medications has been made by the Investigator
independently of the decision to include the patient in the study.
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Cimzia cohort

Patient must be about to receive treatment with Cimzia as part of a pre-existing 
management plan for Crohn’s disease or has already been receiving treatment with 
Cimzia for < 6 months.
Comparison cohort 

Patient must be about to receive treatment with any other medication as part of a pre-
existing management plan for Crohn’s disease or has already been receiving treatment.  
Previous Cimzia treatment is prohibited for the control arm.

Patients are eligible for the comparison cohort if one of the following criteria is fulfilled: 

currently receiving or history of anti-TNF treatment

currently receiving or history of immunosuppressant therapy within 6 months

currently receiving or history of systemic steroid therapy within 6 months
Change #9
8.5
Schedule of Assessments
Direct patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via 
a web-based system.  If a patient does not enter the information via the web within 
approximately 1 week after the 3 month due date, the study patient interview service will call 
the patient to obtain the required information over the phone.
Has been changed to:
Direct patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via 
a web-based system, by mail or phone as requested by the patient.  If a patient does not 
provide the information via the web, mail or phone within approximately 1 week after the 
3 month due date, the study patient interview service will call the patient to obtain the 
required information over the phone.
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Change #10
8.5
Schedule of Assessments
Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10
Direct Patient 
Follow-up Year 
1-10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Written informed 
consent/assent
X
Assessment of 
inclusion/exclusion criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia® 
or other medication
X
Planned Cimzia® or other 
medication treatment period 
X
X
CD treatment medication 
changes and reason 
X
X
Concomitant medications 
X
X
X
SAEs and AEs of interest since 
time of last completed follow-
up
X
Major changes in health status 
since last completed follow-up
X
Investigator’s assessment of 
disease
X
X
HBI (see APPENDIX A)
X
X
Patient’s disease assessment
X
X
Reasons for discontinuation 
from registry (early 
termination or end of Year 10)
X
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Has been changed to:
Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10
Direct Patient 
Follow-up Year 
1-10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Written informed consent/assent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or 
other medication
X
Planned Cimzia or other 
medication treatment period 
X
X
CD treatment medication changes 
and reason 
X
X
Concomitant medications 
X
X
X
All SAEs and nonserious AEs of 
interest since time of last 
completed follow-up*
X
Major changes in health status
since last completed follow-up
X
Investigator’s assessment of 
disease
X
X
HBI (see APPENDIX A)
X
X
Patient’s disease assessment
X
X
Reasons for discontinuation from 
registry (early termination or end 
of Year 10)
X
*All serious adverse events; and nonserious adverse events of interest from both study arms are to be 
reported through the registry.
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Change #11
8.7
Participation and Retention Strategies
As a means to retain patient participation, patients are followed up directly via web-based 
system every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete an on-line patient survey.  “Lost to follow-up” is 
defined as a patient who goes one year with no data being collected/reported (1 year without 
Investigator visit and 4 consecutive quarterly patient surveys not completed).  After informed 
consent/assent is obtained, the patient will complete a “Patient Contact Form”, which will 
request contact information (phone number, email address, and physical address).  This form 
will be submitted to an independent patient interview service by the enrolling physician.  The 
patients will receive emails reminding them to complete the survey.  If they have not 
completed the survey after one week, or they do not have internet access, they will be called 
by the independent patient interview service to complete the survey via telephone.  For each 
survey the patient completes, they will receive a nominal appreciation gift.
Has been changed to:
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey.  “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without Investigator
visit and 4 consecutive quarterly patient surveys not completed).  After informed 
consent/assent is obtained, the patient will complete a “Patient Contact Form”, which will 
request contact information (phone number, email address, and physical address).  This form 
will be submitted to an independent patient interview service by the enrolling physician.  The 
patients will receive emails or mail reminding them to complete the survey.  If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone.  For each survey the patient 
completes, they will receive a nominal appreciation gift.
Change #12
8.8
Data Collection Strategies
All Investigator-reported data must be retained as source data in the patient’s medical record.  
Data will be collected for this registry study from both the enrolling physicians and patients 
using electronic data capture (EDC).  Participating enrolling physicians and enrolled patients 
will enter the applicable data for each collection interval into a specific electronic case report 
form (eCRF).
Has been changed to:
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All Investigator-reported data must be retained as source data in the patient’s medical record.  
Data will be collected for this registry study from both the enrolling physicians and patients 
using electronic data capture (EDC).  Participating enrolling physicians and enrolled patients 
(web-based participants) will enter the applicable data for each collection interval into a 
specific electronic case report form (eCRF).  Enrolled patients requesting mail surveys will 
return the completed paper survey in the prepaid self-addressed return envelope and the 
applicable data will be entered in the specific eCRF by the independent patient interview 
service.  Data collected from enrolled patients by phone will be entered in the eCRF by the 
independent patient interview service.
Change #13
8.8.1
Enrollment Visit
Bullet point #2

Crohn’s disease history, including length of time since initial presentation of symptoms, 
date of diagnosis, all past treatment and surgeries for Crohn’s disease (with special focus 
on anti-TNFα biologics), and reason for switch to Cimzia or other medications since 
diagnosis and within the past 3 months
Has been changed to:

Crohn’s disease history, including length of time since initial presentation of symptoms, 
date of diagnosis, all past treatment and surgeries for Crohn’s disease (with special focus 
on anti-TNFα and other biologics), and reason for switch to Cimzia or other medications 
since diagnosis and within the past 3 months
Change #14
8.8.2
Follow-up Period
Each study enrolling physician or patient will be contacted at regular intervals throughout the 
study to ensure they are entering required data at the following frequencies:

every six months for Investigator-reported information 

every three months for patient-reported information (web survey or telephone) 
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The following data will be collected by the enrolling physician in EDC at each follow-up 
interval:

Any SAEs/AEs of interest that may have occurred since last follow-up

HBI

Investigator’s disease severity assessment (including HBI)

Full details on exposure (e.g., dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for Crohn’s disease
Has been changed to:
Each study enrolling physician or patient will be contacted at regular intervals throughout the 
study to ensure they are entering required data at the following frequencies:

every six months for Investigator-reported information 

every three months for patient-reported information (web, mail survey or phone) 
The following data will be collected by the enrolling physician in EDC at each follow-up 
interval:

All SAEs and nonserious AEs of interest that have been reported since last follow-up

HBI

Investigator’s disease severity assessment (including HBI)

Full details on exposure (e.g., dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for Crohn’s disease
Change #15
9.1
Definitions
Serious Adverse Event (SAE): Any adverse drug reaction which results in:
Has been changed to:
Serious Adverse Event (SAE): Any untoward medical occurrence which results in:
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And the following has been added:
All Serious Adverse Events (of interest or other) must be reported within 24 hours of being 
acknowledged by the Investigator.
Change #16
9.2
Adverse Events of Interest

Lymphoma and other malignancies, such as:

hepatosplenic T-cell lymphoma

non-Hodgkin’s lymphoma
Has been changed to:

Lymphoma and other malignancies, such as:

hepatosplenic T-cell lymphoma

non-Hodgkin’s lymphoma

solid malignancies
And the following was added:

Acute hypersensitivity reactions occurring within 2 hours of drug administration, such as:

urticaria, rash, pruritus, flushing, swollen lips/tongue/pharynx, wheezing, dyspnea, 
hypotonia, cramping, abdominal pain, and vomiting
Change #17
The following has been deleted:
9.3
Other Adverse Events
Other adverse event for both Cimzia and Control arms will be collect through the registry 
according to the judgment of the Investigator.
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Change #18
9.4
Case Definition:
Cimzia Case:
Cases will be attributable to Cimzia identified by two methods.  The first method will assume 
a case will be attributable to Cimzia after the first dose of the medication regardless of 
medication discontinuation and time to onset of disease.  The second method will be a series 
of sensitivity analyses and stratifications to evaluate different clinically driven definition of 
cases attributable to drug.  Specifics on data handling guidelines for managing missing or 
partial data will be documented in the SAP.
Control Case:
Cases will be attributable to non-Cimzia medications identified by two methods.  The first 
method will assume a case will be attributable to the non-Cimzia medication after the first 
dose of the medication regardless of medication discontinuation and time to onset of disease.  
The second method will be a series of sensitivity analyses and stratifications to evaluate 
different clinically driven definition of cases attributable to drug.  Specifics on data handling 
guidelines for managing missing or partial data will be documented in the SAP.
Has been changed to:
9.3
Case Definition:
Cimzia Case:
Cases will be attributable to Cimzia identified by two methods.  The first method will assume 
a case will be attributable to Cimzia after the first dose of the medication regardless of 
medication discontinuation and time to onset of the event.  The second method will be a 
series of sensitivity analyses and stratifications to evaluate different clinically driven 
definition of cases attributable to drug.  Specifics on data handling guidelines for managing 
missing or partial data will be documented in the Statistical Analysis Plan (SAP).
Control Case:
Cases will be attributable to non-Cimzia medications identified by two methods.  The first 
method will assume a case will be attributable to the non-Cimzia medication after the first 
dose of the medication regardless of medication discontinuation and time to onset of the 
event.  The second method will be a series of sensitivity analyses and stratifications to 
evaluate different clinically driven definition of cases attributable to drug.  Specifics on data 
handling guidelines for managing missing or partial data will be documented in the SAP.
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Change #19
9.7
Adverse Event Reporting
All adverse events will be forwarded to UCB Global Clinical Safety and Pharmacovigilance 
for assessment of reportability (expedited 15-day or periodic report) as per UCB standard 
pharmacovigilance plan in compliance with 21 CFR 600 (see Figure 9.1– Event Reporting 
Process for flow of activity).
Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the enrolling physician for medical confirmation.  Once medical 
confirmation is obtained, the enrolling physician will enter the event into the study EDC 
system and will be forwarded to UCB Global Clinical Safety and Pharmacovigilance for 
assessment of reportability (expedited 15-day or periodic report) as per UCB standard 
pharmacovigilance plan in compliance with 21 CFR 600 as described above.
Has been changed to:
Serious adverse events and nonserious adverse events of interest from both study arms are to 
be reported through the registry.
All adverse events reported through registry will be forwarded to UCB Global Clinical Safety 
and Pharmacovigilance for assessment and further processing as per regulatory requirements 
and UCB procedures (see Figure 5‒1 – Event Reporting Process for flow of activity).
Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the enrolling physician for medical confirmation.  Once medical 
confirmation is obtained, the enrolling physician will report the event through the study EDC 
system. 
Information and instructions informing patients about the follow-up period and how to report 
adverse events is included in the Informed Consent Form.
Change #20
9.8
Pregnancy
All reports of pregnancy (fetal-exposure) for an enrolled patient during the registry will be 
evaluated and processed as an SAE per UCB standard pharmacovigilance plans.  Enrolling 
physician will be instructed to report a pregnancy in the study EDC system via a check-box.  
Completion of the pregnancy check-box in the study EDC will trigger a notification to UCB 
Global Clinical Safety and Pharmacovigilance.  The enrolling physician will be prompted to 
manually complete the UCB Pregnancy Report and Outcome Form and fax to UCB Global 
Clinical Safety and Pharmacovigilance.  All cases will be followed to outcome of the 
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pregnancy.  All newborns will be monitored and evaluated for any adverse events due to in-
utero exposure.
Figure 9-1
Event Reporting Process
Has been changed to:
9.8
Pregnancy and breastfeeding
Physicians will be instructed to report pregnancy and breastfeeding of study participants; and 
pregnancy of study participant partners.  An informed consent form will be provided to a 
study participant’s partner who becomes pregnant during the study; and who will be willing 
to provide information on pregnancy course and outcome.
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Figure 9-1
Event Reporting Process
Change #21
10.2
Endpoints
Primary Endpoints
The objective of this registry study is to track safety outcomes of patients who have taken 
Cimzia for treatment of Crohn’s disease compared to a non-Cimzia control population.  All 
AEs and SAEs will be collected and summarized.  The AEs of primary interest are:

Autoimmune disorders 

Demyelinating disorders 

Serious and opportunistic infections

Lymphoma and other malignancies
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Has been changed to:
Primary Endpoints
The objective of this registry study is to track safety outcomes of patients who have taken 
Cimzia for treatment of Crohn’s disease compared to a non-Cimzia control population.  All 
SAEs and nonserious AEs of interest will be collected and summarized.  
The AEs of primary interest are:

Autoimmune disorders 

Demyelinating disorders 

Serious infections including opportunistic infections

Lymphoma and other malignancies

Hypersensitivity reactions
Change #22
10.2
Endpoints
Secondary Endpoints
Characteristics and potential confounders of the population will be assessed on the basis of 
data collecting regarding: 

Demographics (gender, age, race, ethnicity, socioeconomic status, occupation and 
smoking status ) including special populations such as pregnant women, children and the 
elderly

Crohn’s disease history (including all past treatment for Crohn’s disease with special 
focus on all previous treatment with anti-TNFα biologics, and reason for switch to Cimzia
or other medication, if applicable)

Other medical history including medical status at study entry

Concomitant medications

SAE/other AEs
Has been changed to:
Characteristics and potential confounders of the population will be assessed on the basis of 
data collecting regarding: 
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
Demographics (gender, age, race, ethnicity, socioeconomic status, occupation and 
smoking status ) including special populations such as pregnant women, children and the 
elderly

Crohn’s disease history (including all past treatment for Crohn’s disease with special 
focus on all previous treatment with anti-TNFα or other biological therapies, and reason 
for switch to Cimzia or other medication, if applicable)

Other medical history including medical status at study entry

Concomitant medications

SAE/other AEs
Change #23
10.4
Statistical Analyses
Primary Analyses:
Frequency and counts will be calculated for the occurrence of serious infections, including 
opportunistic infections, and malignancies including lymphoma, demyelinating disorders and 
autoimmune disorders.  Calculations will be performed using both the cumulative incidence 
(proportion) and the incidence rate of events (events per person-time).
And the last sentence
Further details on all analyses will be provided in the Statistical Analysis Plan (SAP).
Have been changed to:
Primary Analyses:
Frequency and counts will be calculated for the occurrence of serious infections including 
opportunistic infections, and malignancies including lymphoma, demyelinating disorders, 
hypersensitivity reactions, and autoimmune disorders.  Calculations will be performed using 
both the cumulative incidence (proportion) and the incidence rate of events (events per 
person-time).
And the last sentence
Further details on all analyses will be provided in the SAP.
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Change #24
17.
PROTOCOL SIGNATURE PAGE
Authorized signature on behalf of UCB:
UCB Clinical Program Director (or designee)
_______________________
________
Signature
Date
Name:
Clinical Program Director
Has been changed to:
18.
PROTOCOL SIGNATURE PAGE
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Authorized signature on behalf of UCB:
UCB Clinical Program Director (or designee)
_______________________
________
Signature
Date
Name:
Clinical Program Director
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14.2
Protocol amendment 2
Rationale for the amendment:
The protocol has been amended to comply with FDA guidance for anticipated SAEs, revise 
the AE, SAE, and AE of interest reporting process, and to allow telephone contacts. 
Assessment of disease severity and HBI were clarified at Enrollment and Follow-Up visits. 
Selection of the study population was changed from frequency-matched recruitment to 
retrospective frequency matching. UCB contact information was updated. Other changes to 
correct inconsistencies and to adhere to current UCB style and formatting were made. 
Specific changes
Change #1 Title page, Company address
Old text –
UCB Inc
1950 Lake Park Drive
USA - GA 30080 Smyrna 
UNITED STATES
Has been changed to –
UCB Biosciences, Inc.
A Member of the UCB Group of Companies
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Change #2 Section 2; Contact information
Old text –
UCB Contributors:
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Clinical Program Director (Study related questions)
Name:
Phone:
Fax:
Clinical Project Manager (CPM)
Name:
Phone:
Fax:
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www. secure-cimziadata.com
Alternative
Fax:
+1 (800) 880 6949 
Has been changed to –
UCB Contributors:
Sponsor Clinical Program Director (Study related questions)
Name:
, 
DVM
Phone:
Fax:
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Clinical Project Manager
Name:
Phone:
Fax:
Clinical Trial Biostatistician
Name:
Phone:
Fax:
Study Investigator
Name:
, MD
Phone:
Fax:
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www. secure-cimziadata.com
Fax:
+1 (888) 772 6919 (to be used if site is unable to access the electronic 
data capture [EDC] system)
Phone:
+1 (800) 772 3125 Study code 707501 (PRA number for EDC 
questions)
Phone:
+1 (678) 799 4007 (for questions related to adverse event reporting)
Email:
chosafety@praintl.com
Change #3 – Section 8.2 Selection of study population, paragraph 2
Old – text –
Recruitment into both cohorts will be monitored and controlled as needed in order to ensure 
balanced enrollment over time.  In order to ensure reasonable balance between both cohorts, 
recruitment will be frequency matched for disease severity (mild/moderate/severe), age 
categories and gender.
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Has been changed to –
Recruitment into both cohorts will be monitored and controlled as needed in order to ensure 
balanced enrollment over time.  In order to ensure reasonable balance between both cohorts, 
retrospective frequency matching will be applied for disease severity 
(mild/moderate/severe), age categories and gender.
Change #4 Section 8.3 Subject Inclusion/Exclusion Criteria 
Old text –
Cimzia cohort 
Patient must be about to receive treatment with Cimzia as part of a pre-existing management 
plan for Crohn’s disease or has already been receiving treatment with Cimzia for <6 months.
Has been changed to –
Cimzia cohort 
Patient must be about to receive treatment with Cimzia as part of a pre-existing management 
plan for Crohn’s disease or has already been receiving treatment with Cimzia for ≤6 months.
Change # 5 Section 8.5 Schedule of assessments
Old text –
Physicians will complete the baseline data for each patient after enrollment into the study.  
Although patient care will follow the Investigator’s clinical judgment, it is recommended to 
the enrolling physician to report follow-up data on the patients approximately every 6 months 
after enrollment (months 6, 12, 18,…).  In an effort to avoid missing data and unreported 
events over the 10 year follow-up period, patients will directly report data in parallel to the 
enrolling physician reported data.  Direct patient follow-up will occur every 3 months after 
enrollment (months 3, 6, 9, 12,...) via a web-based system, by mail or phone as requested by 
the patient.  If a patient does not provide the information via the web, mail or phone within 
approximately 1 week after the 3 month due date, the study patient interview service will call 
the patient to obtain the required information over the phone.  Safety information collected 
directly from the patient will be available for the study investigative site to review.
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Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10
Direct Patient 
Follow-up Year 
1-10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Written informed consent/assent
X
Assessment of 
inclusion/exclusion criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or 
other medication
X
Planned Cimzia or other 
medication treatment period 
X
X
CD treatment medication changes 
and reason 
X
X
Concomitant medications 
X
X
X
All SAEs and nonserious AEs of 
interest since time of last 
completed follow-up*
X
Major changes in health status
since last completed follow-up
X
Investigator’s assessment of 
disease
X
X
HBI (see APPENDIX A)
X
X
Patient’s disease assessment
X
X
Reasons for discontinuation from 
registry (early termination or end 
of Year 10)
X
*All serious adverse events; and nonserious adverse events of interest from both study arms are to be 
reported through the registry.
Has been changed to –
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Physicians will complete the baseline data for each patient after enrollment into the study.  
Although patient care will follow the Investigator’s clinical judgment, it is recommended to 
the enrolling physician to report follow-up data on the patients approximately every 6 months 
after enrollment (months 6, 12, 18,…). Telephone contacts are permitted every other 
6-month period, with the understanding that patients are typically seen by the 
Investigator every 12 months at a minimum per usual practice. All planned assessments 
described in Section 8.8.2 are to be completed during the telephone contacts. 
In an effort to avoid missing data and unreported events over the 10 year follow-up period, 
patients will directly report data in parallel to the enrolling physician reported data.  Direct 
patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via a 
web-based system, by mail or phone as requested by the patient.  If a patient does not provide 
the information via the web, mail or phone within approximately 1 week after the 3 month 
due date, the study patient interview service will call the patient to obtain the required 
information over the phone.  Safety information collected directly from the patient will be 
available for the study investigative site to review. If 4 consecutive quarterly patient 
surveys have not been at least partially completed, the patient will be considered lost to 
follow-up and further attempts at contact are not required.
Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10b
Direct Patient 
Follow-up Year 
1-10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Written informed consent/assent
X
Assessment of 
inclusion/exclusion criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or 
other medication
X
Planned Cimzia or other 
medication treatment period 
X
X
CD treatment medication changes 
and reason 
X
X
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Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10b
Direct Patient 
Follow-up Year 
1-10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Concomitant medications 
X
X
X
All SAEs and nonserious AEs of 
interest since time of last 
completed follow-upa
X
Major changes in health status
since last completed follow-up
X
Investigator’s assessment of 
disease severity
X
X
Investigator’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease 
severity
X
X
Reasons for discontinuation from 
registry (early termination or end 
of Year 10)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey-Bradshaw Index; SAE=serious adverse 
event
aAll serious adverse events; and nonserious adverse events of interest from both study arms are to be 
reported through the registry. 
b Telephone contacts are permitted every other 6-month period, with the understanding that 
patients are typically seen by the Investigator every 12 months at a minimum per usual practice.
c. This may also be completed by qualified site personnel as designated by the Investigator.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the Investigator telephone contact instead of the full 
HBI.
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Change #6 Section 8.7 Participation and Retention Strategies
Old text –
Individual patient follow-up is approximately 10 years after enrollment, regardless of 
discontinuation of Cimzia or other medications.
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey.  “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without Investigator
visit and 4 consecutive quarterly patient surveys not completed.  After informed 
consent/assent is obtained, the patient will complete a “Patient Contact Form”, which will 
request contact information (phone number, email address, and physical address).  This form 
will be submitted to an independent patient interview service by the physician.  The patients 
will receive emails or mail reminding them to complete the survey.  If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone.  For each survey the patient 
completes, they will receive a nominal appreciation gift.
In addition, patients will receive via postal mail an annual calendar with stickers placed on 
the months that they will be requested to complete their quarterly patient survey.  They will 
receive a new calendar each year of their participation.  Patients will also receive a registry 
newsletter once a year in an attempt to keep them engaged in the registry.
In the event an Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients.  The 
Informed Consent/Assent Forms include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and contact them with the name and contact information of another study 
Investigator that they can contact during the remainder of their participation in the registry.  
The wording also states that the registry can continue to collect the direct patient-reported 
data without the need for re-consent.
In the event a patient moves to a new location or chooses to leave their current Investigator, 
patients are provided with information upon enrollment as to how to locate a participating 
Investigator in their area or how to provide the registry information to a new Investigator that 
may not yet be participating.  Participating patients will have access to all of this information 
on the study specific web portal as well as being reminded of this process in the annual 
patient newsletters they will receive throughout their participation in the study.
The goal of these strategies is to enhance patient retention activity, potentially resulting in a 
lower drop-out rate and improved quality of data.
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Over the course of a long-term study, patient death may occur.  Additionally, patients may 
develop serious co-morbidities that cause them to become “lost to follow-up” in the Registry.  
Periodically throughout the study, and in case of “lost to follow-up”, search in the National 
Death Index (NDI) and cancer registries will be performed for any matches.
Has been changed to –
Individual patient follow-up is approximately 10 years after enrollment, regardless of 
discontinuation of Cimzia or other medications.
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey.  “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without Investigator
visit/telephone contact and failure to at least partially complete 4 consecutive quarterly 
patient surveys; further attempts at patient contact are not required).  After informed 
consent/assent is obtained, the patient will complete a “Patient Contact Form”, which will 
request contact information (phone number, email address, and physical address).  This form 
will be submitted to an independent patient interview service by the physician.  The patients 
will receive emails or mail reminding them to complete the survey.  If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone.  For each survey the patient 
completes, they will receive a nominal appreciation gift.
In addition, patients will receive via postal mail an annual calendar with stickers placed on 
the months that they will be requested to complete their quarterly patient survey.  They will 
receive a new calendar each year of their participation.  Patients will also receive a registry 
newsletter once a year in an attempt to keep them engaged in the registry.
In the event an Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients.  The 
Informed Consent/Assent Forms include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and contact them with the name and contact information of another study 
Investigator that they can contact during the remainder of their participation in the registry.  
The wording also states that the registry can continue to collect the direct patient-reported 
data without the need for re-consent. If the patient is unable or unwilling to be followed by 
a new Investigator, the patient must be discontinued from the study.
In the event a patient moves to a new location or chooses to leave their current Investigator, 
patients are provided with information upon enrollment as to how to locate a participating 
Investigator in their area or how to provide the registry information to a new Investigator that 
may not yet be participating.  Participating patients will have access to all of this information 
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on the study specific web portal as well as being reminded of this process in the annual 
patient newsletters they will receive throughout their participation in the study.
The goal of these strategies is to enhance patient retention activity, potentially resulting in a 
lower drop-out rate and improved quality of data.
Over the course of a long-term study, patient death may occur.  Additionally, patients may 
develop serious co-morbidities that cause them to become “lost to follow-up” in the Registry.  
Periodically throughout the study, and in case of “lost to follow-up”, searches of death or 
cancer registries, as appropriate, will be performed for any matches.
Change #7 Section 8.8.1 Enrollment Visit
Old text –
For each patient enrolled in this registry, the enrolling physician will document the following 
information into the corresponding eCRFs within the registry study EDC system:

Demographic information such as gender, age, race, ethnicity, socioeconomic status, 
occupation and smoking status

Crohn’s disease history, including length of time since initial presentation of symptoms, 
date of diagnosis, all past treatment and surgeries for Crohn’s disease (with special focus 
on anti-TNFα and other biologics), and reason for switch to Cimzia or other medications 
since diagnosis and within the past 3 months

Crohn’s disease severity as assessed by the Investigator

Harvey-Bradshaw Index (HBI) – See Section 16.1 APPENDIX A

Patient’s disease assessment 

Other medical history including current medical status, concomitant medications, and 
planned treatment period (if known) with special focus on previous occurrence of each 
AE of interest and related risk factors (e.g., history of serious infections, conditions that 
might place a patient at higher risk of serious infection)
Has been changed to –
For each patient enrolled in this registry, the enrolling physician will document the following 
information into the corresponding eCRFs within the registry study EDC system:

Demographic information such as gender, age, race, ethnicity, socioeconomic status, 
occupation and smoking status

Crohn’s disease history, including length of time since initial presentation of symptoms, 
date of diagnosis, all past treatment and surgeries for Crohn’s disease (with special focus 
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on anti-TNFα and other biologics), and reason for switch to Cimzia or other medications 
since diagnosis and within the past 3 months

Investigator’s assessment of Crohn’s disease severity 

Investigator’s completion of the Harvey-Bradshaw Index (HBI) – See Section 16.1
APPENDIX A. This may also be completed by qualified site personnel as designated 
by the Investigator.

Patient’s assessment of Crohn’s disease severity

Patient’s completion of the modified HBI. The modified HBI does not include the 
abdominal mass question contained in the full HBI.

Other medical history including current medical status, concomitant medications, and 
planned treatment period (if known) with special focus on previous occurrence of each 
AE of interest and related risk factors (e.g., history of serious infections, conditions that 
might place a patient at higher risk of serious infection)
Change #8 Section 8.8.2 Follow-up Period
Old text –
Each study enrolling physician or patient will be contacted at regular intervals throughout the 
study to ensure they are entering required data at the following frequencies:

every six months for Investigator-reported information 

every three months for patient-reported information (web, mail survey or phone) 
The following data will be collected by the physician in EDC at each follow-up interval:

All SAEs and nonserious AEs of interest that have been reported since last follow-up

HBI

Investigator’s disease severity assessment (including HBI)

Full details on exposure (e.g., dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for Crohn’s disease
The following data will be collected from the patient at each quarterly interval: 

Any major changes in health status that may have occurred since last follow-up

Patient’s disease assessment

Full details on exposure to Cimzia or other medications
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
Any changes in medication

Any administrative changes such as change in contact information
Has been changed to –
Each study enrolling physician or patient will be contacted at regular intervals throughout the 
study to ensure they are entering required data at the following frequencies:

Every six months for Investigator-reported information. Telephone contacts are permitted 
every other 6-month period, with the understanding that patients are typically seen by the 
Investigator every 12 months at a minimum per usual practice.

Every three months for patient-reported information (web, mail survey or phone) 
The following data will be collected by the physician in EDC at each follow-up interval:

All SAEs and nonserious AEs of interest that have been reported since last follow-up

Investigator’s HBI completed at clinic visits or modified HBI completed during 
telephone contacts. This may also be completed by qualified site personnel as 
designated by the Investigator.

Investigator’s assessment of disease severity

Full details on exposure (e.g., dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for Crohn’s disease
The following data will be collected from the patient at each quarterly interval: 

Any major changes in health status that may have occurred since last follow-up

Patient’s disease assessment

Full details on exposure to Cimzia or other medications

Any changes in medication

Any administrative changes such as change in contact information
Change #9 Section 9 Adverse events of interest, serious adverse events, case and exposure 
definitions
New text added –
Although serious adverse events and nonserious adverse events of interest are the focus of 
this registry, Investigators are expected to enter all AEs in the eCRF.
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Change #10 Section 9.2 Adverse events of interest
New text (final bullet) –

Other events: 

Congestive heart failure 

Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia and leucopenia

Serious bleeding events

Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme)
Change #11 Section 9.3 Anticipated serious adverse events (new section)
New text -
The following list of Anticipated SAEs has been identified as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure. This original list will remain in effect for the duration of the protocol.
This list does not change the Investigator’s obligation to report all serious AEs (including 
Anticipated SAEs) as detailed in Section 9.7.
Crohn’s disease
perianal abscess
abdominal pain
Change #12 Section 9.5 Exposure definition
Old text -
Cimzia Exposure:
Cimzia exposure will be calculated by two methods.  The first method will assume exposure 
from day one of the first dose of Cimzia medication regardless of medication discontinuation 
through the date of the last follow-up evaluation.  The second method will be a series of 
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sensitivity analyses and stratifications to evaluate the different clinically driven definitions of 
exposure to drug.  Specifics to these definitions will be outlined in the SAP.
Control Exposure:
Non-Cimzia® medication exposure will be calculated by two methods.  The first method will 
assume exposure from day one of the first dose of the non-Cimzia® medication regardless of 
medication discontinuation through the date of the last follow-up evaluation.  The second 
method will be a series of sensitivity analyses and stratifications to evaluate the different 
clinically driven definitions of exposure to drug.  Specifics to these definitions will be 
outlined in the SAP.
Has been changed to –
Cimzia Exposure:
Cimzia exposure will be calculated by two methods.  The first method will assume exposure 
from day one of the first dose of Cimzia medication after enrollment regardless of medication 
discontinuation through the date of the last follow-up evaluation.  The second method will be 
a series of sensitivity analyses and stratifications to evaluate the different clinically driven 
definitions of exposure to drug.  Specifics to these definitions will be outlined in the SAP.
Control Exposure:
Non-Cimzia medication exposure will be calculated by two methods.  The first method will 
assume exposure from day one of the first dose of the non-Cimzia medication after 
enrollment regardless of medication discontinuation through the date of the last follow-up 
evaluation.  The second method will be a series of sensitivity analyses and stratifications to 
evaluate the different clinically driven definitions of exposure to drug.  Specifics to these 
definitions will be outlined in the SAP.
Change #13 Section 9.7 Adverse event reporting and Figure 9.1
Old text –
Serious adverse events and nonserious adverse events of interest from both study arms are to 
be reported through the registry. 
All adverse events reported through registry will be forwarded to UCB Global Clinical Safety 
and Pharmacovigilance for assessment and further processing as per regulatory requirements 
and UCB procedures (see Figure 9:1 – Event Reporting Process for flow of activity).
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Any major changes in health status reported by the patient during the every 3 month patient
follow-up will be sent to the physician for medical confirmation.  Once medical confirmation 
is obtained, the physician will report the event through the study EDC system. 
Information and instructions informing patients about the follow-up period and how to report 
adverse events is included in the Informed Consent Form. 
Figure 9:1 Event Reporting Process
Has been changed to –
All AE are expected to be entered in the eCRF. Serious adverse events and nonserious 
adverse events of interest from both study arms are to be reported through the registry.
All SAEs and all AEs of interest will be entered in the EDC system within 24 hours of 
site notification and will be automatically forwarded to PRA, International for 
assessment and further processing as per regulatory requirements and UCB procedures
(see Figure 9:1 – Event Reporting Process for flow of activity).
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Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the physician for medical confirmation.  Once medical confirmation 
is obtained, the physician will report the event through the study EDC system. 
Information and instructions informing patients about the follow-up period and how to report 
adverse events is included in the Informed Consent Form. More detailed instructions to 
sites regarding reporting of SAEs are provided in the UCB safety Guidance booklet.
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Figure 9:1 Event Reporting Process
AE=adverse event; EDC=electronic data capture; SAE=serious adverse event
Change #14 Section 9.8 Pregnancy and breastfeeding
Old text –
Investigators will be instructed to report pregnancy and breastfeeding of study participants; 
and pregnancy of study participant partners.  An informed consent form will be provided to a 
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study participant’s partner who becomes pregnant during the study; and who will be willing 
to provide information on pregnancy course and outcome. 
Has been changed to –
Investigators are required to report pregnancy and breastfeeding of study participants; and 
pregnancy of study participant partners.  An informed consent form will be provided to a 
study participant’s partner who becomes pregnant during the study; and who will be willing 
to provide information on pregnancy course and outcome. More detailed instructions to 
sites regarding reporting of pregnancy and breastfeeding are provided in the UCB 
safety Guidance booklet. 
Change #15 Section 10.2 Endpoints
Old text –
Primary Endpoints
The objective of this registry study is to track safety outcomes of patients who have taken 
Cimzia for treatment of Crohn’s disease compared to a non-Cimzia control population.  All 
SAEs and nonserious AEs of interest will be collected and summarized.  
The AEs of primary interest are:

Autoimmune disorders 

Demyelinating disorders 

Serious infections including opportunistic infections

Lymphoma and other malignancies

Hypersensitivity reactions
Has been changed to –
Primary Endpoints
The objective of this registry study is to track safety outcomes of patients who have taken 
Cimzia for treatment of Crohn’s disease compared to a non-Cimzia control population.  All 
SAEs and nonserious AEs of interest will be collected and summarized.  
The AEs of primary interest are:

Autoimmune disorders 

Demyelinating disorders 
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
Serious infections or opportunistic infections

Lymphoma and other malignancies

Hypersensitivity reactions
Change #16 Section 18, Protocol signature page
UCB Clinical Program Director updated and additional UCB signatories added –
Authorized signature on behalf of UCB:
UCB Clinical Program Director
_______________________
________
Signature
Date
Name:
, DVM
UCB Clinical Project Manager
_______________________
________
Signature
Date
Name:
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UCB Clinical Trial Biostatistician 
_______________________
________
Signature
Date
Name:
UCB Study Investigator
_______________________
________
Signature
Date
Name:
, MD
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14.3
Protocol amendment 3
Rationale for the amendment:
The protocol has been amended to revise analytic strategy methods and analysis providing 
more flexibility in treatment over the duration of the registry. The safety outcomes, exposure 
to Cimzia and other medications will continue to be collected and evaluated.
Specific changes
Change #1 
The following was added to the title page:
IND Number: 011197
Change #2
The following was added to the title page:
Protocol/Amendment Number
Date
Protocol
06-Jan-2009
Protocol Amendment 1
24-Jun-2009
Protocol Amendment 2
05-Dec-2011
Protocol Amendment 3
04-Dec-2013
Change #3
Contact Information
OLD TEXT
UCB Contributors:
Clinical Program Director (Study related questions)
Name:
, DVM
Phone:
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Fax:
Clinical Project Manager
Name:
Phone:
Fax:
Clinical Trial Biostatistician
Name:
Phone:
Fax:
Study Investigator
Name:
, MD
Phone:
Fax:
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www. secure-cimziadata.com
Fax:
+1 (888) 772 6919 (PRA number to be used if site is unable to access 
the electronic data capture [EDC] system)
Phone:
+1 (800) 772 3125 Study code 707501 (PRA number for EDC 
questions)
Phone:
+1 (678) 799 4007 (UCB number for questions related to adverse event 
reporting)
Email:
chosafety@praintl.com (PRA contact)
Site Support
Phone:
+1 (800) 772 3125 (reference number: 707501)
Patient Interview Service
Phone:
+1 (877) 580 7246
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NEW TEXT:
UCB Contributors:
Clinical Program Director (Study related questions)
Name:
, MD
Phone:
Fax:
Clinical Project Manager
Name:
, MPH
Phone:
Fax:
Clinical Trial Biostatistician
Name:
, PhD
Phone:
Fax:
Study Investigator
Name:
, MD
Phone:
Fax:
Study Epidemiologist
Name
, PhD
Phone:
Fax:
SAEs, Pregnancy, and Breastfeeding Reporting (24h/7d)
Primary
Internet
www. secure-cimziadata.com
Fax:
+1 (888) 772 6919 (PRA number to be used if site is unable to access 
the electronic data capture [EDC] system)
Phone:
+1 (800) 772 3125 Study code 707501 (PRA number for EDC 
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questions)
Phone:
+1 (866) 822 0068 (UCB number for questions related to adverse event 
reporting)
Email:
chosafety@praintl.com (PRA contact)
Site Support
Phone:
+1 (800) 772 3125 (reference number: 707501)
Patient Interview Service
Phone:
+1 (877) 580 7246
Change #4
The following was added to the Table of Contents:
LIST OF FIGURES
Figure 5‒1: Event reporting process ........................................................................................22
Figure 6‒1: Example person-time at risk for malignancy events.............................................26
Figure 6‒2: Example person-time at risk for acute events.......................................................27
LIST OF TABLES
Table 5‒1: Standardized MedDRA Queries for select adverse events of interest..................17
Change #5
List of Abbreviations
OLD TEXT:
AE
Adverse event
CD
Crohn’s disease
CPD
Clinical Program Director
CPM
Clinical Project Manager
eCRF
Electronic case report form
CRO
Contract research organization
EDC
Electronic data capture
FDA
Food and Drug Administration
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HBI
Harvey-Bradshaw index
IRB
Institutional Review Board
MedDRA®
Medical Dictionary for Regulatory Activities
p-y
Patient years
SAE
Serious adverse event
SAP
Statistical analysis plan
Anti-TNFα
Anti-tumor necrosis factor alpha
USA
United States of America
WHO Drug
World Health Organization Drug
NEW TEXT:
AE
adverse event
anti-TNFα
anti-tumor necrosis factor alpha
CD
Crohn’s disease
CI
confidence interval
CPM
Clinical Project Manager
CRO
Contract Research Organization
CSE
cross-section echocardiography
eCRF
electronic case report form
EDC
electronic data capture
EEG
Electroencephalogram
EMG
Electromyogram
FDA
Food and Drug Administration
HBI
Harvey-Bradshaw Index
IRB
Institutional Review Board
MedDRA®
Medical Dictionary for Regulatory Activities
p-y
patient years
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RR
Rate ratio
SAE
serious adverse event
SAP
statistical analysis plan
TNF
tumor necrosis factor
USA
United States of America
WHO Drug
World Health Organization Drug
Change #6
Section 5, Introduction
OLD TEXT:
Following the Food and Drug Administration (FDA) approval of certolizumab pegol 
(Cimzia) for Crohn’s disease (CD), UCB has committed to collect additional long-term, post-
marketing safety data on patients exposed to the product in a real-life setting.  To achieve this 
goal, a pharmacoepidemiologic registry study was designed.  Prospective data collected on 
2000 patients prescribed Cimzia will be compared to a 2000 patient prospective control group 
prescribed other treatments (including biologics) for Crohn’s disease.  Both the safety 
outcomes, exposure to Cimzia and other medications will be collected and calculated.  This 
will be a significant addition to post-marketing safety assessments based on spontaneous 
reports.  The study is anticipated to start 1st Quarter 2009 and continue monitoring all patients 
for approximately 10 years after enrollment.
NEW TEXT:
Following the Food and Drug Administration (FDA) approval of certolizumab pegol 
(Cimzia) for Crohn’s disease (CD), UCB has committed to collect additional long-term, post-
marketing safety data on patients exposed to the product in a real-life setting. To achieve this 
goal, a pharmacoepidemiologic study entitled SECURE was designed. The study began in 
January 2009 with the goal of collecting prospective data on 2000 patients prescribed Cimzia 
and a 2000 patient comparator group prescribed other treatments (including biologics) for 
CD. 
The protocol has been amended (Amendment 3) to revise analytic strategy methods and 
analysis providing more flexibility in treatment over the duration of the registry. The safety 
outcomes, exposure to Cimzia and other medications will continue to be collected and 
evaluated. 
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The SECURE registry represents a significant addition to post-marketing safety assessments 
based on spontaneous reports. The study is anticipated to continue monitoring all enrolled 
patients for approximately 10 years after enrollment.
Change #7
Section 6, Registry Rationale
OLD TEXT:
This study is a post approval commitment study designed to monitor the long-term safety of 
Cimzia when used in customary clinical practice in patients with Crohn’s disease and 
compared to a non-Cimzia control population.  Patients will be included in the Cimzia arm of 
the registry when they are elected to be treated with Cimzia by their Investigator.  The control 
group will also be included in the registry when elected by the Investigator.  Patient 
enrollment into each of the cohorts will be tracked on an ongoing basis.  When one of the 
cohorts reaches 2000, it will be assessed to discontinue enrollment in the applicable arm and 
continue enrollment in the other arm until it reaches 2000 patients. 
Patients will be followed for approximately 10 years during normal Investigator visits and 
through direct patient follow-up in the form of web, mail surveys and/or phone follow-up 
calls, during which the counts and frequency of all serious adverse events (SAEs) and 
nonserious adverse events (AEs) of interest will be collected.  All patients will receive and 
use their medications according to their normal course of medical treatment per Investigator
clinical judgment.
NEW TEXT:
This study is a post-approval commitment study designed to monitor the long-term safety of 
Cimzia compared to other CD treatments when used in customary clinical practice in patients 
with CD. Enrolled patients will be followed for approximately 10 years during normal 
Investigator visits and through direct patient follow-up in the form of web, mail surveys 
and/or phone follow-up calls. All patients will receive and use their medications according to 
their normal course of medical treatment per Investigator clinical judgment.
The treating Investigator is requested to report all serious adverse events (SAEs) and 
nonserious adverse events (AEs) of interest to the registry. These events will be collected and 
summarized. 
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Change #8
Section 7, Registry Objective
OLD TEXT:
The objective of this registry study (entitled SECURE) is to track safety outcomes of patients 
who have taken Cimzia for the treatment of Crohn’s disease compared to a non-Cimzia 
control population.
All SAEs and nonserious AEs of interest will be collected and summarized (see Section 5).  
The AEs of primary interest are: autoimmune disorders, demyelinating disorders, serious 
infections including opportunistic infections, hypersensitivity reactions, lymphoma and other 
malignancies.  These events of interest are consistent with the FDA Approval Letter.  In 
addition, UCB plans to evaluate aplastic anemia and serious cardiac events.  All these events 
represent serious risks known to the class of TNF blocking agents.  During the development 
program for Crohn's disease and rheumatoid arthritis consisting of over 5,000 subjects, 
reported events were consistent with the class.
NEW TEXT:
The objective of this registry is to measure the safety outcomes among Cimzia patients 
compared to those that occur while on a different CD treatment regimen.
All SAEs and AEs of interest will be collected and summarized (see Section 5). The AEs of 
interest are: autoimmune disorders, demyelinating disorders, serious infections including 
opportunistic infections, hypersensitivity reactions, lymphoma and other malignancies. In 
addition, UCB plans to evaluate aplastic anemia and serious cardiac events. All these events 
represent serious risks known to the class of tumor necrosis factor (TNF) blocking agents. 
During the development program for CD and rheumatoid arthritis consisting of over 5,000 
subjects, reported events were consistent with the class.
Change #9
Section 8.2, Selection of Study Population, paragraphs 1 and 2
OLD TEXT:
This is a long-term observational study in the USA that will include 2000 Cimzia-treated 
Crohn’s disease patients and 2000 patients treated with other Crohn’s disease medications.  
The study will be conducted in all regions in the USA at approximately 300 enrolling 
investigative sites.
Recruitment into both cohorts will be monitored and controlled as needed in order to ensure 
balanced enrollment over time.  In order to ensure reasonable balance between both cohorts, 
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retrospective frequency matching will be applied for disease severity (mild/moderate/severe), 
age categories and gender.
NEW TEXT:
This is a long-term observational study in the USA that will include approximately 4000 
CD patients. To ensure a sufficient number of Cimzia-treated patients in the registry, 
approximately half of enrolled patients will be receiving Cimzia for ≤12 months or about to 
receive Cimzia at the time of enrollment. The study will be conducted in all regions in the 
USA at approximately 300 enrolling investigative sites.
Recruitment of Cimzia-treated and comparator patients will be monitored and controlled as 
needed in order to ensure balanced enrollment over time.
Change #10
Section 8.3, Subject Inclusion/Exclusion Criteria
OLD TEXT:
Patients who meet all of the following criteria will be eligible for inclusion into the SECURE 
Registry:

Patient (or his/her legally acceptable representative) is able to provide written informed 
consent (patients under the age of consent must provide assent) to permit collection of 
data.  Patients who join the registry prior to legal age of consent will provide written 
informed consent as an adult upon reaching the legal age of consent.

Patient must have medically documented Crohn’s disease.

The decision to prescribe Cimzia or other medications has been made by the Investigator
independently of the decision to include the patient in the study.
Cimzia® cohort 

Patient must be about to receive treatment with Cimzia as part of a pre-existing 
management plan for Crohn’s disease or has already been receiving treatment with 
Cimzia for ≤6 months.
Comparison cohort 

Patient must be about to receive treatment with any other medication as part of a pre-
existing management plan for Crohn’s disease or has already been receiving 
treatment.  Previous Cimzia treatment is prohibited for the control arm.

Patients are eligible for the comparison cohort if one of the following criteria is 
fulfilled: 

currently receiving or history of anti-TNF treatment

currently receiving or history of immunosuppressant therapy within 6 months
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
currently receiving or history of systemic steroid therapy within 6 months
NEW TEXT:
Patients who meet all of the following criteria will be eligible for inclusion into the SECURE 
Registry:

Patient (or his/her legally acceptable representative) is able to provide written informed 
consent to permit collection of data.

Patient must be 18 years of age or older.

Patient must have medically documented CD.

The decision to prescribe Cimzia or other medications has been made by the Investigator
independently of the decision to include the patient in the study.

Patients participating in randomized, blinded clinical trials for CD or other conditions are 
not eligible for inclusion into the SECURE registry. Involvement in other registries, 
where patients follow routine clinical practice, is permitted, however.
Cimzia-treated patients
For a patient to qualify as being treated with Cimzia, they must meet one of the following 
criteria:

Patient is receiving treatment with Cimzia for the first time. Patient must receive Cimzia 
treatment within 2 months of enrollment into the registry. 

Patient is currently receiving treatment with Cimzia for ≤12 months. Patients must also 
receive a Cimzia dose within 2 months following enrollment into the registry.
Comparator patients
Patients enrolled in the comparator group are eligible to participate in the registry if one of 
the following criteria is fulfilled:

Patient is switching CD treatments or beginning CD treatment for the first time. Previous 
Cimzia treatment is prohibited in the comparator group. Patient must receive new CD 
treatment within 2 months of enrollment into the registry.

Patient is currently receiving anti-TNF treatment for ≤12 months. Patient must receive 
anti-TNF treatment within 2 months following enrollment into the registry.

Patient is currently receiving immunosuppressant therapy for ≤12 months. Patient must 
receive immunosuppressant therapy within 2 months following enrollment into the 
registry.

Patient is currently receiving systemic steroid therapy for ≤12 months. Patient must 
receive systemic steroid therapy within 2 months following enrollment into the registry.
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Change #11
Section 8.5, Schedule of Assessment
OLD TEXT:
Enrolling physicians will complete the baseline data for each patient after enrollment into the 
study.  Although patient care will follow the Investigator’s clinical judgment, it is 
recommended to the enrolling physician to report follow-up data on the patients 
approximately every 6 months after enrollment (months 6, 12, 18,…). Telephone contacts are 
permitted every other 6-month period, with the understanding that patients are typically seen 
by the Investigator every 12 months at a minimum per usual practice. All planned 
assessments described in Section 4.8.2 are to be completed during the telephone contacts.  
In an effort to avoid missing data and unreported events over the 10 year follow-up period, 
patients will directly report data in parallel to the enrolling physician reported data.  Direct 
patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via a 
web-based system, by mail or phone as requested by the patient.  If a patient does not provide 
the information via the web, mail or phone within approximately 1 week after the 3 month 
due date, the study patient interview service will call the patient to obtain the required 
information over the phone.  Safety information collected directly from the patient will be 
available for the study investigative site to review. If 4 consecutive quarterly patient surveys 
have not been at least partially completed, the patient will be considered lost to follow-up and 
further attempts at contact are not required. 
Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10b
Direct Patient 
Follow-up Year 1-
10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
Written informed consent/assent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or other 
medication
X
Planned Cimzia or other medication 
treatment period 
X
X
CD treatment medication changes 
and reason 
X
X
Concomitant medications 
X
X
X
All SAEs and nonserious AEs of 
interest since time of last completed 
X
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Study Entry 
(Baseline)
Investigator-
Reported 
Follow-up 
Year 1-10b
Direct Patient 
Follow-up Year 1-
10
ENROLLMENT
EVERY 6 
MONTHS
EVERY 3 
MONTHS
follow-upa
Major changes in health status since 
last completed follow-up
X
Investigator’s assessment of disease 
severity
X
X
Investigator’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease 
severity
X
X
Reasons for discontinuation from 
registry (early termination or end of 
Year 10)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey Bradshaw Index; SAE=serious adverse event
aAll serious adverse events; and nonserious adverse events of interest from both study arms are to be 
reported through the registry. 
b Telephone contacts are permitted every other 6-month period, with the understanding that patients are 
typically seen by the Investigator every 12 months at a minimum per usual practice.
c. This may also be completed by qualified site personnel as designated by the Investigator.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the Investigator telephone contact instead of the full HBI. 
NEW TEXT:
No visits are required as part of this protocol. All visits will be scheduled and conducted per 
standard of care. It is anticipated that visits will occur based on routine clinical practice.
Enrolling physicians will complete the baseline data for each patient after enrollment into the 
study. Although patient care will follow the Investigator’s clinical judgment, it is anticipated 
that the enrolling physician will see and, therefore, report follow-up data on the patients 
approximately every 6 months after enrollment (months 6, 12, 18,…). Telephone contacts are
permitted every other 6-month period, with the understanding that patients are typically seen 
by the Investigator every 12 months at a minimum per usual practice. All data, as described in 
Section 4.8.2, are to be collected as available during the telephone contacts. 
In an effort to minimize missing data and unreported events over the 10-year Follow-Up 
Period, patients will directly report data in parallel to the enrolling physician reported data. 
Direct patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via 
a web-based system, by mail or phone as requested by the patient. If a patient does not 
provide the information via the web, mail or phone within approximately 1 week after the 
3 month due date, the study patient interview service will call the patient to obtain the 
required information over the phone. Safety information collected directly from the patient 
will be available for the study investigative site to review. If 4 consecutive quarterly patient 
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surveys have not been at least partially completed, the patient will be considered lost to 
follow-up and further attempts at contact are not required.
Study Entry 
(Baseline)
Investigator-
Reported Follow-
up Year 1-10b
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
EVERY 
6 MONTHS
EVERY 
3 MONTHS
Written informed consent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or other 
medication
X
Planned Cimzia or other medication 
treatment period 
X
X
CD treatment medication changes and 
reason 
X
X
Concomitant medications 
X
X
X
All SAEs and AEs of interest since time 
of last completed follow-upa
X
Major changes in health status since last 
completed follow-up
X
Investigator’s assessment of disease 
severity
X
X
Investigator’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease severity
X
X
Reasons for discontinuation from 
registry (early termination or end of 
Year 10)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey-Bradshaw Index; SAE=serious adverse event
aAll SAEs and AEs of interest are to be reported through the registry. 
b Telephone contacts are permitted every other 6-month period, with the understanding that patients are 
typically seen by the Investigator every 12 months at a minimum per usual practice. No study visits are 
required as part of this protocol; treating Investigators are to manage patients based on clinical 
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Study Entry 
(Baseline)
Investigator-
Reported Follow-
up Year 1-10b
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
EVERY 
6 MONTHS
EVERY 
3 MONTHS
judgment and standard of care.
c. This may also be completed by qualified site personnel as designated by the Investigator.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the Investigator telephone contact instead of the full HBI. 
Change #12
Section 8.6, Informed Consent
OLD TEXT:
Patient (or his/her legally acceptable representative) is able to provide written informed 
consent or assent for participation in this registry and release of their blinded data to UCB, 
Inc. (sponsor) and the Contract Research Organization (CRO) for analysis.  Prior to obtaining 
informed consent/assent, the enrolling physician or designee will explain to the patient the 
nature and purpose of the study.  For patients who join the registry prior to legal age of 
consent, their legal representative will complete the informed consent form.  Patients under 
the legal age of consent who are of established age of assent (approximately 7 years of age) 
will complete the informed assent form.  These patients will be re-consented upon reaching 
legal age of consent.  After informed consent/assent is obtained, the original document will be 
placed in the patient’s medical record and a signed copy given to the patient.
For patients having been prescribed Cimzia, a Cimzia Medication Guide will be provided, 
and serious risks of Cimzia explained.
Upon enrollment, patients will receive an enrollment kit that includes general registry 
information, including a patient card that identifies them as a participant in the SECURE 
Registry.  The card informs the treating Investigator that the patient is participating in a 
registry study, and provides instructions for the treating Investigator on how to report adverse 
event or other treatment information to the enrolling physician.
NEW TEXT:
The patient (or his/her legally acceptable representative) must be able to provide written 
informed consent for participation in this registry and release of their data to UCB (sponsor) 
and the Contract Research Organization (CRO) for analysis. Prior to obtaining informed 
consent, the enrolling physician or designee will explain to the patient the nature and purpose 
of the study. After informed consent is obtained, the original document will be placed in the 
patient’s medical record and a signed copy given to the patient.
Medication guides will be provided per standard of care.
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Upon enrollment, patients will receive an enrollment kit that includes general registry 
information, including a patient card that identifies them as a participant in the SECURE 
Registry. The card informs the treating Investigator that the patient is participating in a 
registry study, and provides instructions for the treating Investigator on how to report AE or 
other treatment information to the enrolling physician.
Change #13
Section 8.7, Participation and Retention Strategies, paragraph 2 and 4
OLD TEXT:
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey.  “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without Investigator
visit/telephone contact and failure to at least partially complete 4 consecutive quarterly 
patient surveys; further attempts at patient contact are not required).  After informed 
consent/assent is obtained, the patient will complete a “Patient Contact Form”, which will 
request contact information (phone number, email address, and physical address).  This form 
will be submitted to an independent patient interview service by the enrolling physician.  The 
patients will receive emails or mail reminding them to complete the survey.  If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone.  For each survey the patient 
completes, they will receive a nominal appreciation gift.
In the event a Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients.  The 
Informed Consent/Assent Forms include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and contact them with the name and contact information of another study 
Investigator that they can contact during the remainder of their participation in the registry.  
The wording also states that the registry can continue to collect the direct patient-reported 
data without the need for re-consent. If the patient is unable or unwilling to be followed by a 
new Investigator, the patient must be discontinued from the study.
NEW TEXT:
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey. “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without Investigator
visit/telephone contact and failure to at least partially complete 4 consecutive quarterly 
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patient surveys; further attempts at patient contact are not required). After informed consent is 
obtained, the patient will complete a “Patient Contact Form”, which will request contact 
information (phone number, email address, and physical address). This form will be 
submitted to an independent patient interview service by the enrolling physician. The patients 
will receive emails or postal mail reminding them to complete the survey. If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone. For each survey the patient 
completes, they will receive a nominal appreciation gift.
In the event a Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients. The 
Informed Consent Form include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and contact them with the name and contact information of the closest 
participating study Investigator that they can contact during the remainder of their 
participation in the registry. The wording also states that the registry can continue to collect 
the direct patient-reported data without the need for re-consent. If the patient is unable or 
unwilling to be followed by a new Investigator, the patient must be discontinued from the 
study. 
Change #14
Section 8.8, Data Collection Strategies, paragraph 3
OLD TEXT:
As this is an approximately 10-year follow up registry study, the technologies used for this 
registry such as EDC will be 21 CFR Part 11 compliant and evaluated on an on-going basis 
throughout the registry study to ensure upgrades are made when necessary.
NEW TEXT:
As this is a 10-year follow up registry study, the technologies used for this registry such as 
EDC will be 21 CFR Part 11 compliant and evaluated on an on-going basis throughout the 
registry study to ensure upgrades are made when necessary.
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Change #15
Section 8.8.1, Enrollment Visit
The reference to “Crohn’s Disease” was replaced by the abbreviation  “CD”
Change #16
Section 8.8.2, Follow-Up Period
OLD TEXT:
The following data will be collected by the enrolling physician in EDC at each follow-up 
interval:

All SAEs and nonserious AEs of interest that have been reported since last follow-up

Investigator’s HBI completed at clinic visits or modified HBI completed during telephone 
contacts. This may also be completed by qualified site personnel as designated by the 
Investigator.

Investigator’s assessment of disease severity

Full details on exposure (e.g., dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for Crohn’s disease
NEW TEXT:
The following data will be collected as available by the enrolling physician in EDC at each 
follow-up interval:

All SAEs and AEs of interest that have been reported since last follow-up

Investigator’s HBI completed at clinic visits or modified HBI completed during telephone 
contacts. This may also be completed by qualified site personnel as designated by the 
Investigator

Investigator’s assessment of disease severity

Full details on exposure (eg, dose, frequency) to Cimzia or other medication

Any changes in medication

Reasons for discontinuation of Cimzia and/or other medication for CD
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Change #17
Section 9, Adverse Events of Interest, Serious Adverse Events, Case and Exposure 
Definitions
OLD TEXT:
Although serious adverse events and nonserious adverse events of interest are the focus of 
this registry, Investigators are expected to enter all AEs in the eCRF.
NEW TEXT:
Serious adverse events and AEs of interest are the focus of this registry; Investigators are not 
expected to enter nonserious AEs in the eCRF.
Change #18
Section 9.1, Definitions; last paragraph
OLD TEXT:
All Serious Adverse Events (of interest or other) must be reported within 24 hours of being 
acknowledged by the Investigator.
NEW TEXT:
All SAEs must be reported within 24 hours of being acknowledged by the Investigator.
Change #19
Section 9.2, Adverse Events of Interest
OLD TEXT:

Other events:

Congestive heart failure

Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia and leucopenia

Serious bleeding events

Serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, 
and erythema multiforme)
NEW TEXT:

Other events: 

congestive heart failure 
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
aplastic anemia, pancytopenia, thrombocytopenia, neutropenia and leucopenia

serious bleeding events

serious skin reactions (eg, Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme)
When available, narrow scope SMQs (Standardized MedDRA Queries) from the Medical 
Dictionary for Regulatory Activities (MedDRA®) version 16.0 will be used to define the AEs
of interest (Table 9-1).  Adverse events of interest that are the  clinical endpoints for the 
SECURE registry will be confirmed by review of  the results of diagnostic tests and 
diagnostic criteria used by the Investigator which are further explained within each section 
below.
Table 9-1
Standardized MedDRA Queries for select adverse events of interest
Event
SMQ Title
SMQ Code
SMQ Scope
Malignancy
Malignant tumours
20000194
Narrow PTs
Congestive Heart Failure 
Cardiac failure 
20000004
Narrow PTs
Serious skin reactions 
Severe cutaneous adverse 
reactions
20000020
Selected Narrow PTs
Hypersensitivity 
reactions
Anaphylactic reaction
20000021
Narrow/Broad PTs
Serious bleeding events
Haemorrhage 
20000038 
Narrow PTs
Aplastic anemia 
Haematopoietic 
cytopenias affecting more 
than one type of blood cell 
20000028
Narrow PTs
Aplastic anemia 
Haematopoietic 
erythropenia
20000029
Narrow PTs
Aplastic anemia
Haematopoietic 
leukopenia
20000030
Narrow PTs
Aplastic anemia 
Haematopoietic 
thrombocytopenia 
20000031
Narrow PTs
For events in which SMQs are not available, MedDRA v 16.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. These PTs are listed in the Statistical Analysis Plan (SAP). Additional detail on 
the clinical validation of the primary endpoints is presented below although all safety events 
that meet the definition of AEs of interest will be collected and summarized as part of the 
study.
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9.2.1
Autoimmune disorders
For this category, the primary events are Systemic Lupus Erythematosus and Rheumatoid 
Arthritis.
The diagnosis has to be supported with medical history and physical findings, serologic 
evidence and other evidence from biopsy, laboratory results, imaging results, or other 
specialized testing, where appropriate, and the exclusion of other disorders which might cause 
a similar pattern of findings.  
9.2.2
Demyelinating disorders 
For this category, the primary event is Multiple Sclerosis. Guillain-Barre syndrome and 
chronic inflammatory demyelinating polyneuropathy will be analyzed as autoimmune 
disorders.  
Medical history and physical findings, laboratory results, imaging results (eg, MRI) and any 
other specialized test (EEG, EMG, CSF analysis) results have to be considered in determining 
the final diagnosis.  
9.2.3
Serious and Opportunistic Infections 
Serious infections are defined as all infections meeting the definition of an SAE, and/or an 
infection requiring parenteral administration of antibiotics.
For the opportunistic infection category, the primary events are tuberculosis and pneumonia. 
The definitive diagnosis of pneumonia and tuberculosis may be confirmed by obtaining 
sputum smears or relevant biopsies and verifying by cultures. Infections not usually seen in 
immunocompetent patients or infections that have an accelerated pathogenesis or a more 
severe outcome in a given setting will also be considered opportunistic infections.
9.2.4
Lymphoma and Other Malignancies
For this category, the primary events are lymphoma, including hepatosplenic T cell 
lymphoma and non-Hodgkin lymphoma, and solid malignant tumors. 
Diagnosis has to be confirmed by tissue biopsy for histopathology (sources of tissue samples 
for review may include those obtained from an excisional biopsy -a tissue sample from the 
affected nodes or organ, a needle aspiration, or a bone marrow biopsy. Pathohistological 
results have to correlate clinically with imaging results and/or any other pertinent information 
prior to determining the final diagnosis.
9.2.5
Hypersensitivity Reaction
Primary endpoints for hypersensitivity reaction are events meeting the criteria of an 
anaphylactic reaction and acute hypersensitivity reaction occurring within 2 hours of drug
administration. As described in the case definition below, anaphylactic events include all 
terms listed in Category A, which consists of the narrow terms Type I hypersensitivity, 
anaphylactic shock and anaphylactoid reaction. In addition, combinations of the AE terms 
listed in Categories B, C and D will also be defined as anaphylactic events. 
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Category A: anaphylactic reaction, Type I hypersensitivity, anaphylactic shock, 
anaphylactoid reaction
Category B: dyspnoea, chest discomfort, cough, swollen tongue, oedema mouth, throat 
tightness, wheezing, laryngeal oedema, respiratory distress, sensation of foreign body, 
asthma, sneezing
Category C: swelling face, urticaria, pruritus, rash, eye swelling, pruritus generalized, rash, 
generalized, flushing, erythema, swelling, eye pruritus, lip swelling, rash pruritic, rash, 
erythematous, eyelid oedema, ocular hyperaemia, injection site urticaria, angioedema
Category D: hypotension, blood pressure decreased
To meet the definition of an anaphylactic event, a case has to meet one of the following 
criteria:
4. A narrow term or a term from Category A;
5. A term from Category B (Upper Airway/Respiratory) AND a term from Category C 
(Angioedema/Urticaria/Pruritus/Flush);
6. A term from Category D (Cardiovascular/Hypotension) AND either a term from 
Category B (Upper Airway/Respiratory) or a term from Category C 
(Angioedema/Urticaria/Pruritus/Flush)
9.2.6
Congestive heart failure
Congestive heart failure (CHF) is the primary endpoint for cardiac events of interest. CHF 
will be defined by Framingham criteria. The diagnostic criteria include physical findings of 
low cardiac output or increased cardiac workload and radiographic evidence (chest X-ray, 
ECG, Echocardiogram, CT, MRI, angiogram) and laboratory findings, ECG and imaging 
results and any other specialized test results have to be considered for final diagnosis. CHF 
present at baseline and worsening during the study (worsening of New York Heart 
Association (NYHA) functional classification) will be captured, as well as new onset CHF. 
9.2.7
Aplastic anemia
Aplastic anemia is a primary endpoint. Diagnosis must be confirmed by complete blood count 
(CBC) with peripheral smear, and bone marrow biopsy. Findings of pancytopenia 
(neutropenia, thrombocytopenia, and anemia), a reduction in the absolute number of 
reticulocytes, and a hypocellular bone marrow could be used to confirm the diagnosis.  
9.2.8
Serious bleeding events 
For this category, bleeding events meeting the criteria of an SAE are primary endpoints. 
9.2.9
Serious skin reactions
For this category, primary endpoints are Erythema multiforme, Stevens Johnson’s syndrome, 
and Toxic epidermal necrolysis.
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Change #20
Deletion of former Section 9.4 through Section 9.6
9.4
Case Definition:
Cimzia Case:
Cases will be attributable to Cimzia identified by two methods.  The first method will assume 
a case will be attributable to Cimzia after the first dose of the medication regardless of 
medication discontinuation and time to onset of the event.  The second method will be a 
series of sensitivity analyses and stratifications to evaluate different clinically driven 
definition of cases attributable to drug.  Specifics on data handling guidelines for managing 
missing or partial data will be documented in the Statistical Analysis Plan (SAP).
Control Case:
Cases will be attributable to non-Cimzia medications identified by two methods.  The first 
method will assume a case will be attributable to the non-Cimzia medication after the first 
dose of the medication regardless of medication discontinuation and time to onset of the 
event.  The second method will be a series of sensitivity analyses and stratifications to 
evaluate different clinically driven definition of cases attributable to drug.  Specifics on data 
handling guidelines for managing missing or partial data will be documented in the SAP.
9.5
Exposure Definition:
Cimzia Exposure:
Cimzia exposure will be calculated by two methods.  The first method will assume exposure 
from day one of the first dose of Cimzia medication after enrollment regardless of medication 
discontinuation through the date of the last follow-up evaluation.  The second method will be 
a series of sensitivity analyses and stratifications to evaluate the different clinically driven 
definitions of exposure to drug.  Specifics to these definitions will be outlined in the SAP.
Control Exposure:
Non-Cimzia medication exposure will be calculated by two methods.  The first method will 
assume exposure from day one of the first dose of the non-Cimzia medication after 
enrollment regardless of medication discontinuation through the date of the last follow-up 
evaluation.  The second method will be a series of sensitivity analyses and stratifications to 
evaluate the different clinically driven definitions of exposure to drug.  Specifics to these 
definitions will be outlined in the SAP.
9.6
Adverse Event Collection Period
All AEs collected from the registry will be reported to the FDA as per regulatory reporting 
guidelines.  Any reports received prior to start of the registry and after completion of the 
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study will be evaluated and reported as per standard UCB pharmacovigilance plans for 
spontaneous reporting.
To ensure the capture of any events that might occur between patient or Investigator data 
entry intervals, each patient will be provided a safety reporting process patient card that they 
can present to a Investigator if they have an event.  The card will contain instructions for the 
Investigator on how to report event information.
Change #21
Renumbering of former Section 9.7 to Section 9.4 and all subsequent sections within Section 
9
OLD TEXT
9.7
Adverse Event Reporting
All AE are expected to be entered in the eCRF. Serious adverse events and nonserious 
adverse events of interest from both study arms are to be reported through the registry.
All SAEs and all AEs of interest will be entered in the EDC system within 24 hours of site 
notification and will be automatically forwarded to PRA, International for assessment and 
further processing as per regulatory requirements and UCB procedures (see Figure 5‒
1 -Event Reporting Process for flow of activity).
Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the enrolling physician for medical confirmation.  Once medical 
confirmation is obtained, the enrolling physician will report the event through the EDC 
system. 
Information and instructions informing patients about the follow-up period and how to report 
adverse events is included in the Informed Consent Form. More detailed instructions to sites 
regarding reporting of SAEs are provided in the UCB safety Guidance booklet. 
NEW TEXT
9.4
Adverse Event Reporting to the Registry
Serious adverse events and AEs of interest are the focus of this registry; Investigators are 
expected to enter all SAEs and AEs of interest in the eCRF.
All SAEs and all AEs of interest will be entered in the EDC system within 24 hours of site 
notification and will be automatically forwarded to PRA, International for assessment and 
further processing as per regulatory requirements and UCB procedures (see Event reporting 
process)
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-Event Reporting Process for flow of activity
Any major changes in health status reported by the patient during the every 3 month patient 
follow-up will be sent to the enrolling physician for medical confirmation. Once medical 
confirmation is obtained, the enrolling physician will report the event through the EDC 
system. 
To ensure the capture of any events that might occur between patient or Investigator data 
entry intervals, each patient will be provided a safety reporting process patient card that they 
can present to a Investigator if they have an event. The card will contain instructions for the 
Investigator on how to report event information.
Information and instructions informing patients about the Follow-Up Period and how to 
report AEs is included in the Informed Consent Form. More detailed instructions to sites 
regarding reporting of SAEs and AEs of interest are provided in the UCB safety Guidance 
booklet. 
Change #22
Addition of Section 9.6, UCB Pharmacovigilance Reporting
NEW TEXT
Adverse events collected from the registry that occur within 70 days of last Cimzia dose will 
be included in UCB’s safety database and reported to the FDA as per regulatory reporting 
guidelines. Registry cases of malignancy, death, and pregnancy will be included in UCB’s 
safety database and reviewed and evaluated for FDA reporting even if the event occurs after 
70 days of last Cimzia dose. Any reports received prior to start of the registry and after 
completion of the study will be evaluated and reported as per standard UCB 
pharmacovigilance plans for spontaneous reporting.
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Change #23
Replacement of Section 10 and its sub-Sections
Change #24
Section 15, References
OLD TEXT
1.
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, et al. 
Serious infections and mortality in associate with therapies for Crohn’s disease: 
TREAT registry. Clin Gastroenterol Hepatol 2006;4:621-30.
2.
Lichtenstein GR, Cohen RD, Feagan BGG, Sandborn WJ, Salzberg BA, Chen DM, et 
al. Safety of infliximab and other Crohn’s disease therapies – TREAT Registry data 
with nearly 15,000 patient-years of follow-up. Gastroenterology 2006;130 (4 Suppl 2): 
A71.
NEW TEXT
Ecsedy J, Hunter D. Textbook of Cancer Epidemiology. Eds, Hans-Olov Adami, David 
Hunger, and Dimitrios Trichopoulos. New York, NY: Oxford University Press, Inc; 2002.
Lash TL, Fox MP, Fink AK. Applying Quantitative Bias Analysis to Epidemiologic Data. 
Springer. 2009.
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, et al. 
Serious infections and mortality in associate with therapies for Crohn’s disease: TREAT 
registry. Clin Gastroenterol Hepatol 2006;4:621-30.
Lichtenstein GR, Cohen RD, Feagan BGG, Sandborn WJ, Salzberg BA, Chen DM, et al. 
Safety of infliximab and other Crohn’s disease therapies – TREAT Registry data with nearly 
15,000 patient-years of follow-up. Gastroenterology 2006;130 (4 Suppl 2):A71.
Massey, FJ. The Kolmogorov-Smirnov Test for Goodness of Fit. Journal of the American 
Statistical Association. Vol. 46, No. 253, 1951, pp. 68–78.
Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 
2008 Oct 30;8:70
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14.4
Protocol amendment 4
Rationale for the amendment
The protocol has been amended to address clarification language in regards to patient visit 
requirements or lost-to-follow-up language. In addition, language was added to allow the 
sponsor to utilize patient-centric data warehouse organization(s), to extract de-identified data 
from healthcare channels in the US, including hospitals, providers and pharmacies. The 
statistical section was updated per FDA comments to account for treatment switch patterns.
Specific changes
Change #1

Throughout the document, the term “physician” has been replaced with the term 
“Investigator”.

Throughout the document, the term “enrolling physician” has been replaced with the 
term “Investigator”.
Change #2
Removal and replacement of second paragraph in Section 1, Introduction - second paragraph
NEW TEXT:
The protocol has been amended (Amendment 4) to address clarification language in regards 
to patient visit requirements or lost-to-follow-up language. In addition, language was added to 
allow the sponsor to utilize patient-centric data warehouse organization(s), to extract de-
identified data from healthcare channels in the US, including hospitals, providers and 
pharmacies. The statistical section was updated per FDA comments to account for treatment 
switch patterns.
Change #3
Section 4.3, Subject Inclusion/Exclusion Criteria
Clarification for subject inclusion/exclusion criteria specific to comparator patients and 
biologics.
NEW TEXT:

Patient is currently receiving for CD anti-TNF treatment (or other approved biologics) for 
≤12 months. Patient must receive anti-TNF treatment (or other biologics) within 2 months 
following enrollment into the registry.
Change #4
Section 4.5, – Schedule of Assessments
OLD TEXT:
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No visits are required as part of this protocol.  All visits will be scheduled and conducted per 
standard of care.
Enrolling physicians will complete the baseline data for each patient after enrollment into the 
study. Although patient care will follow the physician’s clinical judgment, it is anticipated 
that the enrolling physician will see and, therefore, report follow-up data on the patients 
approximately every 6 months after enrollment (months 6, 12, 18,…). Telephone contacts are 
permitted every other 6-month period, with the understanding that patients are typically seen 
by the physician every 12 months at a minimum per usual practice. All data, as described in 
Section 4.8.2, are to be collected as available during the telephone contacts. 
In an effort to minimize missing data and unreported events over the 10-year Follow-Up 
Period, patients will directly report data in parallel to the enrolling physician reported data. 
Direct patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12,...) via 
a web-based system, by mail or phone as requested by the patient. If a patient does not 
provide the information via the web, mail or phone within approximately 1 week after the 
3 month due date, the study patient interview service will call the patient to obtain the 
required information over the phone. Safety information collected directly from the patient 
will be available for the study investigative site to review. If 4 consecutive quarterly patient 
surveys have not been at least partially completed, further attempts at patient contact are not 
required. 
Study Entry 
(Baseline)
Physician-
Reported Follow-
up Year 1-10b
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
EVERY 
6 MONTHS
EVERY 
3 MONTHS
Written informed consent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or other 
medication
X
Planned Cimzia or other medication 
treatment period 
X
X
CD treatment medication changes and 
reason 
X
X
Concomitant medications 
X
X
X
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Study Entry 
(Baseline)
Physician-
Reported Follow-
up Year 1-10b
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
EVERY 
6 MONTHS
EVERY 
3 MONTHS
All SAEs and AEs of interest since time 
of last completed follow-upa
X
Major changes in health status since last
completed follow-up
X
Physician’s assessment of disease 
severity
X
X
Physician’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease severity
X
X
Reasons for discontinuation from 
registry (early termination or end of 
Year 10)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey-Bradshaw Index; SAE=serious adverse event
aAll SAEs and AEs of interest are to be reported through the registry. 
b Telephone contacts are permitted every other 6-month period, with the understanding that patients are 
typically seen by the physician every 12 months at a minimum per usual practice. No study visits are 
required as part of this protocol; treating physicians are to manage patients based on clinical judgment 
and standard of care.
c. This may also be completed by qualified site personnel as designated by the physician.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the physician telephone contact instead of the full HBI. 
NEW TEXT:
No mandatory visits are required as part of this protocol. All visits will be scheduled and 
conducted per sites standard of care. Standard of care is defined as: A diagnostic and 
customary clinical treatment/practice process that a clinician should follow for a Crohn’s 
disease patient, a certain type of illness, or clinical circumstance.
Investigators will complete the baseline data for each patient after enrollment into the study 
and includes the signing of the Informed Consent Form (ICF). Follow-up data for patient 
visits will be reported in accordance to sites standard of care or clinical judgment 
appointments. Telephone contacts are permitted. All data, as described in Section 4.8.2, are to 
be collected as available during the telephone contacts.
In an effort to minimize missing data and unreported events over the 10-year Follow-Up 
Period, patients will directly report data in parallel to the Investigator reported data. Direct 
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patient follow-up will occur every 3 months after enrollment (months 3, 6, 9, 12, etc) via a 
web-based system, by mail or by phone - as preferred by the patient. If a patient does not 
provide the information via the web, mail or by phone within approximately 1 week after the 
3 month due date, the study patient interview service will call the patient to obtain the 
required information over the phone. Safety information collected directly from the patient 
will be available for the study investigative site to review. If 8 consecutive quarterly patient 
surveys have not been at least partially completed, further attempts at patient contact are not 
required.  Investigator will be requested to confirm whether the patient status should be 
changed to ‘Lost to Follow-up’. 
Study Entry 
(Baseline)
Investigator-
Reported Follow-
upb
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
PER STANDARD 
OF CARE
EVERY 
3 MONTHS
Written informed consent
X
Assessment of inclusion/exclusion 
criteria
X
Demography
X
Crohn’s disease history
X
Medical and surgical history
X
Family history
X
Reason for initiating Cimzia or other 
medication
X
Planned Cimzia or other medication 
treatment period 
X
X
CD treatment medication changes and 
reason 
X
X
Concomitant medications 
X
X
X
All SAEs and AEs of interest since time 
of last completed follow-upa
X
Major changes in health status since last 
completed follow-up
X
Investigator’s assessment of disease 
severity
X
X
Investigator’s HBIc
(see APPENDIX A)
X
Xe
Patient’s Modified HBId
X
X
Patient’s assessment of disease severity
X
X
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Study Entry 
(Baseline)
Investigator-
Reported Follow-
upb
Direct Patient 
Follow-up 
Year 1-10
ENROLLMENT
PER STANDARD 
OF CARE
EVERY 
3 MONTHS
Reasons for discontinuation from 
registry (early termination or end of 
Year 10)
X
AE=adverse event; CD=Crohn’s disease; HBI=Harvey-Bradshaw Index; SAE=serious adverse event
aAll SAEs and AEs of interest are to be reported through the registry. 
b Telephone contacts are permitted.
c.This may also be completed by qualified site personnel as designated by the Investigator.
d The Modified HBI does not include the abdominal mass question. 
e The Modified HBI is completed during the Investigator telephone contact instead of the full HBI. 
Change #5
Moving of Informed Consent sentences from Section 4.7 -Participation and Retention 
Strategies to more appropriately Section 4.6 – Informed Consent.
“After informed consent is obtained, the patient will complete a “Patient Contact Form”, 
which will request contact information (phone number, email address, and physical address). 
This form will be submitted to an independent patient interview service by the Investigators.
Change #6
Section 4.7, Participation and Retention Strategies
OLD TEXT:
Individual patient follow-up is approximately 10 years after enrollment, regardless of 
discontinuation of Cimzia or other medications.
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if requested, by mail (including a prepaid self-addressed return envelope) or by 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey. “Lost to follow-up” is defined as a 
patient who goes one year with no data being collected/reported (1 year without physician 
visit/telephone contact and failure to at least partially complete 4 consecutive quarterly 
patient surveys; further attempts at patient contact are not required). After informed consent is 
obtained, the patient will complete a “Patient Contact Form”, which will request contact 
information (phone number, email address, and physical address). This form will be 
submitted to an independent patient interview service by the enrolling physician. The patients 
will receive emails or postal mail reminding them to complete the survey. If they have not 
completed the survey one week after the due date, they will be called by the independent 
patient interview service to complete the survey via phone. For each survey the patient 
completes, they will receive a nominal appreciation gift.
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In addition, patients will receive via postal mail an annual calendar with stickers placed on 
the months that they will be requested to complete their quarterly patient survey. They will 
receive a new calendar each year of their participation. Patients will also receive a registry 
newsletter once a year in an attempt to keep them engaged in the registry.
In the event a physician retires, or discontinues participation from the registry, the following 
transition plan is in place to enable continuing participation of their patients. The Informed 
Consent Form include wording explaining that if the patient’s physician discontinues 
participation in the registry, or retires, the independent patient interview service will be 
notified and contact them with the name and contact information of the closest participating 
study physician that they can contact during the remainder of their participation in the 
registry. The wording also states that the registry can continue to collect the direct 
patient-reported data without the need for re-consent. If the patient is unable or unwilling to 
be followed by a new physician, the patient must be discontinued from the study. 
In the event a patient moves to a new location or chooses to leave their current physician, 
patients are provided with information upon enrollment as to how to locate a participating 
physician in their area or how to provide the registry information to a new physician that may 
not yet be participating. Participating patients will have access to all of this information on 
the study specific web portal as well as being reminded of this process in the annual patient 
newsletters they will receive throughout their participation in the study.
The goal of these strategies is to enhance patient retention activity, potentially resulting in a 
lower drop-out rate and improved quality of data.
Over the course of a long-term study, patient death may occur. Additionally, patients may 
develop serious co-morbidities that cause them to become “lost to follow-up” in the Registry. 
Periodically throughout the study, and in case of “lost to follow-up”, searches of appropriate 
databases, such as the national death index and state cancer registries, death or cancer 
registries will be performed for any matches.
NEW TEXT:
Individual patient follow-up is approximately 10 years after enrollment, regardless of 
discontinuation of Cimzia or other medications.
As a means to retain patient participation, patients are followed up directly via a web-based 
system or if preferred, by mail (including a prepaid self-addressed return envelope) or by the 
phone every 3 months throughout the study (unless the patient withdraws consent or is 
deemed lost to follow-up) to complete a patient survey. “Lost to follow-up” is defined as a 
patient who goes 2 years with no data being collected/reported (2 years without Investigator
visit/telephone contact or failure to at least partially complete 8 consecutive quarterly patient 
surveys; further attempts at patient contact are not required). The patients will receive emails 
or postal mail reminding them to complete the survey. If they have not completed the survey 
one week after the due date, they will be called by the independent patient interview service 
to complete the survey via phone. Patients completing the quarterly surveys will receive a 
nominal appreciation gift (if approved by the site’s IRB).
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In addition, patients will receive via postal mail an annual calendar with stickers placed on 
the months that they will be requested to complete their quarterly patient survey. They will 
also receive a new calendar and a registry newsletter once a year in an attempt to keep them 
engaged in the registry.
In the event an Investigator retires, or discontinues participation from the registry, the 
following transition plan is in place to enable continuing participation of their patients. The 
Informed Consent Form include wording explaining that if the patient’s Investigator
discontinues participation in the registry, or retires, the independent patient interview service 
will be notified and the name and contact information of the closest participating study 
Investigator that they can contact during the remainder of their participation in the registry. 
The new Investigator and the patient should document re-consent of the transition. The 
registry can continue to collect the direct patient-reported data without the need for re-
consent. If the patient is unable or unwilling to be followed by a new Investigator, the patient 
must be discontinued from the study. 
In the event a patient moves to a new location or chooses to leave their current Investigator, 
patients are provided with information upon enrollment as to how to locate a participating 
Investigator in their area or how to provide the registry information to a new Investigator that 
may not yet be participating. Participating patients will have access to all of this information 
on the study specific web portal as well as being reminded of this process in the annual 
patient newsletters they will receive throughout their participation in the study.
The goal of these strategies is to enhance patient retention activity, potentially resulting in a 
lower drop-out rate and improved quality of data.
Over the course of a long-term study, patient death may occur. Additionally, patients may 
develop serious co-morbidities that cause them to become “lost to follow-up” in the Registry. 
Periodically throughout the study, and in case of “lost to follow-up”, searches of appropriate 
databases, such as the national death index and state cancer registries, death or cancer 
registries will be performed for any matches. In addition, the sponsor may utilize patient-
centric data warehouse organization(s), to extract de-identified data from healthcare channels 
in the US. Data sources include, but are not limited to, medical claims, pharmacy claims, 
hospital charge master records, behavioral and demographic information, oncology electronic 
medical records (EMR), long-term care pharmacy, and laboratory data. The output from this 
activity will not be used to solicit additional events from Investigators.
Change #7
Section 5.2, Adverse Events of Interest
Correction of last paragraph
OLD TEXT:
For events in which SMQs are not available, MedDRA v 16.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. These PTs are listed in the Statistical Analysis Plan (SAP). Additional detail on 
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the clinical validation of the primary endpoints is presented below although all safety events 
that meet the definition of AEs of interest will be collected and summarized as part of the 
study.
NEW TEXT:
For events in which SMQs are not available, MedDRA v 16.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. For AEs of interest, where no SMQ is available, medical review will occur to 
select AEs (eg demyelinating disorders, autoimmune disorders and serious infections). 
Additional detail on the clinical validation of the primary endpoints is presented below 
although all safety events that meet the definition of AEs of interest will be collected and 
summarized as part of the study.
Change #8
Figure 5-1, Event reporting process
Replaced process flow chart in its entirety to reflect change of terms “Enrolling physician” 
with “Investigator”
Change #9
Section 6.1.1, Primary Endpoints
OLD TEXT:
The primary events interested in this registry are incidence and recurrence rates as well as the 
time-to-event for the following safety events: 

Autoimmune disorders 

Demyelinating disorders 

Serious infections or opportunistic infections

Lymphoma and other malignancies

Hypersensitivity reactions

Other events: 

congestive heart failure 

aplastic anemia

serious bleeding events

serious skin reactions
NEW TEXT:
The primary outcome of this observational study is malignancy. Additionally, the following 
safety events will be investigated: 
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
Autoimmune disorders 

Demyelinating disorders 

Serious infections or opportunistic infections

Hypersensitivity reactions

Other events: 

congestive heart failure 

aplastic anemia

serious bleeding events

serious skin reactions
Change #10
Removal of sections formerly entitled:

11.4.1.1, Determination of Event Rate Numerator

11.4.1.2, Person time at Risk Calculations

11.4.1.2.1, Person time at risk calculation for malignancy events

11.4.1.2.2, Person time at risk calculations for acute events

11.4.1.5, Time to Event Analyses
Change #11
Section 6.4.1, Primary Analysis
Safety events will be categorized based on event types (eg, malignancies, infections, 
demyelinating disorders, hypersensitivity reactions, and autoimmune disorders) with analyses 
conducted for each category. Analysis of specific outcomes may be conducted if appropriate.
Event rates will be calculated by dividing the number of reported safety events by the 
person-years at risk. Cimzia-specific rates will be calculated and compared to all other CD 
treatment rates. Incidence rates will be calculated by dividing the number of subjects who had 
reported safety events by the appropriate person-years at risk. 
For incidence rate and event rate calculations, the number of events will be determined for 
Cimzia and for all other CD treatments based on the date of the last dose received before 
event onset and treatment class-specific half-life exposure of the medication. The exposure 
half-lives used for rate calculations for each treatment class are as follows: 

Corticosteroids: 7 days

Immunosuppressants: 28 days

Biologic agents (including Cimzia): 70 days
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Propensity scores will be used to assess the comparability of patients who are receiving 
Cimzia at baseline and those who are receiving another CD medication and will be 
incorporated into the primary analysis. Two-sided 95% confidence intervals (CIs) will be 
calculated for all rates.
Appropriate analytical methodologies will be used to investigate the effect of time varying 
confounders.
Cancer progresses in several stages before reaching a detectable, malignant state. While this 
latency period may differ by cancer type, it is generally believed to occur over a long time 
period (Ecsedy and Hunter, 2002). Thus, a treatment-related event may not be seen until years 
after the initial exposure. In contrast, acute events typically have very short latency periods; 
therefore, it is unlikely that a treatment-related event will occur after exposure to the product 
has ended. For this reason, 2 different methods of person-time at risk calculations will be 
used, one for malignancy events (Section 6.4.1.1) and one for acute events (Section 6.4.1.2).
Change #12
Added Section 6.4.1.1, Malignancy Events
NEW TEXT:
The following analyses will be conducted to better elucidate treatment patterns and treatment 
attribution in malignancy events:

The number of malignancy events and number of patients experiencing malignancy 
events will be tabulated by the number of CD treatments received during the study. Also, 
the mean number of treatments received per patient in the Cimzia and comparator groups 
(based on baseline assignment) will be calculated, as well as for both groups combined.

The number of malignancy events and number of patients experiencing malignancy 
events will be tabulated by treatment patterns for biologics observed in the study. The 
name and order of the biologic treatment will be specified in the summary table (eg, “A-
B” implies that patients received two different biologics, “A” followed by “B”; “C” 
implies that patients received one biologic “C” throughout the study; “A-C-D” implies 
that patients received three different biologics, in the order of “A”, “C”, then “D”, etc.).

The number of malignancy events and the number of patients experiencing malignancy 
events will be tabulated by the type of CD therapy received (monotherapy versus 
combination therapy). If a patient received combination therapy (TNF-α antagonist plus 
immunosuppressant) at least once during the study, then this patient will be included in 
the combination therapy category.
Change #13
Added Section 6.4.1.2, Acute Events
NEW TEXT:
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The primary analysis for acute events will be time-to-event analyses using Cox proportional 
hazard modeling. A Kaplan-Meier analysis will be performed censoring patients at the time 
of their first treatment switch during the study period, including patients who switch from one 
non-Cimzia treatment to another non-Cimzia treatment, as a secondary analysis.
14.5
Protocol amendment 5
Rationale for the amendment
The protocol has been amended to close the enrollment period and to revise the patient follow 
up period to 8 years. Interim analysis data was provided to support the enrollment time and 
patient follow up period.
In addition, minor grammatical and typographical errors were corrected.
Global Changes
Change #1
The follow up period for patients enrolled was changed from 10 years to 8 years throughout 
the document. The following sections were affected:

Section 1: Introduction, third paragraph, second sentence

Section 2: Registry Rationale, first paragraph, second sentence

Section 4.5: Schedule of Assessments, third paragraph, first sentence

Section 4.5: Schedule of Assessments table, “Direct Patient Follow-up Year” column title

Section 4.5: Schedule of Assessments table, first column, last row

Section 4.7: Participation and Retention Strategies, first sentence

Section 4.8: Data Collection Strategies, third paragraph, first sentence

Section 6.2: Comparator Group, first sentence

Section 6.3: Determination of Sample Size, first paragraph, first and second to last 
sentences
Specific Changes
Change #1
Study Contact Information
Name: 
, MD
Phone:
Fax: 
Has been changed to:
Name: 
Phone: 
 
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Fax: Not Applicable
Change #2
Study Contact Information
Clinical Project Manager
Name: 
, MPH
Phone: 
Fax: 
Has been changed to:
Senior Clinical Project Manager
Name: 
Phone: 
Fax: Not Applicable
Change #3
Study Contact Information
Clinical Trial Biostatistician
Name: 
, PhD
Phone: 
Fax: 
Has been changed to:
Senior Biostatistician 
Name: 
Phone: 
Fax: Not Applicable
Change #4
Study Contact Information
Name: 
, MD
Phone: 
Fax: 
Has been changed to:
Name: 
, MD
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Phone: 
Fax:
Change #5
Study Contact Information
Name: 
, PhD
Phone: 
Fax: 
Has been changed to:
Name: 
, PhD
Phone: 
Fax: Not Applicable
Change #6
Section 1: Introduction
Second paragraph
The protocol has been amended (Amendment 4) to address clarification language in regards 
to patient visit requirements or lost-to-follow-up language. In addition, language was added to 
allow the sponsor to utilize patient-centric data warehouse organization(s), to extract de-
identified data from healthcare channels in the US, including hospitals, providers and 
pharmacies. The statistical section was updated per FDA comments to account for treatment 
switch patterns.
Has been changed to:
The protocol has been amended (Amendment 5) to cease enrolling patients into the 
SECURE registry (protocol C87075). The decision was based on the results of a current 
interim analysis that indicated that no new safety issues had emerged from the currently 
known safety profile of Cimzia. Patients who already enrolled in C87075 at the time of 
discontinuation will continue to be followed. 
Change #7
Section 4.2: Selection of Study Population
First paragraph
This is a long-term observational study in the USA that will include approximately 4000 CD 
patients. To ensure a sufficient number of Cimzia-treated patients in the registry, 
approximately half of enrolled patients will be receiving Cimzia for ≤12 months or about to 
receive Cimzia at the time of enrollment. The study will be conducted in all regions in the 
USA at approximately 300 enrolling investigative sites.
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Has been changed to:
This is a long-term observational study in the USA that includes a total of 3045 CD patients
(1371 in the Cimzia Cohort and 1674 in the Comparison Cohort) as of Mar 2017. To 
ensure a sufficient number of Cimzia-treated patients in the registry, approximately half of 
enrolled patients will be receiving Cimzia for ≤12 months or about to receive Cimzia at the 
time of enrollment. The study will be conducted in all regions in the USA at approximately 
280 enrolling investigative sites.
Change #8
Section 4.7: Participation and Retention Strategies
The third paragraph was deleted:
In addition, patients will receive via postal mail an annual calendar with stickers placed on 
the months that they will be requested to complete their quarterly patient survey. They will 
also receive a new calendar and a registry newsletter once a year in an attempt to keep them 
engaged in the registry
Change #9
Section 4.7: Participation and Retention Strategies
The fourth paragraph, end of the last sentence
as well as being reminded of this process in the annual patient newsletters.
Change #10
Section 5.2: Adverse Events of Interest
First paragraph, first sentence
When available, narrow scope SMQs (Standardized MedDRA Queries) from the Medical 
Dictionary for Regulatory Activities (MedDRA®) version 16.0 will be used to define the AEs
of interest (Section 5.2). 
Has been changed to:
When available, narrow scope SMQs (Standardized MedDRA Queries) from the Medical 
Dictionary for Regulatory Activities (MedDRA®) version 17.0 will be used to define the AEs 
of interest (Section 5.2).
Change #11
Section 5.2: Adverse Events of Interest
Last paragraph, first sentence
For events in which SMQs are not available, MedDRA v 16.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. For AEs of interest, where no SMQ is available, medical review will occur to 
select AEs (eg demyelinating disorders, autoimmune disorders and serious infections). 
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Has been changed to:
For events in which SMQs are not available, MedDRA v 17.0 Preferred Terms (PT) for the 
System Organ Class (SOC) and High-Level Group Term (HLGT) categories will be used as 
appropriate. For AEs of interest, where no SMQ is available, medical review will occur to 
select AEs (eg demyelinating disorders, autoimmune disorders and serious infections).
Change #12
Section 6.1.1: Primary Endpoints
MedDRA coding version 16.0 will be used to identify and define AEs of interest. The 
specific MedDRA codes used to determine AEs of interest will be provided in the SAP. 
Narrow scope SMQs and clinical validation of primary endpoints are provided in Section 5.2
of the protocol. 
Has been changed to:
MedDRA coding version 17.0 will be used to identify and define AEs of interest. The 
specific MedDRA codes used to determine AEs of interest will be provided in the SAP. 
Narrow scope SMQs and clinical validation of primary endpoints are provided in Section 5.2
of the protocol. 
Change #13
Section 6.3: Determination of Sample Size
First paragraph
A total of 4000 patients (2000 patients per arm) are planned to be enrolled in the first 5 years 
of the study, with a total duration of participation (treatment and follow-up) of 10 years for 
each patient. Assuming an 8% annual drop-out rate (1) (withdrawal, lost-to-follow-up or 
death), approximately 25,000 (12,500 per arm) total patient years (p-y) post-enrollment is 
expected in this registry. With a two-sided significance level of 0.05, the study is designed to 
have at least 80% power to detect incidence rate ratios (calculated based on observed rates in 
the control group) of 1.5 for serious infections, 3.3 for lymphoma, and 1.56 for solid 
malignancies after 10 years. Event rate estimates for this study were calculated using 
corresponding event rates observed in a CD anti-TNFα registry study control group (1, 2).
Has been changed to:
Prior to Amendment 5, the study planned for a total of 4000 patients (2000 patients per 
arm. A total of 3045 patients (1371 in the Cimzia Cohort and 1674 in the Comparison 
Cohort) were enrolled as of Mar 2017. The total duration of participation (treatment and 
follow-up) of 8 years is planned for each patient. Assuming an 8% annual drop-out rate (1) 
(withdrawal, lost-to-follow-up or death), approximately 25,000 (12,500 per arm) total patient 
years (p-y) post-enrollment is expected in this registry. With a two-sided significance level of 
0.05, the study is designed to have at least 80% power to detect incidence rate ratios 
(calculated based on observed rates in the control group) of 1.5 for serious infections, 3.3 for 
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lymphoma, and 1.56 for solid malignancies after 8 years. Event rate estimates for this study 
were calculated using corresponding event rates observed in a CD anti-TNFα registry study 
control group (1, 2).
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Approval Date 
(dd-mon-yyyy 
(HH:mm)) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C87075 Protocol Amendment 5 SECURE
Clinical Approval
13-Sep-2017 17:13 GMT+02
Clinical Approval
13-Sep-2017 18:38 GMT+02
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