Conditions: Crohn's Disease
Keywords: Crohn's Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 252
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long term efficacy, safety, and tolerability of repeated administration of adalimumab in participants with Crohn's disease.

Detailed description:

Arms:
arm 1: Participants received open-label adalimumab 40 mg by subcutaneous injection every other week for 40 weeks.

Interventions: intervention 1: Adalimumab
Intervention descriptions: intervention 1: Adalimumab pre-filled syringe, administered by subcutaneous injection

Protocol document:
Prot_000.pdf: 
Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
1
1.0
Title Page
Clinical Study Protocol M14-347
A Multicenter, Open-Label Study to Evaluate the 
Long Term Efficacy, Safety, and Tolerability of 
Repeated Administration of Adalimumab in Subjects 
with Crohn's Disease
Incorporating Amendments 1 and 2
AbbVie Investigational
  Product:
Adalimumab
Date:
04 December 2014
Development Phase:
3
Study Design:
Phase 3, Multicenter, Open-label, Efficacy and Safety Study
EudraCT Number:
2013-004034-15
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor*:
Sponsor/Emergency 
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
*The specific contact details of the AbbVie legal/legal regulatory entity (person) within the relevant country 
are provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
2
1.1
Protocol Amendment:  Summary of Changes
The purpose of this amendment is as follows:
●
Update synopsis to reflect Amendment Changes below.
●
Update definition of Inadequate Response in Section 5.1.
Rationale for change:  to allow for subjects to escalate without the need to 
have results from two visits.
●
Update the first week subjects are allowed to dose escalate in Section 5.1.
Rationale for change:  to clarify the point in the study subjects are first able to 
dose escalate.
●
Remove serological biomarkers/mRNA testing, Abdominal Pain Rating Scale, 
and IBDQ, EQ-5D, and WPAI questionnaires from "Unscheduled Visit" in 
Table 2.
Rationale for change: to clarify which activities are required at an 
unscheduled visit.
●
Updated table note "k." for Table 2.
Rationale for change:  to clarify which visits are considered unscheduled 
visits.
●
Update the Urinalysis subsection in Section 5.3.1.1.
Rationale for change:  to clarify when a microscopic analysis will be 
performed.
●
Update Other Laboratory Assessments subsection in Section 5.3.1.1.
Rationale for change:  to clarify the time in which all stool samples should be 
returned to the site.
●
Update Additional Efficacy Variables in Section 5.3.3.2.
Rationale for change:  to reflect changes made in Section 5.1 concerning the 
time in which subjects can be dose escalated if criteria are met.
●
Update Section 5.2.3.2 with new contact information.
Rationale for change:  there is a change in the Secondary Study Designated 
Physician and an addition of a back-up 24/7 contact number for medical 
emergencies and safety concerns.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
3
●
Update typographical grammatical errors throughout protocol.
An itemized list of all protocol amendment changes can be found in Appendix M.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-347
Name of Study Drug: Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  04 December 2014
Protocol Title:  A Multicenter, Open-Label Study to Evaluate the Long Term Efficacy, Safety, and 
Tolerability of Repeated Administration of Adalimumab in Subjects with Crohn's Disease
Objectives:
The primary objective of this study is to evaluate the long-term efficacy, safety, and tolerability of 
repeated administration of adalimumab in subjects with Crohn's disease (CD) who participated in and 
successfully completed Study M14-115.
The secondary objective is to assess pharmacokinetics (PK) and immunogenicity of adalimumab 
following subcutaneous (SC) administration.
Investigators:  Multicenter
Study Sites:  Only sites that have enrolled subjects from Study M14-115 will be included.
Study Population:  Subjects with CD who previously participated in and successfully completed 
Study M14-115.
Number of Subjects to be Enrolled:  Approximately 300 subjects who participated in and successfully 
completed Study M14-115.
Methodology:
This is an open-label extension (OLE) study which comprises a 40-week open-label period designed to 
evaluate the long-term efficacy, safety, and tolerability of adalimumab.  Approximately 300 subjects 
with CD who participated in and successfully completed Study M14-115 will be enrolled.
Subjects will be evaluated for entry into Study M14-347 at the final study visit (Week 12) of 
Study M14-115.  Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be 
eligible to participate in this study.  The Week 12 visit of Study M14-115 will be considered Week 0 
(Baseline) of Study M14-347.  All subjects will receive open-label adalimumab 40 mg every other week 
(eow) beginning at Week 0.  Subjects may be escalated to adalimumab 40 mg every week (ew) at or 
after Week 1 should the subject meet the criteria for inadequate response:
Inadequate Response:
Crohn's disease activity index (CDAI) ≥ 200 at any one visit and at least one of the following criteria is 
met:  an increase of at least 1 mg/L in level of high-sensitivity C-reactive protein (hs-CRP) from 
Baseline or an hs-CRP ≥ 5 mg/L.  The hs-CRP results used to determine inadequate response can be 
from the prior or current visit.  Assessment of inadequate response should include consideration by the 
Investigator to rule out symptoms caused by reasons other than Crohn's disease related inflammation.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
5
Methodology (Continued):
For subjects taking corticosteroids at Baseline of Study M14-115, adalimumab dose escalation should be 
considered in lieu of increases in steroid dose.  Subjects who continue to experience  inadequate 
response on 40 mg ew who were taking corticosteroids at Baseline may have their steroid dose 
increased, per the Investigator's discretion, in order to manage the subject's symptoms.  Any subject who 
continues to experience inadequate response on 40 mg ew may be discontinued from the study at the 
investigator's discretion after discussion with the Study designated physician (SDP).  Subjects who dose 
escalated to adalimumab 40 mg ew, have one opportunity to de-escalate adalimumab dose to 40 mg eow 
provided the following criteria have been met:  CDAI < 200, and  high-sensitivity C-reactive protein 
(hs-CRP) value equal to or lower than that observed at the time of dose escalation.  Subjects who 
experience inadequate response after dose de-escalation (using the same criteria outlined above) may 
again be escalated to 40 mg ew.  A subject has only one opportunity to dose-de-escalate and 
one opportunity to re-escalate to ew adalimumab dosing.
Study visits for clinical and safety assessments will be performed at Weeks 0, 8, 16, 24, 32 and 
40/Premature Discontinuation (PD).  All subjects will be provided a paper subject diary in which they 
will record CD-related symptoms (number of liquid or very soft stools, abdominal pain rating, general 
well-being) and adalimumab dosing information throughout the study.  Blood samples will be collected 
at various timepoints for hs-CRP, adalimumab serum concentrations, anti-adalimumab antibody (AAA) 
levels and other biomarker analyses.  In addition, stool samples for calprotectin and microbiota will be 
collected.  The stool samples should be taken before starting bowel preparations for endoscopy.  
Endoscopic evaluation will be performed at Week 40/PD if the PD occurs after Week 24.  CDAI 
evaluations will be calculated based on entries recorded into the subject's diary at all study visits.  The 
SFPS (Stool [liquid/soft] Frequency + Abdominal Pain Score) will be calculated using the weighted 
values for the CDAI components "Number of liquid or very soft stools" and "Abdominal pain."  Subjects 
will be discontinued from the study if they withdraw consent or if they are deemed unsuitable to 
continue for any reason by the Investigator.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject must have successfully enrolled in and completed Study M14-115, including the Week 12 
ileocolonoscopy.
2.
If female, subject is either not of childbearing potential, defined as postmenopausal for at least 
1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy and/or hysterectomy) or 
is of childbearing potential and is practicing an approved method of birth control throughout the 
study and for 150 days after last dose of study drug.  Examples of approved methods of birth control 
which result in a low failure rate (i.e., less than 1% per year) when used consistently are (see local 
informed consent for more detail):
!
Implants, injectables, some intrauterine devices (IUDs), intrauterine hormone-releasing system 
(IUS)
!
Sexual abstinence (when in line with preferred and usual lifestyle of the subject)
!
A vasectomized partner
!
Hormonal contraceptives for at least 90 days prior to study drug administration
Note:  low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 
0.5 mg are not considered adequate 


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
6
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
3.
Subject must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.
4.
Subject must be able and willing to self-administer SC injections or have a qualified person 
available to administer SC injections.
Main Exclusion:
1.
For any reason subject is considered by the investigator to be an unsuitable candidate. 
2.
Known hypersensitivity to adalimumab or its excipients.
3.
Subject with an active systemic viral infection, or any active viral infection, that based on the 
investigator's clinical assessment makes the subject an unsuitable candidate for the study. 
4.
Positive pregnancy test at Baseline (Week 12 of Study M14-115).
5.
Female subject who is considering becoming pregnant during the study. 
6.
History of malignancy other than a successfully treated non-metastatic cutaneous squamous cell, 
basal cell carcinoma and/or localized carcinoma in situ of the cervix.  If the Week 12 
(Study M14-115) colonoscopy shows evidence of dysplasia or a malignancy, subject must not be 
enrolled in the study.
7.
Subject with a poorly controlled medical condition, such as uncontrolled diabetes, unstable ischemic 
heart disease, moderate or severe congestive heart failure, recent cerebrovascular accidents and any 
other condition which, in the opinion of the investigator or sponsor, would put the subject at risk by 
participation in this study.
8.
Subject is not in compliance with prior and concomitant medication requirements throughout 
Study M14-115.
9.
History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
10. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency 
syndrome (HIV).
11. Subject who developed active Tuberculosis (TB) during Study M14-115, or subject who is 
non-compliant with prophylaxis for latent TB initiated per Study M14-115 procedures.
Investigational Products:
Adalimumab (40 mg/0.8 ml)
Doses:
Open-Label Period
40 mg eow or 40 mg ew for subjects whose disease is not controlled on 
40 mg eow beginning at Week 0.  No dose will be administered at 
Week 40. 
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:
The study will include an open-label period of up to 40 weeks.  There will be a 70-day follow-up phone 
call for subjects who complete the study or discontinue from the study prematurely.  The 70-day 
follow-up phone call will not be required for any subject who initiates commercial adalimumab.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
7
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint
!
Proportion of subjects with endoscopic improvement, defined as an SES-CD ≤ 4 with an 
Ulcerated Surface subscore no greater than 1 in any segment, at Week 40 among subjects with 
endoscopic improvement at Week 0 of Study M14-347.
Additional Efficacy Endpoints: 
For additional efficacy endpoints, the baseline is defined as the Baseline in Study M14-115.
!
Proportion of subjects with CDAI remission (CDAI < 150) at Week 40 among subjects with 
CDAI remission at Week 0 of Study M14-347.
!
Proportion of subjects with a SFPS remission (SFPS < 50) at Week 40 among subjects with 
SFPS remission at Week 0 of Study M14-347.
!
Proportion of subjects who achieve CDAI remission (CDAI < 150) over time.
!
Time in CDAI remission (CDAI < 150) for subjects in CDAI remission at Week 0 of 
Study M14-347.
!
Time to achieve CDAI remission (CDAI < 150) for subjects who were not in CDAI remission 
at Week 0 of Study M14-347. 
!
Time to first dose escalation.
!
Proportion of subjects who require weekly dosing at Week 1 of Study M14-347.
!
Time to achieve SFPS remission (SFPS < 50) for subjects who were not in SFPS remission at 
Week 0 of Study M14-347.
!
Time in SFPS remission (SFPS < 50) among subjects with SFPS remission at Week 0 of Study 
M14-347.
!
Proportion of subjects who achieve a Simplified Endoscopic Score for Crohn's Disease 
(SES-CD ≤ 4) with an Ulcerated Surface subscore no greater than 1 in any segment at Week 40.
!
Proportion of subjects who achieve a SFPS < 50 over time.
!
Proportion of subjects who entered Study M14-347 who were taking corticosteroids at Week 0 
of Study M14-115 who discontinue corticosteroid use and achieved CDAI remission 
(CDAI < 150) at Week 40.
!
Proportion of subjects who entered Study M14-347 who were taking corticosteroids at Week 0 
of Study M14-115 who discontinue corticosteroid use at each visit.
!
Proportion of subjects with CDAI response (decrease in CDAI ≥ 70 points from Baseline) over 
time.
!
Proportion of subjects with enhanced CDAI response (decrease in CDAI ≥ 100 points from 
Baseline) over time.
!
Proportion of subjects with endoscopic response (decrease ≥ 50% SES-CD from Baseline) at 
Week 40.
!
Proportion of subjects with Inflammatory Bowel Disease Questionnaire (IBDQ) response 
(decrease ≥ 16 points from Baseline) over time.
!
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) over time.
!
Change in IBDQ from Baseline over time.
!
Change from Baseline in fecal calprotectin level over time.
!
Change from Baseline in hs-CRP level over time.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
8
Criteria for Evaluation (Continued):
Efficacy (Continued):
Additional Efficacy Endpoints (Continued):
!
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g over time.
!
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal calprotectin < 250 μg/g 
over time.
!
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 with an Ulcerated 
Surface subscore no greater than 1 in any segment, and fecal calprotectin < 250 μg/g over time.
!
Change in WPAI from Baseline over time.
!
Change in European Quality of Life 5 Dimensions (EQ-5D) from Baseline over time.
!
Change in CDAI from Baseline over time. 
!
Change in SFPS from Baseline over time.
!
Change in Abdominal Pain Rating Scale score from Baseline over time.
!
Proportion of subjects with major CD related event (e.g., hospitalization, bowel surgery, 
abscess drainage).
!
Proportion of subjects with SES-CD = 0 at Week 40.
!
Proportion of subjects with a decrease of SES-CD ≥ 3 points from Baseline of Study M14-115 
at Week 40.
!
Change in each CDAI component subscore (number of liquid or very soft stools, abdominal 
pain rating, general well-being, CD related complications, anti-diarrhea use, abdominal mass, 
hematocrit, body weight) from Baseline over time.
!
Proportion of subjects requiring dose escalation to weekly dosing during this study.
!
The proportion of subjects with no draining fistulas over time among subjects with draining 
fistula at Baseline of Study M14-115.
!
The proportion of subjects in each treatment group with ≥ 50% reduction from Baseline of 
Study M14-115 in the number of draining fistulas over time among subjects with draining 
fistula at Baseline of Study M14-115.
!
Proportion of subjects with CDAI < 150 at Week 40 and SES-CD ≤ 4 with an ulcerated surface 
subscore no greater than 1 in any segment at Week 40.
!
Change in presence of extraintestinal manifestations over time.
!
Proportion of subjects with predicted endoscopic improvement at Week 40, using the 
3 definitions and equations listed below:
1.
Index score predicting the mucosal ulceration status (presence/absence) developed using 
retrospective CDEIS (≤ 4.24 versus > 4.24), laboratory and patient questionnaire data.  The 
CDEIS based prediction index score is defined as
PCDEIS = exp(A)/[1+exp(A)], where
A = 2.0291 – 0.0432*Age + 0.0429*Albumin (g/L) – 0.0060*Platelet Count (109/L) 
–0.3286*CRP (mg/dL) – 0.0058*CDAI1 – 0.001*CDAI3
2.
Index score predicting the mucosal ulceration status (presence/absence) developed using 
retrospective visual assessment of ileocolonoscopy recordings, laboratory and patient 
questionnaire data.  The visual assessment based prediction index score is defined as


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
9
Criteria for Evaluation (Continued):
Efficacy (Continued):
Additional Efficacy Endpoints (Continued):
PVISUAL = exp(B)/[1+exp(B)], where
B = 1.142 – 0.013*Age – 0.061*Duration CD – 0.002*Platelet Count (109/L) –
0.138*CRP (mg/dL) – 0.228*Rectal Bleeding Previous Two Weeks – 0.01*CDAI1
3.
Index score predicting the mucosal ulceration status (presence/absence) developed using 
retrospective SES-CD (≤ 5 versus > 5), laboratory and patient questionnaire data.  The 
SES-CD based prediction index score is defined as
PSESCD = exp(C)/[1+exp(C)], where C = 1.796– 0.337 (If Female) – 0.002*Platelet Count 
(109/L) – 0.438*CRP (mg/dL) – 0.469*Rectal Bleeding Previous Two Weeks –
0.012*CDAI1 [CDAI1 and CDAI3 are Crohn's Disease Activity Index subscores 1 
(liquid/soft stools) and 3 (general well-being) respectively.]
!
Correlation between actual SES-CD and Predicted SES-CD (equation 2, above).
!
Proportion of subjects who de-escalated the adalimumab dose from ew to eow in subjects who 
dose escalated.
Pharmacokinetic:
Blood samples for measurement of adalimumab concentrations will be obtained at Weeks 0 (from 
Week 12 of Study M14-115), 8, 16, 24, 32, 40/PD, and unscheduled visits if dose escalating or 
de-escalating.  AAA concentrations will be obtained at Weeks 0, 24, 40/PD, and unscheduled visits if 
dose escalating or de-escalating.
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of study drug.  Incidence 
of adverse events (AEs), changes in vital signs, physical examination results, and clinical laboratory data 
will be assessed.
Statistical Methods:
Efficacy:
The primary efficacy variable is proportion of subjects with CD with endoscopic improvement, defined 
as an SES-CD ≤ 4 with an Ulcerated Surface subscore no greater than 1 in any segment, at Week 40 
among the subjects with endoscopic improvement at Week 0 of Study M14-347  A two-sided 95% 
confidence interval for the proportion will be calculated.  The Intent-to-treat (ITT) set includes all 
subjects who enrolled into this study and received at least one dose of study drug.  Missing SES-CD at 
Week 40 will be imputed using the non-responder imputation (NRI) approach.  Subjects who dose 
escalate will be imputed using NRI for visits after dose escalation.  The last observation carried forward 
(LOCF) method will also be used as the sensitivity analyses.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
10
Statistical Methods (Continued):
Efficacy (Continued):
For categorical additional efficacy endpoints, the two-sided 95% confidence interval for the proportions 
will be provided.  The non-responder imputation method will be used for subjects with missing data at 
the time point evaluated.  Subjects who dose escalate will be imputed using NRI for visits after dose 
escalation.  The LOCF method will also be used as the sensitivity analyses.  For continuous additional 
efficacy endpoints, change from Baseline of Study M14-347 will be summarized by descriptive statistics 
using mean, standard deviation, minimum, median and maximum.
Both LOCF and observed case analyses will be performed.
For time to event additional efficacy endpoints, the number of event and the 25th, median, and 75th
percentiles of time to event will be summarized.
Pharmacokinetic:
Adalimumab trough serum concentrations will be summarized by treatment group at each time point 
using descriptive statistics.  In addition, pharmacokinetic model based analyses will be performed with 
the focus on apparent clearance (CL/F) and apparent volume of distribution (V/F) of adalimumab.
Immunogenicity:
AAA will be evaluated for each subject and each dose, and rates of AAA positive will be calculated.  As 
appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment 
emergent AEs may be evaluated.
Safety:
Laboratory data, AEs, and vital signs are the primary safety parameters in this study.  All safety analyses 
will be performed using the Safety set, which includes all subjects who enrolled into this study and 
received at least one dose of study drug.  Treatment emergent AEs are defined as events that begin or 
worsen either on or after the first dose of the study drug and within 70 days after the last dose of the 
study drug.  An overview of treatment-emergent AEs, including AEs of special interest such as AEs 
leading to death and AEs leading to premature discontinuation (see details in the SAP), AEs by Medical 
Dictionary for Drug Regulatory Activities (MedDRA Version 15.1 or later) preferred term and system 
organ class, AEs by maximum relationship to study drug, and AEs by maximum severity will be 
summarized by number and percentage.
Changes in laboratory data will be described using statistical characteristics.  In addition, shift tables and 
listings will be provided for abnormal values, whereby the normal range of the analyzing laboratory will 
be used.  Vital signs will be analyzed similarly.


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
11
1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-mercaptopurine 
AAA
Anti-adalimumab antibody 
ADA
Adalimumab 
AE
Adverse event 
ALT
Alanine transaminase
AST
Aspartate transaminase
BUN
Blood urea nitrogen
CD
Crohn's disease 
CDAI
Crohn's disease activity index
CRA
Clinical Research Associate
CRF
Case report form
CRP
C-Reactive protein
DNA
Deoxyribonucleic acid
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EIM
Extra-Intestinal Manifestations
eow
every other week
ew
every week
EQ-5D
European Quality of Life 5 Dimensions
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
hs-CRP
High-sensitivity C-reactive protein
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG1
Immunoglobulin 
IRB
Institutional Review Board 
ITT
Intent-to-treat
IVRS
Interactive Voice Response System 
LOCF
Last observation carried forward 


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
12
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTX
Methotrexate 
OLE
Open-Label Extension
PD
Premature Discontinuation
PK
Pharmacokinetics 
RA
Rheumatoid arthritis 
SAE
Serious adverse event
SC
Subcutaneous 
SDP
Study designated physician
SES-CD
Simplified endoscopic score for Crohn's disease
SFPS
Stool [liquid/soft] Frequency + Abdominal Pain Score
SUSAR
Suspected Unexpected Serious Adverse Reactions
TNF
Tumor Necrosis Factor
TB
Tuberculosis
UC
Ulcerative Colitis


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
13
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................11
2.0
Table of Contents...................................................................13
3.0
Introduction ...........................................................................17
3.1
Differences Statement..............................................................................18
3.2
Benefits and Risks....................................................................................18
3.3
Adalimumab Overview............................................................................18
3.4
Safety information ...................................................................................19
4.0
Study Objectives....................................................................20
5.0
Investigational Plan...............................................................20
5.1
Overall Study Design and Plan:  Description ..........................................20
5.2
Selection of Study Population..................................................................25
5.2.1
Inclusion Criteria .....................................................................................25
5.2.2
Exclusion Criteria ....................................................................................26
5.2.3
Prior and Concomitant Therapy...............................................................27
5.2.3.1
Prior Therapy ...........................................................................................27
5.2.3.2
Concomitant Therapy...............................................................................28
5.2.3.3
Prohibited Therapy...................................................................................28
5.3
Efficacy and Safety Assessments/Variables ............................................30
5.3.1
Efficacy, Pharmacokinetic and Safety Measurements Assessed 
and Flow Chart.........................................................................................30
5.3.1.1
Study Procedures .....................................................................................34
5.3.1.2
Blood Samples for Biomarkers Analysis.................................................43
5.3.2
Drug Concentration Measurements .........................................................44
5.3.2.1
Collection of Samples for Analysis .........................................................44
5.3.2.2
Handling/Processing of Samples .............................................................45
5.3.2.3
Disposition of Samples ............................................................................45
5.3.2.4
Measurement Methods.............................................................................45
5.3.3
Efficacy Variables....................................................................................46


Adalimumab
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EudraCT 2013-004034-15
14
5.3.3.1
Primary Efficacy Variables......................................................................46
5.3.3.2
Additional Efficacy Variables..................................................................46
5.3.4
Safety Variables.......................................................................................50
5.3.5
Pharmacokinetic Variables ......................................................................50
5.3.6
Serologic Variables..................................................................................50
5.4
Removal of Subjects from Therapy or Assessment.................................51
5.4.1
Discontinuation of Individual Subjects....................................................51
5.4.2
Discontinuation of Entire Study...............................................................52
5.5
Treatments................................................................................................53
5.5.1
Treatments Administered.........................................................................53
5.5.2
Identity of Investigational Products.........................................................53
5.5.2.1
Packaging and Labeling...........................................................................53
5.5.2.2
Storage and Disposition of Study Drugs..................................................54
5.5.3
Method of Assigning Subjects to Treatment Groups...............................54
5.5.4
Selection and Timing of Dose for Each Subject......................................55
5.5.5
Treatment Compliance.............................................................................55
5.5.6
Drug Accountability.................................................................................56
5.6
Discussion and Justification of Study Design..........................................57
5.6.1
Discussion of Study Design and Choice of Control Groups....................57
5.6.2
Appropriateness of Measurements...........................................................57
5.6.3
Suitability of Subject Population .............................................................57
5.6.4
Selection of Doses in the Study ...............................................................57
6.0
Adverse Events.......................................................................58
6.1
Definitions................................................................................................58
6.1.1
Adverse Event..........................................................................................58
6.1.2
Serious Adverse Events ...........................................................................59
6.2
Adverse Event Severity............................................................................60
6.3
Relationship to Study Drug......................................................................60
6.4
Adverse Event Collection Period.............................................................61
6.5
Adverse Event Reporting.........................................................................62
6.6
Pregnancy.................................................................................................64
6.7
Toxicity Management ..............................................................................64
7.0
Protocol Deviations................................................................65


Adalimumab
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15
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................66
8.1
Statistical and Analytical Plans................................................................66
8.1.1
Analyzable Population.............................................................................66
8.1.2
Planned Methods of Statistical Analysis..................................................66
8.1.3
Demographics and Baseline Characteristics............................................66
8.1.4
Statistical Analyses of Efficacy ...............................................................67
8.1.4.1
Primary Efficacy Variable .......................................................................67
8.1.4.2
Additional Efficacy Variables..................................................................67
8.1.5
Statistical Analyses of Safety...................................................................68
8.1.6
Other Statistical Analyses of Efficacy.....................................................68
8.1.7
Interim Analysis.......................................................................................69
8.1.8
Pharmacokinetic Analyses.......................................................................69
8.2
Determination of Sample Size .................................................................70
9.0
Ethics.......................................................................................70
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................70
9.2
Ethical Conduct of the Study...................................................................71
9.3
Subject Information and Consent.............................................................71
10.0
Source Documents and Case Report Form 
Completion .............................................................................71
10.1
Source Documents ...................................................................................71
10.2
Case Report Forms...................................................................................72
11.0
Data Quality Assurance ........................................................73
12.0
Use of Information.................................................................73
13.0
Completion of the Study .......................................................74
14.0
Investigator's Agreement......................................................76
15.0
Reference List ........................................................................77
List of Tables
Table 1.
Inadequate Response................................................................................21
Table 2.
Study Activities........................................................................................31


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Table 3.
Clinical Laboratory Tests.........................................................................38
Table 4.
Study Drugs .............................................................................................53
List of Figures
Figure 1.
Dose Adjustment Algorithm....................................................................23
Figure 2.
Study Schematic.......................................................................................24
Figure 3.
Adverse Event Collection ........................................................................62
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator............................................78
Appendix B.
List of Protocol Signatories......................................................................80
Appendix C.
Sample Work Productivity and Activity Impairment 
Questionnaire:  Crohn's Disease V2.0 (WPAI:CD).................................81
Appendix D.
Sample EQ-5D Questionnaires................................................................83
Appendix E.
Sample Quality of Life in Inflammatory Bowel Disease 
Questionnaire (IBDQ)..............................................................................85
Appendix F.
Abdominal Pain Rating Scale ..................................................................95
Appendix G.
Injection Instructions – Sample Pre-Filled Syringe.................................96
Appendix H.
Crohn's Disease Activity Index (CDAI) ................................................102
Appendix I.
Standard Weights...................................................................................103
Appendix J.
70-Day Follow-Up Phone Call – Sample ..............................................106
Appendix K.
SES-CD Scoring ....................................................................................107
Appendix L.
Bristol Stool Form Scale........................................................................108
Appendix M.
Protocol Amendment:  List of Changes.................................................109


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3.0
Introduction
Crohn's disease (CD) encompasses a spectrum of clinical and pathological processes 
manifested by focal asymmetric, transmural, and occasionally granulomatous 
inflammation that can affect any segment of the gastrointestinal tract.1  The disease can 
affect persons of any age, and its onset is most common in the second and third decades.  
Females are affected slightly more than males, and the risk for disease is higher in some 
ethnic groups.2,3  In North America, the incidence of CD is estimated to be 3.1 to 
14.6 cases per 100,000 persons.2  Prevalence rates range from 26 to 99 cases per 
100,000 persons.  In Europe, CD has an incidence of 0.7 to 9.8 cases per 100,000 persons 
and a prevalence of 8.3 to 214 cases per 100,000 persons.2
Traditionally, therapy for CD has been focused on symptomatic improvement and 
achievement of clinical remission as measured using the Crohn's disease activity index 
(CDAI).  In addition to improving symptoms, an emerging goal of therapy is to improve 
the condition of the intestinal mucosa.  It has been shown that patients with endoscopic 
evidence of ulceration of the gastrointestinal mucosa are at increased risk of experiencing 
a complicated disease course.4  Therefore, it is reasonable that another goal of therapy be 
improvement of the intestinal mucosal as visualized on endoscopy; as this has been found 
to be associated with positive clinical benefits, including higher rates of clinical 
remission, fewer hospitalizations, and fewer abdominal surgeries.5,6  In addition, at the 
2012 United States (US) Food and Drug Administration (FDA)-sponsored 
Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT) 
Workshop, there was significant discussion on the use of endoscopy to support 
determination of disease activity, as opposed to using symptomatic improvements alone.  
However, improvement of the appearance of the intestinal mucosa may be more difficult 
to achieve than symptomatic improvement alone as it requires reducing the extent of 
mucosal ulceration.
Study M14-115 assessed the efficacy and safety of two adalimumab induction regimens in 
achieving endoscopic improvement, (SES-CD ≤ 4 with an Ulcerated Surface sub-score no 


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greater than 1 in any segment) at Week 12 and clinical remission (CDAI < 150) at Week 4 
as well as the pharmacokinetics (PK) and immunogenicity of the two adalimumab 
induction regimens.  This study is designed to investigate the long-term efficacy, safety, 
and tolerability of repeated administration of adalimumab in adult subjects with CD who 
participated and successfully completed Study M14-115.
3.1
Differences Statement
Study M14-347 is a Phase 3 open-label clinical study to evaluate the long-term efficacy, 
safety, and tolerability of adalimumab in the treatment of adult subjects with CD who 
participated in and successfully completed Study M14-115.  Subjects will receive 
adalimumab 40 mg every other week (eow) with the opportunity to dose escalate to 
adalimumab 40 mg every week (ew), if the subject meets the criteria for inadequate 
response as defined in Table 1.
3.2
Benefits and Risks
Extensive clinical and post marketing experience exists with adalimumab in a wide range 
of disease states including CD and ulcerative colitis (UC).  The safety profile of 
adalimumab in those indications is well-established with more than 50,000 patient years 
of adalimumab clinical trial experience.  The clinical studies in adult CD have not altered 
this safety profile and demonstrated a positive benefit/risk balance.  Conditions which 
may present a risk specifically for patients with CD are exclusion criteria in this study 
(e.g., evidence of colonic dysplasia or active infections).
3.3
Adalimumab Overview
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody 
containing only human peptide sequences.  Adalimumab is produced by recombinant 
deoxyribonucleic acid (DNA) technology in a mammalian cell expression system.  It 
consists of 1,330 amino acids and has a molecular weight of approximately 
148 kilodaltons.  Adalimumab is composed of fully human heavy and light chain variable 
regions, which confer specificity to human tumor necrosis factor (TNF), and human IgG1 


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heavy chain and kappa light chain sequences.  Adalimumab binds with high affinity and 
specificity to soluble TNF-α but not to lymphotoxin-α (TNF-β).
TNF is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses.  Elevated levels of TNF play an important role in pathologic 
inflammation.  Adalimumab binds specifically to TNF and neutralizes the biological 
function of TNF by blocking its interaction with the p55 and p75 cell surface TNF 
receptors.  Adalimumab also modulates biological responses that are induced or regulated 
by TNF.  After treatment with adalimumab, levels of acute phase reactants of 
inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate) and serum 
cytokines rapidly decrease.
Adalimumab was first approved in US and EU for the treatment of rheumatoid arthritis 
(RA) in 2002 and 2003, respectively.  Additional indications have been approved in the 
US and EU including psoriasis, psoriatic arthritis, axial spondylitis, CD, juvenile arthritis 
and UC.  Additional updates regarding approved indications can be found in the current 
edition of the Humira Investigational Drug Brochure.
3.4
Safety information
Adalimumab therapy has a well-established and well described safety profile in adults 
based on extensive post marketing experience and continued clinical trial patient exposure 
since the first approved indication in 2002 for RA.  A detailed discussion of the 
pre-clinical toxicology, metabolism, pharmacology and safety experience with 
adalimumab can be found in the current Investigator's Brochure.  AbbVie is committed to 
continue to collect safety information including those events that may occur in this trial in 
order to confirm this established safety profile and to identify any unknown potential 
adverse reactions, rare events and those events with a long latency.  AbbVie is 
participating in a FDA-requested, TNF inhibitor class wide exploration of the rare 
appearance of malignancy in patients who are 30 years of age or younger at the time of 
diagnosis.  The risk of malignancy in this age group has not been established and is 
difficult to study due to its rarity.  AbbVie appreciates your attention to the additional 


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reporting requirements needed in this unlikely event, outlined in Section 6.5 under 
Adverse Event Reporting.
4.0
Study Objectives
The primary objective of this study is to evaluate the long-term efficacy, safety, and 
tolerability of repeated administration of adalimumab in subjects with CD who 
participated in and successfully completed Study M14-115.
The secondary objective is to assess PK and immunogenicity of adalimumab following 
subcutaneous (SC) administration.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, multicenter, open-label extension (OLE) study which comprises a 
40-week open-label period designed to evaluate the long-term efficacy, safety, and 
tolerability of adalimumab.  Approximately 300 adult subjects who participated and 
successfully completed Study M14-115 and who meet all of the inclusion criteria and
none of the exclusion criteria will be eligible to enroll into this study.
Subjects will be evaluated for entry into Study M14-347 at the final study visit (Week 12) 
of Study M14-115.  A subject's participation in the study is anticipated to be up to 
40 weeks.  There is a ± 3-day window for all study visits.  An effort will be made to bring 
the subject back to their original study visit (calculated from Week 0) if they are out of the 
visit window.
Study visits for clinical and safety assessments will be performed at Weeks 0, 8, 16, 24, 
32 and 40/Premature Discontinuation (PD).  All subjects will be provided with a paper 
subject diary in which they will record CD-related symptoms (number of liquid or very 
soft stools, abdominal pain rating, general well-being) and adalimumab dosing 
information throughout the study.  Blood samples will be collected at various time points 
for routine labs, along with hs-CRP, adalimumab serum concentrations, anti-adalimumab 


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antibody (AAA) levels and other biomarker analyses.  In addition, stool samples for 
calprotectin and microbiota will be collected.  The stool samples should be taken before 
starting bowel preparations for endoscopy.  Endoscopic evaluation will be performed at 
Week 40/PD, if the PD occurs after Week 24.  CDAI evaluations will be calculated based 
on entries recorded into the subject's diary at all study visits.  The SFPS (Stool 
[liquid/soft] Frequency + Abdominal Pain Score) will be calculated using the weighted 
values for the CDAI components "Number of liquid or very soft stools" and "Abdominal 
pain."
The Week 12 visit of Study M14-115 will be considered Week 0 (Baseline) of 
Study M14-347.  All subjects will receive open-label adalimumab 40 mg every other 
week (eow) beginning at Week 0.  No dose will be administered at Week 40.  Subjects 
may be escalated to adalimumab 40 mg every week (ew) at or after Week 1 should the 
subject meet the criteria for inadequate response (Table 1).
Table 1.
Inadequate Response
Response Type
Definition
Inadequate response
Crohn's disease activity index (CDAI) of ≥ 200 at any one visit and at least 
one of the following criteria is met:  an increase of at least 1 mg/L in level of 
high-sensitivity C-reactive protein (hs-CRP) from Baseline or an hs-CRP 
≥5 mg/L.  The hs-CRP results used to determine inadequate response can be 
from the prior or current visit.  Assessment of inadequate response should 
include consideration by the Investigator to rule out symptoms caused by 
reasons other than Crohn's disease related inflammation.
For subjects taking corticosteroids at Baseline of Study M14-115 adalimumab dose 
escalation should be considered in lieu of increases in steroid dose. Subjects who 
continue to experience inadequate response on 40 mg ew who were taking corticosteroids 
at Baseline of Study M14-115 may have their steroid dose increased, per the Investigator's 
discretion, in order to manage the subject's symptoms.  Any subject who continues to 
experience inadequate response on 40 mg ew may be discontinued from the study at the 
investigator's discretion after discussion with the study designated physician (SDP).  
Subjects who dose escalated to adalimumab 40 mg ew, have one opportunity to de-


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escalate adalimumab dose to 40 mg eow provided the following criteria have been met:  
CDAI < 200 and high-sensitivity C-reactive protein (hs-CRP) value equal to or lower than 
that observed at the time of dose escalation.  Subjects who experience inadequate 
response after dose de-escalation (using the same criteria outlined above), may again be 
escalated to 40 mg ew.  A subject has only one opportunity to dose de-escalate and one 
opportunity to re-escalate to ew adalimumab dosing.
Changes in adalimumab dosing may only occur when the above criteria are met but are 
not mandatory.
A schematic for dose adjustments is presented in Figure 1.






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(for subjects who meet inadequate response criteria) should be considered in 
lieu of increases in the steroid dose.
5.2
Selection of Study Population
5.2.1
Inclusion Criteria
1.
Subject must have successfully enrolled in and completed Study M14-115, 
including the Week 12 ileocolonoscopy.
2.
If female, subject is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral 
oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing 
an approved method of birth control throughout the study and for 150 days after 
last dose of study drug.  Examples of approved methods of birth control which 
result in a low failure rate (i.e., less than 1% per year) when used consistently are 
(see local informed consent for more detail):
●
Implants, injectables, some intrauterine devices (IUDs), intrauterine 
hormone-releasing system (IUS)
●
Sexual abstinence (when in line with preferred and usual lifestyle of the 
subject)
●
Vasectomized partner
●
Hormonal contraceptives for at least 90 days prior to study drug administration
Note:  low-dose progestin-only oral contraceptives such as norethindrone 
0.35 mg and lynestenol 0.5 mg are not considered adequate
3.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.
4.
Subject must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections.


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Criteria
Rationale
1 – 4
In order to select the appropriate subject population with a disease status representative of 
the target population for evaluation.
5.2.2
Exclusion Criteria
1.
For any reason subject is considered by the investigator to be an unsuitable 
candidate.
2.
Known hypersensitivity to adalimumab or its excipients.
3.
Subject with an active systemic viral infection or any active viral infection that 
based on the investigator's clinical assessment makes the subject an unsuitable 
candidate for the study. 
4.
Positive pregnancy test at Baseline (Week 12 of Study M14-115).
5.
Female subject who is considering becoming pregnant during the study. 
6.
History of malignancy other than a successfully treated non-metastatic cutaneous 
squamous cell, basal cell carcinoma and/or localized carcinoma in situ of the 
cervix.  If the Week 12 (Study M14-115) colonoscopy shows evidence of dysplasia 
or a malignancy, subject must not be enrolled in the study.
7.
Subject with a poorly controlled medical condition, such as uncontrolled diabetes, 
unstable ischemic heart disease, moderate or severe congestive heart failure, recent 
cerebrovascular accidents and any other condition which, in the opinion of the 
investigator or sponsor, would put the subject at risk by participation in this study.
8.
Subject is not in compliance with prior and concomitant medication requirements 
throughout Study M14-115.
9.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
10.
History of invasive infection (e.g., listeriosis and histoplasmosis) or human 
immunodeficiency syndrome (HIV).


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11.
Subject who developed active Tuberculosis (TB) during Study M14-115, or subject 
who is non-compliant with prophylaxis for latent TB initiated per Study M14-115 
procedures.
Criteria
Rationale
1 – 7, 9 – 11
To reduce the risk to subjects or others and/or to exclude underlying conditions that 
would compromise the subject's safety.
8
To avoid bias for the evaluation of efficacy and safety by concomitant use of other 
medications or treatments.
5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Subjects may continue taking permitted therapies from Study M14-115.
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment 
into M14-347, or receives during the study, must be recorded along with the reason for 
use, date(s) of administration including start and end dates, and dosage information 
including dose, route and frequency on the appropriate electronic case report form 
(eCRF).
The AbbVie SDP identified in Section 6.5 should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).
In addition, for subjects age ≤ 30 with a reported malignancy AE, prior exposure to, or 
current use of, antineoplastics, or other drugs which have a risk of malignancy as stated in 
their label and other relevant dosing information to estimate total exposure will be 
collected in the source documents and appropriate electronic case report form (eCRF) 
pages.  At the time of the reported malignancy AE, sites will be asked if any of the prior 
and concomitant medications contributed to the event.  Any medications used prior to the 
study will be captured on the appropriate eCRF.  Information on the reason for use, 


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date(s) of administration including start and end dates, highest maintained dose, dosage 
information including dose, route and frequency, and reason for stopping the medication 
will be collected in the source documents and appropriate eCRF pages.
5.2.3.2
Concomitant Therapy
Doses of immunosuppressants (including but not limited to) azathioprine, 
6-mercaptopurine (6-MP), methotrexate (MTX), aminosalicylates, and CD-related 
medications taken at Baseline of Study M14-347 will be continued.  Doses must remain 
stable throughout the duration of the study.  Doses may be decreased or terminated, in the 
event of treatment-related toxicities (e.g., leukopenia or elevated liver enzymes) 
considered moderate to severe in the opinion of the investigator, or, in the case of CD-
related antibiotics, concerns about antibiotic resistance.
Subjects in whom systemic corticosteroids that were not being taken at Baseline of 
Study M14-347 and are initiated during the study or who have dosages of corticosteroids 
increased to greater than the dose taken at Baseline of Study M14-115 may continue in the 
study, but will be censored for efficacy assessments (i.e., will be considered 
non-responders for categorical endpoints and will have Baseline values (from 
Study M14-115) carried forward for non-categorical assessments) from that point through 
the end of the study.  These subjects will continue to be evaluated in the safety population.
Subjects who enter the study on probiotics may continue this therapy provided doses 
remained stable during Study M14-115 and remain stable during the duration of 
Study M14-347.
The AbbVie SDP identified in Section 6.5 should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).
5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:


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●
All biologic therapy with a potential therapeutic impact on the disease being 
studied including but not limited to the following:
○
Etanercept (Enbrel®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Efalizumab (Raptiva®);
○
Ustekinumab (Stelara®);
○
Belimumab (Benlysta®);
○
Infiximab (Remicade®);
○
Certolizumab pegol (Cimzia®);
○
Golimumab (Simponi®);
○
Vedolizumab (Entyvio®).
●
Tofacitinib (Xeljanz®)
●
NSAIDs (excluding topical)
●
Live vaccines (during the study and for 70 days after the last dose of study 
drug)
●
Cyclosporine, tacrolimus, or mycophenolate mofetil
●
Recreational or medical marijuana use
Rectal therapy with any therapeutic enemas or suppositories, with the exception of those 
required for endoscopy, is prohibited during the study.
Intravenous corticosteroid use is prohibited during the study.
Investigational drugs of a chemical or biologic nature are prohibited during the study.
The AbbVie SDP identified in Section 6.5 should be contacted if there are any questions 
regarding prohibited therapy.


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5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy, Pharmacokinetic and Safety Measurements 
Assessed and Flow Chart
Study procedures will be performed as summarized in Table 2 and Section 5.3.1.1.  All 
l subjects must meet the study selection criteria outlined in Section 5.2.1 and Section 
5.2.2.


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Table 2.
Study Activities
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Informed Consent
X
Inclusion/Exclusionb
X
Medical/Surgery History Updateb
X
Previous and Concomitant Medication Updateb
X
X
X
X
X
X
X
Vital Signs
Xa
X
X
X
X
X
X
Endoscopyc
Xa
X
SES-CD Score
Xa
X
Physical Examinationd
Xa
X
X
X
X
X
X
Urinalysise
Xa
X
X
X
X
X
X
Pregnancy Testsf
Xa
X
Chemistry and Hematologyh
Xa
X
X
X
X
X
X
hs-CRP
Xa
X
X
X
X
X
X
Provide Stool Kitg
X
X
X
X
X
X
Stool Sample (fecal calprotectin)g
Xa
X
X
X
X
X
X
Stool Sample (microbiota metagenomic analyses)g
Xa
X
X
Bristol Stool Scale for Metagenomic Analysisg
Xa
X
X
Adalimumab Concentrationh
Xa
X
X
X
X
X
X
AAA Concentrationh
Xa
X
X
X
Serological Biomarkers/mRNA
Xa
X
X


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Table 2.
Study Activities (Continued)
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Crohn's Disease Activity Index (CDAI)
Xa
X
X
X
X
X
X
Inflammatory Bowel disease Questionnaire (IBDQ)
Xa
X
X
X
European Quality of Life 5 dimensions (EQ-5D)
Xa
X
X
X
Work Productivity and Impairment Questionnaire 
(WPAI)
Xa
X
X
X
Abdominal Pain Rating Scale
Xa
X
X
X
Monitor Adverse Eventsi
Xa
X
X
X
X
X
X
X
Study Drug Dispensing/Administrationj
X
X
X
X
X
Subject Diary Review
Xm
X
X
X
X
X
X
a.
Information from the activities completed at Week 12 of Study M14-115 will be carried over to the Baseline visit and will serve as the reference for all subsequent visits.  A 
± 3-day window is permitted around scheduled study visits.
b.
Inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information will be assessed to assure subject eligibility.
c.
An ileocolonoscopy will be performed at Week 40/PD, if the PD occurs after Week 24.  A biopsy will be performed at Week 40/PDif a suspicious lesion or suspected 
malignancy, in the assessment of the Investigator, is observed, and evaluated by the local pathologist.  Biopsies to evaluate suspicious lesions and to rule out malignancy may 
be taken during any study endoscopy per the Investigator's discretion and evaluated by the local pathologist.
d.
Physical examination performed at Week 40/Premature Discontinuation Visit is a full physical examination which must include an assessment of extra-intestinal 
manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations performed at all other visits are symptom based and must include a count of the 
number of cutaneous fistulas.
e.
Dipstick urinalysis will be completed by the sites at all required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results 
show protein, ketones or blood greater than negative or glucose greater than normal.


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Table 2.
Study Activities (Continued)
f.
Urine pregnancy test results from Week 12 of Study M14-115 will be carried over to the Baseline Visit.  Urine pregnancy test will be performed at Week 40/PD for all 
women of childbearing potential.  The frequency can be increased up to every visit as per local regulations.  If any urine pregnancy test is positive, a serum pregnancy test will 
be performed by the central laboratory.
g.
A stool sample will be collected for fecal calprotectin and metagenomic analysis at each time points indicated.  Subjects will be sent home with instructions and a stool 
sample supply kit (supplies will be provided at the time points indicated).  The stool from which these samples are prepared should be scored using the Bristol stool scale by 
site.  Stool samples for metagenomic analysis should be collected before any bowel preparation for endoscopy is started and returned to the site within 3 days of collection.
h.
Blood samples for the measurement of adalimumab and anti-adalimumab antibody (AAA) concentrations will be collected prior to dosing.  If the subject is dose escalating or 
de-escalating, blood samples will be taken prior to dosing for the measurement of adalimumab and AAA concentrations which may occur at an unscheduled visit.
i.
Collection of serious adverse events (SAEs) begins the day the subject signs the informed consent.
j.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
k.
Visits for dispensing new study drug in case of temperature excursion, loss, damage, or dose escalation are not considered anUnscheduled Visit.  In addition, visits to retest a 
lab will not be considered an Unscheduled Visit.  Unscheduled visits can be used for situations including the following:  Forevaluation and assessment of the subject, to 
evaluate a subject who meets criteria for inadequate response as outlined in Table 1, to collect samples to determine hs-CRP in those subjects, and to collect PK samples for a 
change in adalimumab dosing.
l.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who continue on commercial 
adalimumab therapy after the end of study participation.
m.
Sites will review the electronic diary utilized and collected from Week 12 of Study M14-115 to obtain the number of liquid or very soft stools, abdominal pain rating, general 
well-being and adalimumab dosing information.  A new paper subject diary will be dispensed to subjects at Baseline.  All subjects should complete their subject diary on a 
daily basis throughout the entire study, including if and when hospitalized whenever possible.  The diary will be reviewed bysite personnel with the subject at each visit and 
collected at the Final/PD visit.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 2 are discussed in detail in this section, with the 
exception of drug concentration measurements, antibody measurements, serological and 
mRNA biomarkers (discussed in Section 5.3.1.2 and Section 5.3.6), and the collection of 
AE information (discussed in Section 6.0).  All study data will be recorded in source 
documents and on the appropriate eCRFs.
Informed Consent
At the Baseline visit (Week 12 of Study M14-115), the subject will sign and date a study 
specific, Independent Ethics Committee (IEC)/Independent Review Board (IRB) 
approved, informed consent form before any study procedures are performed or any 
medications are withheld from the subject in order to participate in this study.  Details 
regarding how informed consent will be obtained and documented are provided in 
Section 9.3.  Consent will be required for any optional testing.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and none of the 
exclusion criteria at the Baseline Visit.
Medical and Surgical History
An update to the medical and surgical history from Study M14-115 will be obtained from 
each subject during the Baseline Visit.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, body weight, and body temperature will be obtained at each visit.  
Blood pressure, pulse rate and respiratory rate should be performed before blood draws 
are performed.  All measurements will be recorded in metric units if possible.


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Endoscopy
An endoscopy will be performed on the following visits:
●
Week 12 of Study M14-115 for Baseline measure
●
Week 40/Premature Discontinuation if PD occurs after Week 24
An ileocolonoscopy will be performed and should be recorded at the site in a video 
format.  Sites should also perform an SES-CD assessment and record findings on the 
provided SES-CD score sheet, refer to Appendix K.  The findings should be entered in the 
appropriate eCRF.  Two primary central reviewers will evaluate the data and provide their 
score.  A third central reviewer will re-read (adjudicate) the endoscopy if there is a 
discrepancy between the two primary central reviewers.  The adjudicator's assessment will 
be considered final.
The endoscopy at Week 40/PD will be used to provide the endoscopy subscores for 
calculating the Simplified endoscopic score for Crohn's disease (SES-CD) at 
Week 40/PD, refer to Appendix K.  The SES-CD values provided by the central reader 
will be used for all endpoint analyses.  The same endoscopist, where possible, should 
perform all endoscopies.
Biopsy During Endoscopy
During the Week 40/PD endoscopy, biopsies to evaluate suspicious lesions or to rule out 
malignancy may be taken per the Investigator's discretion and evaluated by the local 
pathologist.  If a biopsy sample is obtained, the sampling should be recorded and the 
sampling should not interfere with the recording the central reviewers will use for their 
evaluation.  The signed pathology report will be monitored by the responsible Clinical
Research Associate (CRA) and kept with the subject's source documents onsite.  Subjects 
should not be enrolled if colon dysplasia or malignancy is discovered at the 
Study M14-115 Week 12 endoscopy.  If colon dysplasia or malignancy is discovered 
during any subsequent endoscopic evaluation during the course of the study, the findings 
should be recorded as an AE and the subject should be discontinued from the study.


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Physical Examination
A full physical examination will be performed and must include an assessment of 
extra-intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas at 
visits indicated in Table 2.  The physical examination at Week 12 of Study M14-115 will 
serve as the Baseline physical examination for the entire study.  Symptom-based 
examinations will be performed at all other visits; however, a count of the number of 
cutaneous fistulas draining upon gentle compression will be performed during each 
physical exam.  Fistulas will be classified as abdominal or perianal/anal.  Physical exam 
abnormalities noted by the investigator at Week 12 from Study M14-115 (including 
fistulas and fissures) will be recorded in the subject's medical history.
Abnormalities noted after the Baseline visit will be evaluated and documented by the 
investigator as to whether they are AEs.
Additional physical examination findings that are related to or part of each subject's 
medical history will be captured on the appropriate medical history CRFs.
Urinalysis
Urine samples will be obtained and sent to the central laboratory for the tests listed in 
Table 3.  Microscopic urinalysis will only be performed by the central laboratory if the 
dipstick UA results are abnormal, where abnormal is defined as a protein, ketones or 
blood greater than negative or glucose greater than normal.
Pregnancy Tests
Subjects of childbearing potential will have a urine pregnancy test performed locally by 
designated study personnel at the time points indicated in Table 2.  The frequency can be 
increased up to every visit as per local regulations.  If any urine pregnancy test is positive, 
a serum pregnancy test will be performed by the central laboratory.  A lactating or 
pregnant female will not be eligible for participation or continuation in this study.


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Clinical Laboratory Tests
Blood samples will be obtained for the laboratory tests listed in Table 3.  Blood draws 
should be performed after efficacy assessments and questionnaires (CDAI, IBDQ, etc.), 
vital sign determinations are obtained and before study drug administration during a visit.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the investigator will be followed to a satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.


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Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis*
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase/Alanine 
transaminase  (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase/Aspartate 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Stool Samples Collected
Fecal calprotectin
Microbiota metagenomic 
analyses
Additional Blood Samples Collected
hs-CRP
Pharmacokinetic
mRNA
Serologic Biomarkers
*
Microscopic urinalysis will be analyzed when dipstick results are abnormal.
hs-CRP
Blood samples for hs-CRP will be obtained per Table 2.
Blood draws should be performed after all efficacy assessments, questionnaires (CDAI, 
IBDQ, etc.), and vital sign determinations are obtained and before study drug 
administration during a visit.


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Other Laboratory Assessments
Stool Sample (Fecal Calprotectin and Microbiota Metagenomic Analyses)
Fecal calprotectin and microbiota metagenomic analysis will be performed for all subjects 
as indicated in Table 2.  Subjects will be sent home with a stool sample supply kit and 
instructions at the prior visit.  The fecal calprotectin sample will also be collected prior to 
dose escalation or dose de-escalation.
All stool samples should be collected before any bowel preparation for endoscopy is 
started and returned to the site within 3 days of collection.  All microbiota metagenomic 
analyses stool samples should be scored by site staff using the Bristol stool scale 
(Appendix L).  The score of the Bristol stool scale at Baseline in this study will be scored 
using the electronic diary from Study M14-115.  A central laboratory(s) will be utilized to 
process these laboratory tests.
Where allowed by local guidelines at the time of stool collection any remaining stool 
could be used for future exploratory analysis of non-genetic biomarkers related to the 
subject's disease and/or response to study drug or additional therapies, or development of 
AEs.  These samples may also be used for the development of diagnostic tests.  Results of 
exploratory analyses, if any, will not be reported with the study summary.  AbbVie will 
store the samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained for no longer than 20 years after completion 
of the study (where allowed by local guidelines) for possible future research.
Crohn's Disease Activity Index (CDAI)
A CDAI score will be calculated from a subject diary, physical exam, and appropriate 
laboratory values at all study visits beginning at Baseline.  The CDAI calculated at 
Week 12 in Study M14-115 will serve as the Baseline CDAI for this open-label extension 
study.


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Beginning with the Week 0 through Week 40 visits, including unscheduled visits, the 
CDAI scores must be calculated using a hematocrit value from the preceding visit 
laboratory work.
CDAI at Visit
HCT Value Utilized
Week 0
Week 8 (Study M14-115)
Week 8
Week 0
Week 16
Week 8
Week 24
Week 16
Week 32
Week 24
Week 40
Week 32
For calculation of CDAI scores used to determine if subjects meet the criteria for 
inadequate response, the hematocrit value used to calculate the first CDAI score can also 
be used to calculate the second CDAI score.
For calculating CDAI at Week 0 thru Week 40/PD, to answer questions one (1) through 
three (3), entries from the 7 days prior to the visit should be used as recorded by the 
subject from the diary.  Diary entries for calculating CDAI should not be included in the 
7 days evaluated prior to the visit if:  (1) the day the subject received medication for 
bowel preparation prior to endoscopy, (2) the day the subject underwent an endoscopy, 
and (3) 2 days following the endoscopy.  Earlier diary entries will be used accordingly in 
order to provide the most recent data for 7 days prior to the respective study visit.
For the CDAI questions regarding presence of anal fistulas and other fistulas, all fistulas 
detectable on physical examination (draining and non-draining) should be captured on the 
CDAI and calculated into the CDAI score.
When completing question five (5) ("Taking Lomotil/Imodium/Loperamide/opiates for 
diarrhea, 0 = no, 1 = yes") on the CDAI, "no" should be answered if a subject is taking an 
opiate(s) solely for pain.


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For question seven (7), hematocrit results from central laboratory will be used for the 
CDAI calculation.  If the hematocrit value contains more than one decimal point, the 
rounding will be allowed to the tenths decimal (e.g., Hct value 33.44 will be captured as 
33.4, Hct value of 33.45 will be captured as 33.5).  The Hct values either prior to 
completing the calculation or at the subtotal box 7 of the CDAI should not be rounded to a 
whole number.
The height obtained from Study M14-115 should be used when selecting the standard 
weight in Appendix I, and this standard weight should be used for calculating every CDAI 
throughout subject participation in the study.
If the body weight obtained at the time of assessment is not captured in kilograms (kg), 
then when converting into kgs, rounding should occur using the second digit after the 
decimal (also known as the hundredth place) where if the number is 0 – 4 then keep the 
first digit after the decimal (also known as the tenth place) unchanged.  If the second digit 
after the decimal is 5 – 9 then round up the first digit after the decimal (e.g., 90.246 would 
be captured as 90.2, 97.687 would be captured as 97.7).
The subtotal of box 8 should not be rounded to a whole number.
The calculation of the CDAI score is in Appendix H.
Patient Reported Outcomes and Questionnaires
●
IBDQ – Inflammatory Bowel disease Questionnaire (IBDQ) will be completed 
at the time points indicated in Table 2 (Appendix E).
●
WPAI – Work Productivity and impairment Questionnaire will be completed 
at the time points indicated in Table 2.  The data in the subject-completed 
questionnaire will be transferred to the appropriate eCRF by the site personnel 
at each study visit (Appendix C).
●
EQ-5D – A standardized questionnaire for use as a measure of health outcome 
(Appendix D).
●
Abdominal pain rating scale (Appendix F).


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Study Drug Dispensing/Administration
Study drug will be administered to all subjects onsite by either site medical staff or the 
subjects or designee (friend, family member or health care professional) during the first 
visit.  Detailed instructions and training for the administration of adalimumab are 
provided in Appendix G.
Adalimumab injections occurring during study visits will be performed at the visit by the 
subject or their designated family member, friend or Healthcare Professional under the 
supervision of trained medical personnel to reinforce proper aseptic SC injection 
technique.  Subjects or a trained designated family member, friend or Healthcare 
Professional will perform the injections of adalimumab in the subject's home during the 
weeks they are not in for scheduled clinic visits.
Subjects should administer study drug on the same day of the week.  The dosing dates for 
all doses of study drug should be calculated from the Baseline Visit date.  A ± 3-day 
window is allowable for scheduled study dosing dates.  For subjects who deviate from this 
dosing window, every effort should be made to bring the subject back to the original 
dosing schedule as soon as possible.  For situations where bringing the subject back on the 
original dosing schedule will cause the dose to be out of the ± 3-day window, please 
contact the AbbVie SDP for additional instructions.
At all office visits, subjects should be observed after study drug administration until 
judged clinically stable by the study personnel.  If an anaphylactic reaction or other 
serious allergic reaction occurs, administration of study drug should be discontinued 
immediately and initiate appropriate therapy.  When dosing at home subjects should be 
instructed to contact the site immediately with any signs or symptoms of a reaction.  If 
subjects are unable to reach their study site or experience life-threatening symptoms, they 
will be instructed to call an emergency number or proceed to the nearest emergency room 
and then inform the site as soon as possible.


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Subjects will be instructed to return all used and unused syringes, sharps containers and 
empty boxes at each visit for accountability.
Subject Diary
The subject's electronic diary will be reviewed and collected from Week 12 of 
Study M14-115 to obtain the number of liquid or very soft stools, abdominal pain rating, 
general well-being, use of medications used for endoscopy preparation, and adalimumab 
dosing information.  A new paper subject diary will be dispensed to subjects at Baseline.  
All subjects should complete their subject diary on a daily basis throughout the entire 
study.  The diary will be reviewed by site personnel with the subject at each visit and 
collected at the Final/PD visit.
The dosing records will be reviewed and verified for compliance at each visit by the 
research personnel at the study center and reinforced if necessary.  Additionally, any 
discernible departure from the protocol regarding study drug administration will be 
recorded on the source documents and in the appropriate drug accountability form.
5.3.1.2
Blood Samples for Biomarkers Analysis
Collection of Samples for Serologic Markers
Two 5 mL blood samples for serologic markers analysis will be collected at the time 
points indicated in Table 2.  Please refer to the laboratory manual for specific instructions.  
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
The frozen serum and plasma samples for serologic marker analysis will be packed in dry 
ice sufficient to last during transport and shipped from the study site to the central 
laboratory.  Samples should not be allowed to thaw prior to arrival at AbbVie or the 
designated laboratory.  An inventory of the samples included will accompany the 
package.  Arrangements will be made with the central laboratory for the shipment of 
samples to AbbVie or specified lab for testing.


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See Section 5.3.6 for the variables of this analysis.
Collection of Samples for mRNA Assays
Two 2.5 mL blood samples for mRNA will be collected at the time points indicated in 
Table 2.  Please refer to the laboratory manual for specific instructions.
The frozen samples for mRNA analysis will be packed in dry ice sufficient to last during 
transport and shipped from the study site to the central laboratory.  Samples should not be 
allowed to thaw prior to arrival at AbbVie or the designated laboratory.  An inventory of 
the samples included will accompany the package.  Arrangements will be made with the 
central laboratory for the shipment of samples to AbbVie or specified lab for testing.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for adalimumab and AAA concentrations will be obtained at the time 
points as indicated in Table 2.  Some samples might be obtained and stored to analyze for 
factors contributing to the subject's response to study treatment, in terms of 
pharmacokinetics, pharmacodynamics, tolerability or safety after the study.
The time that each blood sample is collected will be recorded to the nearest minute in the 
source document and on the appropriate eCRF.
Collection of Samples for Adalimumab and AAA Assays
Blood samples for adalimumab and AAA assays will be collected by venipuncture into 
appropriately labeled 4-mL evacuated serum collection tubes (one tube for adalimumab 
and one tube for AAA) without gel separator immediately prior to dosing.  Sufficient 
blood will be collected to provide approximately 2 mL serum for adalimumab assay and 
2 mL serum for AAA assay.  Please refer to the laboratory manual for instructions.


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For subjects who meet the criteria for a dose adjustment (escalation or de-escalation), 
blood samples for the measurement of serum adalimumab and AAA concentrations will 
be collected just prior to receiving their first adjusted dose of adalimumab.
A maximum number of samples that a subject could have collected over the duration of 
the study would be 7 blood samples (not including unscheduled visit sample collections):  
5 samples for the determination of adalimumab concentrations, and 2 samples for the 
determination of AAA concentrations.  The total number of samples will not exceed 
1,500 (5 samples × 300 subjects) for the adalimumab assay and 600 (2 samples × 300 
subjects) for the AAA assay for the entire study.
5.3.2.2
Handling/Processing of Samples
The blood samples for adalimumab and AAA concentrations will be labeled with 
information such as the following:  the type of sample, the study drug number, protocol 
number, subject number, study week/visit name, and assay type (PK-Adalimumab or 
AAA).
Additional detailed instructions for the handling and processing of samples will be 
provided from the central laboratory.
5.3.2.3
Disposition of Samples
Frozen serum samples will be packed in dry ice (pellet form) sufficient to last three days 
during transport.  Samples will be shipped pursuant to instructions from the onsite CRA.  
An inventory of the samples will be included in the package for shipment.  Arrangements 
will be made with the central lab for the transfer of samples.
5.3.2.4
Measurement Methods
Serum concentrations of adalimumab and AAA will be determined using a validated 
ligand binding assay (LBA) method under the supervision of the Bioanalysis Department 
at AbbVie.


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5.3.3
Efficacy Variables
Term
Definition
Endoscopic Improvement
SES-CD ≤ 4 with an Ulcerated Surface subscore no greater than 1 
in any segment 
CDAI Remission
CDAI < 150 
SFPS Remission
SFPS < 50
Response per CDAI
A reduction in CDAI by ≥ 70 (CR-70) from baseline*
Enhanced response per CDAI
Decrease in CDAI ≥ 100 (CR-100) from baseline*
Endoscopic response
Decrease ≥ 50% SES-CD from Baseline
IBDQ Response
Increase in IBDQ score ≥ 16 point from Baseline*
IBDQ Remission
IBDQ ≥ 170
*
Baseline in the additional efficacy variables is defined as the Baseline in Study M14-115.
5.3.3.1
Primary Efficacy Variables
Proportion of subjects with endoscopic improvement, defined as an SES-CD ≤ 4 with an 
Ulcerated Surface subscore no greater than 1 in any segment, at Week 40 among subjects 
with endoscopic improvement at Week 0 of Study M14-347.
5.3.3.2
Additional Efficacy Variables
For additional efficacy endpoints, the baseline is defined as the Baseline in 
Study M14-115.
●
Proportion of subjects with CDAI remission (CDAI < 150) at Week 40 among 
subjects with CDAI remission at Week 0 of Study M14-347.
●
Proportion of subjects with a SFPS remission (SFPS < 50) at Week 40 among 
subjects with SFPS remission at Week 0 of Study M14-347.
●
Proportion of subjects who achieve CDAI remission (CDAI < 150) over time.
●
Time in CDAI remission (CDAI < 150) for subjects in CDAI remission at 
Week 0 of Study M14-347.
●
Time to achieve CDAI remission (CDAI < 150) for subjects who were not in 
CDAI remission at Week 0 of Study M14-347.
●
Time to first dose escalation.


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●
Proportion of subjects who require weekly dosing at Week 1 of 
Study M14-347.
●
Time to achieve SFPS remission (SFPS < 50) for subjects who were not in 
SFPS remission at Week 0 of Study M14-347.
●
Time in SFPS remission (SFPS < 50) among subjects with SFPS remission at 
Week 0 of Study M14-347.
●
Proportion of subjects who achieve a Simplified Endoscopic Score for Crohn's 
Disease (SES-CD ≤ 4) with an Ulcerated Surface subscore no greater than 1 in 
any segment at Week 40.
●
Proportion of subjects who achieve a SFPS < 50 over time.
●
Proportion of subjects who entered Study M14-347 who were taking 
corticosteroids at Week 0 of Study M14-115 who discontinue corticosteroid 
use and achieved CDAI remission (CDAI < 150) at Week 40.
●
Proportion of subjects who entered Study M14-347 who were taking 
corticosteroids at Week 0 of Study M14-115 who discontinue corticosteroid 
use at each visit.
●
Proportion of subjects with CDAI response (decrease in CDAI ≥ 70 points 
from Baseline) over time.
●
Proportion of subjects with enhanced CDAI response (decrease in CDAI 
≥100 points from Baseline) over time.
●
Proportion of subjects with endoscopic response (decrease ≥ 50% SES-CD 
from Baseline) at Week 40.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (decrease ≥ 16 points from Baseline) over time.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) over time.
●
Change in IBDQ from Baseline over time.
●
Change from Baseline in fecal calprotectin level over time.
●
Change from Baseline in hs-CRP level over time.
●
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g 
over time.


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●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal 
calprotectin < 250 μg/g over time.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 with 
an Ulcerated Surface subscore no greater than 1 in any segment, and fecal 
calprotectin < 250 μg/g over time.
●
Change in WPAI from Baseline over time.
●
Change in European Quality of Life 5 Dimensions (EQ-5D) from Baseline 
over time.
●
Change in CDAI from Baseline over time.
●
Change in SFPS from Baseline over time.
●
Change in Abdominal Pain Rating Scale score from Baseline over time.
●
Proportion of subjects with major CD related event (e.g., hospitalization, 
bowel surgery, abscess drainage).
●
Proportion of subjects with SES-CD = 0 at Week 40.
●
Proportion of subjects with a decrease of SES-CD ≥ 3 points from Baseline of 
Study M14-115 at Week 40.
●
Change in each CDAI component subscore (number of liquid or very soft 
stools, abdominal pain rating, general well-being, CD related complications, 
anti-diarrhea use, abdominal mass, hematocrit, body weight) from Baseline 
over time.
●
Proportion of subjects requiring dose escalation to weekly dosing during this 
study.
●
The proportion of subjects with no draining fistulas over time among subjects 
with draining fistula at Baseline of Study M14-115.
●
The proportion of subjects in each treatment group with ≥ 50% reduction from 
Baseline of Study M14-115 in the number of draining fistulas over time among 
subjects with draining fistula at Baseline of Study M14-115.
●
Proportion of subjects with CDAI < 150 at Week 40 and SES-CD ≤ 4 with an 
ulcerated surface subscore no greater than 1 in any segment at Week 40.
●
Change in presence of extraintestinal manifestations over time.


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●
Proportion of subjects with predicted endoscopic improvement at Week 40, 
using the 3 definitions and equations listed below:
1.
Index score predicting the mucosal ulceration status (presence/absence) developed 
using retrospective CDEIS (≤ 4.24 versus > 4.24), laboratory and patient 
questionnaire data.  The CDEIS based prediction index score is defined as
PCDEIS = exp(A)/[1+exp(A)], where
A = 2.0291 – 0.0432*Age + 0.0429*Albumin (g/L) – 0.0060*Platelet Count 
(109/L) – 0.3286*CRP (mg/dL) – 0.0058*CDAI1 – 0.001*CDAI3,
2.
Index score predicting the mucosal ulceration status (presence/absence) developed 
using retrospective visual assessment of ileocolonoscopy recordings, laboratory 
and patient questionnaire data.  The visual assessment based prediction index score 
is defined as
PVISUAL = exp(B)/[1+exp(B)], where
B = 1.142 – 0.013*Age – 0.061*Duration CD – 0.002*Platelet Count (109/L) –
– 0.138*CRP (mg/dL) – 0.228*Rectal Bleeding Previous Two Weeks –
– 0.01*CDAI1
3.
Index score predicting the mucosal ulceration status (presence/absence) developed 
using retrospective SES-CD (≤ 5 versus > 5), laboratory and patient questionnaire 
data.  The SES-CD based prediction index score is defined as
PSESCD = exp(C)/[1+exp(C)], where
C = 1.796– 0.337 (If Female) – 0.002*Platelet Count (109/L) – 0.438*CRP 
(mg/dL)
– 0.469*Rectal Bleeding Previous Two Weeks – 0.012*CDAI1


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[CDAI1 and CDAI3 are Crohn's Disease Activity Index subscores 1 (liquid/soft 
stools) and 3 (general wellbeing) respectively.]
●
Correlation between actual SES-CD and Predicted SES-CD (equation 2, 
above).
●
Proportion of subjects who de-escalated the adalimumab dose from ew to eow 
in subjects who dose escalated.
5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.  Incidence of AEs, changes in vital signs, physical examination results, and clinical 
laboratory data will be assessed throughout the study.
5.3.5
Pharmacokinetic Variables
Blood samples will be collected for measurement of serum adalimumab concentration just 
prior to dosing and AAA outlined in Table 2.
Adalimumab trough serum concentrations will be summarized by treatment group at each 
time point using descriptive statistics.  In addition, pharmacokinetic model based analyses 
will be performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F) of adalimumab.
5.3.6
Serologic Variables
Samples may be analyzed for plasma and serum proteins, peptides, and non-protein 
soluble factors such as lipids that may help predict disease behavior and help determine 
more severe disease phenotypes.
Where allowed by local guidelines at the time of the blood draw for biomarkers, serum 
may be stored for possible future research.  Samples will be stored frozen for future 
exploratory analysis of non-genetic biomarkers related to the subject's disease and/or 
response to study drug or additional therapies, or development of AEs.  These samples 


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may also be used for the development of diagnostic tests.  Results of exploratory analyses, 
if any, will not be reported with the study summary.  AbbVie will store the samples in a 
secure storage space with adequate measures to protect confidentiality.  As allowed by 
local guidelines, the samples will be retained for up to 20 years after completion of the 
study research.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an AE, safety concerns or failure to 
comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:
●
Clinically significant abnormal laboratory result(s) or AE(s), as determined by 
the Investigator in consultation with the AbbVie SDP.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study would place the subject at risk as 
determined by the AbbVie SDP (Section 5.2.1 and Section 5.2.2).
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie SDP.
●
The subject becomes pregnant while on study drug.
●
Subject has dysplasia of the gastrointestinal tract or a malignancy, except for 
localized non-melanoma skin cancer.  Discontinuation for carcinoma in-situ of 
the cervix is at the discretion of the Investigator.
●
Subject is diagnosed with lupus-like syndrome, multiple sclerosis or 
demyelinating disease.


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●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial, as determined by the 
Investigator, in consultation with the AbbVie SDP.
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the Premature Discontinuation Visit must be 
completed within 2 weeks of the last dose of study drug, and preferably prior to the 
initiation of another therapy.  However, these procedures should not interfere with the 
initiation of any new treatments or therapeutic modalities that the Investigator feels are 
necessary to treat the subject's condition.  Following discontinuation of the study drug, the 
subject will be treated in accordance with the Investigator's best clinical judgment.
A final phone call will be made to the subject approximately 70 days after the last dose of 
study drug to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs.  The 70-day follow-up phone call will not be required for any subject who 
initiates commercial adalimumab.
All attempts must be made to determine the date of the last dose of study drug and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.
For subjects who are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 


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notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
All subjects will receive open-label adalimumab 40 mg eow or ew at Week 0 (Week 12 of 
Study M14-115) until Week 38 (Week 39 for subjects receiving weekly dosing).  No drug 
will be administered at Week 40.  Subjects can also escalate and de-escalate adalimumab 
treatment as described in Section 5.1.
5.5.2
Identity of Investigational Products
The individual study drug information is presented in Table 4.
Table 4.
Study Drugs
Drug
Dosage Form
Device
Formulation
Manufacturer
Adalimumab
Parenteral
Pre-filled 
syringe
40 mg/0.8 mL solution for injection 
Adalimumab/Mannitol, Citric acid 
monohydrate, Sodium citrate, 
Disodium phosphate dihydrate, 
Sodium dihydrogen phosphate 
dihydrate, Sodium chloride, 
Polysorbate 80, Water for injections, 
Sodium hydroxide added as necessary 
to adjust pH
AbbVie
5.5.2.1
Packaging and Labeling
Investigational product will be provided in a kit that contains 2 pre-filled syringes 
containing adalimumab 40 mg/0.8 mL injection solution.  Each dosing kit carton contains 
pre-filled syringes to accommodate study design.  The syringe and/or carton labels will 
minimally contain the information as required per country requirements.


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All labels must remain affixed to study drug at all times, and should never be removed for 
any reason.
Detailed instructions and training for the administration of study drug supplies are 
provided in Appendix G.
5.5.2.2
Storage and Disposition of Study Drugs
Adalimumab pre-filled syringes are to be stored protected from light at 2° to 8°C/36° to 
46°F.  Study drug must not be frozen at any time.  A storage temperature log is to be 
maintained to document proper storage conditions.  The clinical site refrigerator 
temperature must be recorded on a temperature log to record proper function.
Malfunctions or any temperature excursion must be reported to the Sponsor immediately.  
Study drug should be quarantined and not dispensed until AbbVie GPRD or AbbVie 
Temperature Excursion Management System (ATEMS) deems the study drug as 
acceptable.
All clinical supplies must be stored and locked in a secure place until they are dispensed 
for subject use or are returned to AbbVie.
Investigational products are for investigational use only and are to be used only within the 
context of this study.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally registered using an Interactive Voice Response System 
(IVRS).  There will be no randomization for this open-label study.  Subjects will keep 
their study subject number from the previous Study M14-115.  Before the study is 
initiated, the directions for the IVRS will be provided to each site.  Returned study drug 
should not be re-dispensed to any subject.
Study drug will be administered at the study visits summarized in Table 2.


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5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.1.
If a subject should forget to administer the injection of study drug on their regularly 
scheduled dosing date, they should take the forgotten injection as soon as they remember 
the dose was missed up to the day of their next scheduled dose.  The subject should not 
administer two doses on the same day.
In the event the incorrect dose is taken or a dose is missed, the subject should be 
instructed to contact the site to determine how to proceed with dosing.  The subject must 
record all dosing information in the Subject Diary.
Doses not administered (e.g., not taken before next dose is scheduled), should be recorded 
as not taken in the source.  The extra dose should be returned to the study site full.  The 
subject should resume their regular dosing schedule based on the first dosing date at 
Baseline.
5.5.5
Treatment Compliance
The Investigator or his/her designated representatives will dispense study drug only for 
use by subjects enrolled in the study.
The subject or their qualified designee will administer all doses of study drug.  
Appropriate site staff will supervise the subject's administration of the study drug at 
required in-office study visits to ensure proper injection technique.  In order to document 
compliance with the treatment regimen, the subject will be given a diary to record all 
injection dates and times.  Compliance information will be documented on the appropriate
eCRF.  Subjects will be counseled on missed doses of study drug.  If the subject does not 
return the diary, IP boxes and sharps containers (when applicable), the site should 
question the subject and obtain as much information as possible as to the dosing of the 
study drug.


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The information should be documented on the source documents as per "best recollection" 
and when possible, re-verified when the diary is returned before completing on the 
applicable eCRF page.
5.5.6
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact, at the 
appropriate temperature and in the correct amounts.  This will be accomplished by 
documenting the condition of the shipment, verifying the kit numbers in the package 
against the Proof of Receipt (POR) or similar document included with each drug 
shipment, and documenting this verification by signing and dating the POR or similar 
document.  The original POR Note or similar document will be kept in the site files as a 
record of what was received.
In addition, an accurate running inventory of study drug will be kept by the site on a Site 
Drug Accountability log including date received, the lot number, kit number(s), date 
dispensed, subject number, and the identification with date of the person dispensing the 
drug.  For this study, unless otherwise prohibited locally, these records will be maintained 
electronically as part of the IVRS/IWRS system.
All empty IP boxes and used pre-filled syringes will be inventoried by the site.  Each 
subject will be given their own sharps disposal container to store used pre-filled syringes.  
Empty IP boxes and sharps containers should be returned by the subject at each visit for 
accountability and compliance purposes and new containers issued as necessary.  Empty
boxes and returned sharps containers will be retained (unless prohibited by local law) until 
the CRA is on site to confirm the returned study drug.  CRAs and site staff will complete 
study drug accountability via study drug logs, source documents, subject dosing diaries, 
empty IP boxes and by visually inspecting the pens/syringes in the sharps container 
whenever possible.  Used sharps containers should never be opened.  Once the CRA has 
verified drug accountability at the site, the site staff and CRA will document that the used 
pre-filled syringes have been destroyed, using appropriate biohazard precautions, when 
appropriate.  A copy of the destruction methodology should be maintained at the site's 


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facility.  Unused study drug will be returned by the CRA after drug accountability has 
been completed at the site.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The design of this clinical trial was chosen to evaluate long-term efficacy, safety, and 
tolerability, of adalimumab in subjects with CD who participated in and successfully 
completed Study M14-115.
This is an open-label study.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, endoscopy-related and laboratory procedures will be utilized 
in this study.  All efficacy measurements in this study are standard for assessing disease 
activity in subjects with CD.  All clinical and laboratory procedures in this study are 
standard and generally accepted.
5.6.3
Suitability of Subject Population
Subjects who participated and successfully completed Study M14-115 and who meet all 
of the inclusion criteria and none of the exclusion criteria will be eligible to enroll into 
this study.
5.6.4
Selection of Doses in the Study
Adalimumab doses were selected based on the US Product Label,7 in which the 
recommended adalimumab maintenance dose regimen for adult patients with moderate to 
severe Crohn's disease is 40 mg eow.  In the EU Summary of Product Characteristics, 8 the 
recommended adalimumab maintenance dose regimen for adult patients with moderate to 
severe Crohn's disease is 40 mg eow, or 40 mg ew for subjects whose disease is not 
controlled on 40 mg eow.


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6.0
Adverse Events
The investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the investigator will provide an Other cause of the event.  For 
adverse events to be considered intermittent, the events must be of similar nature and 
severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.  All AEs will be followed to a satisfactory 
conclusion, including all AEs that are ongoing from Study M14-115.
6.1
Definitions
6.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
the study, necessitate therapeutic medical intervention, (see Section 6.7 for toxicity 
management) and/or if the investigator considers them to be AEs.


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An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry for Study M14-115.  
However, if the pre-existing condition deteriorates unexpectedly during the study 
(e.g., surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an AE.
6.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a SAE 
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each AE:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.


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No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the SAE.
6.4
Adverse Event Collection Period
All adverse events including ongoing AEs from Study M14-115, and reported from the 
time of study drug administration until 70 days following discontinuation of study drug 
administration have elapsed will be collected, whether solicited or spontaneously reported 
by the subject.  In addition, SAEs will be collected from the time the subject signed the 
study-specific informed consent.  Adverse event information will be collected and 
recorded on the appropriate eCRFs.
Subjects will be contacted approximately 70 days following study drug discontinuation 
for an assessment of any new or ongoing AEs, except those subjects who continue on 
adalimumab therapy after the end of study participation.  These subjects are not required 
to complete the 70-day follow-up and any new AEs should be reported through the 
mechanism used for all post-marketing adverse experiences.  The 70-day follow-up phone 
call will be recorded in source document only and confirmation of the contact will be 
faxed to AbbVie (Appendix J).
All AEs identified to AbbVie from the 70-day follow-up phone call will be collected as 
source data to be evaluated and reported (Figure 3).  Thus, all SAEs and nonserious AEs 
as defined by AbbVie, reported during the 70-day follow-up phone call must be captured 


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in the clinical database.  The end of trial is the last subject contact, i.e., the 70 day 
follow-up call.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
SAEs and Nonserious 
AEs Carried Over from 
Study M14-115
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study
Drug 
Stopped
70 Days
After Study 
Drug Stopped
6.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any nonserious event of 
malignancy in patients 30 years of age and younger, whether related to study drug or not, 
the physician will notify the AbbVie Clinical Pharmacovigilance and Immunology Safety 
Management within 24 hours of the physician becoming aware of the event by entering 
the SAE or nonserious event of malignancy in patients 30 years of age and younger data 
into the electronic data capture (EDC) system.  Serious adverse events and nonserious 
events of malignancy in patients 30 years of age and younger, that occur prior to the site 
having access to the Rave® EDC system or if Rave® is not operable, should be 
documented on the SAE Non-CRF forms and send to the AbbVie Clinical 
Pharmacovigilance within 24 hours of being made aware of the serious adverse event.
FAX to:  
Email:  
For safety concerns, contact the Immunology Safety Management Team at:


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For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
Secondary Study Designated Physician:


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Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number: 
Phone:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.2).  Pregnancies will be collected from the date of the 
first dose through 150 days following the last dose of study drug.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a SAE 
and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
6.7
Toxicity Management
Subjects who develop a new infection while undergoing treatment with adalimumab 
should be monitored closely.  Administration of study injections should be interrupted if a 
subject develops an infection requiring IV anti-infective treatment or if an infection meets 
the definition of "serious" (see Section 6.1 for definitions).  Study drug may be restarted 
once the physician determines that the infection has been successfully treated.  Otherwise 
prohibited concomitant medications may be given if medically necessary.  Prior to use, 


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every attempt should be made to contact the AbbVie Study Physician for direction on 
re-introduction of adalimumab therapy after prohibited medication administration.
If the subject must undergo elective surgery, the study injections must be interrupted 
two weeks prior to the surgery.  If the subject must undergo emergency surgery, the study 
injections must be interrupted at the time of the surgery.  The injectable study drug can 
recommence at least two weeks after surgery once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and their assigned CRO Clinical 
Monitor or the following AbbVie Clinical Monitor(s):
Primary Contact:
Alternate Contact:


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Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objectives of the statistical analyses are to evaluate long-term the efficacy and safety 
of repeated administration of adalimumab in subjects with Crohn's disease who 
participated in and successfully complete Study M14-115.
Complete, specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock.
8.1.1
Analyzable Population
The following populations will be used for analyses in this study:
The Intent-to-treat (ITT) Set and Safety Set consists of all subjects who enrolled into the 
study and received at least one injection of study drug.
8.1.2
Planned Methods of Statistical Analysis
Descriptive statistics will be provided.  These include the number of observations, mean, 
standard deviation, minimum, median, and maximum for continuous variables; and counts 
and percentages for discrete variables.  The analysis will be performed using SAS® (SAS 
Institute Inc., Cary, NC, USA).
8.1.3
Demographics and Baseline Characteristics
Demographics and Baseline characteristics of the study subjects will be summarized using 
descriptive statistics.  


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8.1.4
Statistical Analyses of Efficacy
8.1.4.1
Primary Efficacy Variable
The primary efficacy variable is proportion of subjects with CD with endoscopic 
improvement, defined as an SES-CD ≤ 4 with an Ulcerated Surface subscore no greater 
than 1 in any segment, at Week 40 among the subjects with endoscopic improvement at 
Week 0 of Study M14-347.
A two-sided 95% confidence interval for the proportion will be calculated.  The ITT set 
includes all subjects who enrolled into this study and received at least one dose of study 
drug.  Missing SES-CD at Week 40 will be imputed using the non-responder imputation 
(NRI) approach.  Subjects who dose escalate will be imputed using NRI for visits after 
dose escalation.  The last observation carried forward (LOCF) method will also be used as 
the sensitivity analyses.
8.1.4.2
Additional Efficacy Variables
For categorical additional efficacy endpoints, the two-sided 95% confidence interval for 
the proportions will be provided.  The nonresponder imputation method will be used for 
subjects with missing data at the time point evaluated.  Subjects who dose escalate will be 
imputed using NRI for visits after dose escalation.  The LOCF method will also be used 
as the sensitivity analyses.
For continuous additional efficacy endpoints, change from Baseline of Study M14-347 
will be summarized by descriptive statistics using mean, standard deviation, minimum, 
median and maximum.  Both LOCF and observed case analyses will be performed.
For time to event additional efficacy endpoints, the number of event and the 25th, median, 
and 75th percentiles of time to event will be summarized.


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8.1.5
Statistical Analyses of Safety
Laboratory data, AEs, and vital signs are the primary safety parameters in this study.  All 
safety analyses will be performed using the Safety set, which includes all subjects who 
enrolled into this study and received at least one dose of study drug.  Treatment-emergent 
AEs are defined as events that begin or worsen either on or after the first dose of the study 
drug and within 70 days after the last dose of the study drug.  An overview of 
treatment-emergent AEs, including AEs of special interest such as AEs leading to death 
and AEs leading to premature discontinuation (see details in the SAP), AEs by Medical 
Dictionary for Drug Regulatory Activities (MedDRA version 15.1 or later) preferred term 
and system organ class, AEs by maximum relationship to study drug, and AEs by 
maximum severity will be summarized by number and percentage.
Changes in laboratory data will be described using statistical characteristics.  In addition, 
shift tables and listings will be provided for abnormal values, whereby the normal range 
of the analyzing laboratory will be used.  Vital signs will be analyzed similarly.
8.1.6
Other Statistical Analyses of Efficacy
The subgroups listed below will be used in subgroup analyses of the primary endpoint.  
The baseline used for the subgroups below is defined as the baseline in Study M14-115.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Study M14-115 induction dose (higher, standard)
●
Endoscopic improvement status at Week 0 (yes, no)
●
CDAI remission status at Week 0 (yes, no)
●
SFPS remission status at Week 0 (yes, no)
●
Baseline fecal calprotectin [≤ median, > median]
●
Baseline fecal calprotectin [≤ 250 μg/g, > 250 μg/g]
●
Baseline corticosteroid use (yes, no)


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●
Baseline immunosuppressant use (yes, no)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L) 
●
hs-CRP at Baseline (≤ median, > median)
●
Crohn's disease activity (CDAI ≤ 300, > 300) at Baseline
●
Baseline CDAI (≤ median, > median)
●
Baseline SES-CD [≤ median, > median]
●
Prior infliximab use (yes, no)
●
Weight (≤ median, > median)
●
Baseline albumin (≤ median, > median)
●
Disease duration (< 3 years, > 3 years)
●
Disease duration (≤ median, > median)
8.1.7
Interim Analysis
An interim analysis of the primary and additional efficacy variables as well as safety data 
collected will be performed when the results from Study M14-115 are available.  A 
database lock will be performed and any discrepant data will be clarified before the lock.
8.1.8
Pharmacokinetic Analyses
Adalimumab trough serum concentrations will be summarized at each time point using 
descriptive statistics.  In addition, pharmacokinetic model based analyses will be 
performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F) of adalimumab.  The relationship between adalimumab concentrations 
and clinical response will be determined as appropriate.
AAA will be evaluated for each subject and each dose, and rates of AAA positive will be 
calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy 
variable(s), and treatment-emergent AEs may be evaluated.


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8.2
Determination of Sample Size
Approximately 300 subjects who participated in and successfully completed 
Study M14-115.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
endoscopy reports, hospital records, clinical and office charts, laboratory 
data/information, subjects' diaries or evaluation checklists, pharmacy dispensing and other 
records, recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  Data collected during this study must be 
recorded on the appropriate source documents.


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The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms must be completed for each subject screened/enrolled in this study.  
These forms will be used to transmit information collected during the study to AbbVie 
and regulatory authorities, as applicable.  The case report form (CRF) data for this study 
are being collected with an electronic data capture (EDC) system called Rave ® provided 
by the technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system 
and the study specific eCRFs will comply with Title 21 CFR Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, 
while the validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 


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investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
The following assessments will be completed by subjects on paper:
●
IBDQ
●
WPAI
●
EQ-5D
●
Abdominal Pain Rating Scale
●
Diary
Site staff will verify completion of these forms.  All questionnaires must be legible and 
completed in indelible ballpoint ink.  Any necessary corrections are to be made by 
drawing a single line through the incorrect entry and writing in the revision, the date of 
the correction, the reason for the correction, and the initials of the study subject who is 
making the correction.  Data are not to be obliterated by blacking out, using correction 
fluid or by erasing the original entry.
The questionnaire administrator will review the questionnaire for completeness and 
accuracy.  The subject-completed questionnaires will be transcribed into the EDC system 
by study personnel.  The completed paper questionnaire will be considered source.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
All information concerning adalimumab and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 


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information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
adalimumab.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, to the FDA and to other 
governmental agencies.  To allow for the use of the information derived from this clinical 
study and to ensure complete and thorough analysis, the investigator is obligated to 
provide AbbVie with complete test results and all data developed in this study and to 
provide direct access to source data/documents for trial-related monitoring, audits, 
IEC/IRB review, and regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.
13.0
Completion of the Study
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.


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The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for adalimumab.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Multicenter, Open-Label Study to Evaluate the Long Term 
Efficacy, Safety, and Tolerability of Repeated Administration of 
Adalimumab in Subjects with Crohn's Disease
Protocol Date:
04 December 2014
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Hanauer SB, Sandborn W; Practice Parameters Committee of the American 
College of Gastroenterology.  Management of Crohn's disease in adults.  Am J 
Gastroenterol.  2001;96(3):635-43.
2.
Loftus EV Jr.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  
2004;126(6):1504-17.
3.
Probert CS, Jayanthi V, Rampton DS, et al.  Epidemiology of inflammatory bowel 
disease in different ethnic and religious groups:  limitations and aetiological clues.  
Int J Colorectal Dis.  1996;11(1):25-8.
4.
Allez M, Lemann M, Bonnet J, et al.  Long term outcome of patients with active 
Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy.  Am J 
Gastroenterol.  2002;97(4):947-53.
5.
Froslie KF, Johnsen J, Moum BA, et al.  Mucosal healing in inflammatory bowel 
disease:  results from a Norwegian population-based cohort.  Gastroenterology.  
2007;133(2):412-22.
6.
Kakkar A, Wasan SK, Farraye FA.  Targeting mucosal healing in Crohn's disease.  
Gastroenterol Hepatol (NY).  2011;7(6):374-80.
7.
Humira® (adalimumab) [package insert] North Chicago, IL; AbbVie, 2007.
8.
Humira® (adalimumab) [40 mg solution for injection summary of product 
characteristics package insert] North Chicago, IL; AbbVie, 2007.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Statistics
Clinical
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical


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Appendix C.
Sample Work Productivity and Activity Impairment 
Questionnaire:  Crohn's Disease V2.0 (WPAI:CD)


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Appendix D.
Sample EQ-5D Questionnaires


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Appendix F.
Abdominal Pain Rating Scale


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Appendix G.
Injection Instructions – Sample Pre-Filled Syringe
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M14-347
Table of Contents
Dosing Schedule
General Information and Supplies
Injection Procedures


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Study Drug Dosing Schedule
Subject Number:  _____________________________________
You will require subcutaneous injections throughout the study.  Depending how active 
your Crohn's disease is, your dosing schedule may change.  You will receive 1 injection at 
the clinic at your Baseline Visit (the first visit to receive the study medication for this 
study). 
If your Crohn's disease is under control, then you will take 1 injection every other week.  
You will receive the following number of injections during the study:
●
Weeks 2, 4, 6, 10, 12, 14, 18, 20, 22, 26, 28, 30, 34, 36 and 38 you will 
administer 1 injection at home.
●
At Weeks 8, 16, 24 and 32 you will receive 1 injection at the clinic.
If your Crohn's disease worsens, then your study physician may need to change your 
dosing schedule and you could begin taking 1 injection every week. 
If you feel better at a future visit while taking 1 injection every week, then you may go 
back to taking 1 injection every other week.
Please return all used and unused syringes and empty boxes to the clinic on your next 
visit.  Used syringes should be placed in the special sharps container provided.  All 
unused syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
contact your study center immediately for further instructions.  Please record any missed 
doses on your subject dosing diary.
Remember to complete your dosing diary after each injection and to call the doctor's 
office if you are having problems administering your study medication.


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General Information
●
Pre-filled syringes will be labeled "Adalimumab."
●
Store all adalimumab pre-filled syringes in your refrigerator NOT in the 
freezer.  Should the syringes accidentally become frozen, call your study 
doctor's office.
●
Study medication should be taken at about the same time of day, on the same 
day of the week as directed by your study doctor.
●
USE A NEW SYRINGE EVERY INJECTION DAY.  There may be 
medication left in the syringe.  DO NOT RE-USE.
●
Save all study medications.  Pre-filled syringes (used and unused) & empty 
boxes must be returned to the study center at each visit.  Used syringes will 
be disposed of in a sharps container provided to you.
●
Call your doctor IMMEDIATELY if you experience any itching, hives, 
shortness of breath, or any symptom that has you concerned.  If you are unable 
to reach your doctor or if you experience life-threatening symptoms call 
___________________, or proceed to your nearest emergency room.
Injection Procedures (PFS)
1. Setting up for an injection
●
Find a clean flat surface.
●
Do not use if the seals on the carton are broken or missing.  Contact your study 
doctor's office if the seals are broken.
●
Take one kit with the prefilled syringe(s) of adalimumab from the refrigerator.  
Do not use a prefilled syringe that has been frozen or if it has been left in direct 
sunlight.
●
Return any unused syringe(s) to the refrigerator.
You will need the following items for each dose:
●
study medication in pre-filled syringe(s)


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●
alcohol prep(s)
●
cotton ball or gauze pad(s)
If you do not have all of the items you need to give yourself an injection, call your study 
physician.  Use only the items provided in the box your adalimumab comes in.
●
Make sure the liquid in the prefilled syringe is clear and colorless.  Do not use 
a prefilled syringe if the liquid is cloudy or discolored or has flakes or particles 
in it.
●
Have a special sharps (puncture proof) container nearby for disposing of used 
needles and syringes.
For your protection, it is important that you follow these instructions.
2. Choosing and preparing an injection site


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●
Wash your hands well.
●
Choose a site on the front of your thighs or your stomach area (abdomen).  If 
you choose your abdomen, you should avoid the area 2 inches around your 
belly button (navel).
●
Choose a different site each time you give yourself an injection.  Each new 
injection should be given at least one inch from a site you used before.  Never 
inject into areas where the skin is tender, bruised, red or hard or where you 
have scars or stretch marks.
●
If you have psoriasis, you should try not to inject directly into any raised, 
thick, red or scaly skin patches or lesions.
●
You may find it helpful to keep notes on the location of your injection sites.
●
Wipe the site where adalimumab is to be injected with an alcohol prep (swab), 
using a circular motion.  Do not touch this area again until you are ready to 
inject.
3. How to prepare your adalimumab dose for injection with a Prefilled Syringe
●
Hold the syringe upright with the needle facing down.  Check to make sure 
that the amount of liquid in the syringe is the same or close to the 0.8 mL line 
for the 40 mg prefilled syringe.  The top of the liquid may be curved.  If the 
syringe does not have the correct amount of liquid, do not use that syringe.  
Call your study doctor.
●
Remove the needle cover taking care not to touch the needle with your fingers 
or allow it to touch any surface.
●
Turn the syringe so the needle is facing up and slowly push the plunger in to 
push the air in the syringe out through the needle.  If a small drop of liquid 
comes out of the needle that is okay.
●
Do not shake the syringe.
4. Injecting Adalimumab
●
With your other hand, gently squeeze an area of the cleaned area of skin and 
hold it firmly.


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●
You will inject into this raised area of skin.  Hold the syringe like a pencil at 
about a 45° angle (see picture) to the skin.
●
With a quick, short, "dart-like" motion, push the needle into the skin.
●
After the needle is in, let go of the skin.  Pull back slightly on the plunger.  If 
blood appears in the syringe it means that you have entered a blood vessel.  Do 
not inject adalimumab.  Pull the needle out of the skin and repeat the steps to 
choose and clean a new injection site.  Do not use the same syringe. Dispose 
of it in your special sharps container.  If no blood appears, slowly push the 
plunger all the way in until all of the adalimumab is injected.
●
When the syringe is empty, remove the needle from the skin keeping it at the 
same angle it was when it was pushed into the skin.
●
Press a cotton ball or gauze pad over the injection site and hold it for 10 
seconds.  Do not rub the injection site.  You may have slight bleeding.  This is 
normal.
●
Dispose of the syringe right away into your special sharps container.


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Appendix H.
Crohn's Disease Activity Index (CDAI)
Factor
Subtotal
1.
Number of liquid or very soft stools 
(Record the frequency per day)
×
2
2.
Abdominal pain rating:
0 = none, 1 = mild, 2 = moderate,
3 = severe
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
5
3.
General well-being:
0 = generally well, 1 = slightly 
underpar, 2 = poor, 3 = very poor,
4 = terrible
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
7
4.
Number of 6 listed categories the 
subject now has
Check all items that apply:
Arthritis/arthralgia
Iritis/uveitis
Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
Fissure, abscess and/or anal fistula 
(draining/non-draining)
Other cutaneous fistula 
(draining/non-draining)
Fistula
Fever over 100°F (37.8°C) during 
past week
________________________________
________________________________
Record "0" if no categories checked
×
20
5.
Taking Lomotil/Imodium/ 
Loperamide/opiates for diarrhea
0 = no, 1 = yes
________
×
30
6.
Abdominal mass
0 = none, 2 = questionable, 5 = defined
________
×
10
7.
Hematocrit:  ___.__
Male:  (47 – hematocrit) =
Female:  (42 – hematocrit) =
Subtotal If hematocrit > normal, enter 
"0"
×
6
8.
Body weight:  ___.__(kg)
Standard weight:  ___.__(kg)
100 × [1 – (Body wt/Standard wt)] =
Percent below standard weight:  ______
If body wt > std. wt, enter "0"
×
1
Total


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Appendix I.
Standard Weights
Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height cm (Inches)
Standard Weight 
(Men) kg (Pounds)
Standard Weight 
(Women) kg (Pounds)
121.9 (48.0)
40.8 (89.9)
123.2 (48.5)
41.3 (91.0)
124.5 (49.0)
41.8 (92.1)
125.7 (49.5)
42.3 (93.3)
127.0 (50.0)
42.8 (94.4)
128.3 (50.5)
43.4 (95.6)
129.5 (51.0)
43.9 (96.8)
130.8 (51.5)
44.4 (98.0)
132.1 (52.0)
55.5 (122.4)
45.0 (99.2)
133.4 (52.5)
55.7 (122.7)
45.5 (100.4)
134.6 (53.0)
55.8 (123.1)
46.1 (101.6)
135.9 (53.5)
56.0 (123.5)
46.6 (102.8)
137.2 (54.0)
56.2 (123.9)
47.2 (104.1)
138.4 (54.5)
56.4 (124.4)
47.8 (105.3)
139.7 (55.0)
56.7 (124.9)
48.3 (106.6)
141.0 (55.5)
56.9 (125.5)
48.9 (107.9)
142.2 (56.0)
57.2 (126.1)
49.5 (109.1)
143.5 (56.5)
57.4 (126.7)
50.1 (110.4)
144.8 (57.0)
57.7 (127.3)
50.7 (111.7)
146.1 (57.5)
58.1 (128.0)
51.3 (113.0)
147.3 (58.0)
58.4 (128.7)
52.2 (115.0)
148.6 (58.5)
58.7 (129.5)
52.6 (116.0)
149.9 (59.0)
59.1 (130.3)
53.1 (117.0)
151.1 (59.5)
59.5 (131.1)
53.6 (118.3)
152.4 (60.0)
59.9 (132.0)
54.2 (119.5)
153.7 (60.5)
60.3 (132.9)
54.8 (120.8)
154.9 (61.0)
60.7 (133.8)
55.3 (122.0)
156.2 (61.5)
61.1 (134.8)
56.0 (123.5)
157.5 (62.0)
61.7 (136.0)
56.7 (125.0)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height cm (Inches)
Standard Weight 
(Men) kg (Pounds)
Standard Weight 
(Women) kg (Pounds)
158.8 (62.5)
62.1 (137.0)
57.4 (126.5)
160.0 (63.0)
62.6 (138.0)
58.0 (128.0)
161.3 (63.5)
63.0 (139.0)
58.7 (129.5)
162.6 (64.0)
63.5 (140.0)
59.4 (131.0)
163.8 (64.5)
64.1 (141.3)
60.1 (132.5)
165.1 (65.0)
64.6 (142.5)
60.8 (134.0)
166.4 (65.5)
65.2 (143.8)
61.4 (135.5)
167.6 (66.0)
65.8 (145.0)
62.1 (137.0)
168.9 (66.5)
66.4 (146.5)
62.8 (138.5)
170.2 (67.0)
67.1 (148.0)
63.5 (140.0)
171.5 (67.5)
67.8 (149.5)
64.2 (141.5)
172.7 (68.0)
68.5 (151.0)
64.9 (143.0)
174.0 (68.5)
69.2 (152.5)
65.5 (144.5)
175.3 (69.0)
69.8 (154.0)
66.2 (146.0)
176.5 (69.5)
70.5 (155.5)
66.9 (147.5)
177.8 (70.0)
71.2 (157.0)
67.6 (149.0)
179.1 (70.5)
71.9 (158.5)
68.3 (150.5)
180.3 (71.0)
72.6 (160.0)
68.9 (152.0)
181.6 (71.5)
73.4 (161.8)
69.6 (153.5)
182.9 (72.0)
74.1 (163.5)
70.3 (155.0)
184.2 (72.5)
75.0 (165.3)
71.2 (156.9)
185.4 (73.0)
75.7 (167.0)
71.9 (158.5)
186.7 (73.5)
76.6 (169.0)
72.6 (160.2)
188.0 (74.0)
77.5 (171.0)
73.4 (161.8)
189.2 (74.5)
78.4 (172.8)
74.1 (163.4)
190.5 (75.0)
79.1 (174.5)
74.9 (165.1)
191.8 (75.5)
80.2 (176.8)
75.6 (166.8)
193.0 (76.0)
81.2 (179.0)
71.2 (156.9)
194.3 (76.5)
82.0 (180.8)
77.2 (170.1)
195.6 (77.0)
82.9 (182.9)
77.9 (171.8)
196.9 (77.5)
83.9 (185.0)
78.7 (173.5)


Adalimumab
M14-347 Protocol Amendment 2
EudraCT 2013-004034-15
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Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height cm (Inches)
Standard Weight 
(Men) kg (Pounds)
Standard Weight 
(Women) kg (Pounds)
198.1 (78.0)
84.9 (187.2)
79.5 (175.2)
199.4 (78.5)
85.9 (189.4)
80.3 (177.0)
200.7 (79.0)
86.9 (191.6)
81.0 (178.7)
201.9 (79.5)
87.9 (193.9)
81.8 (180.5)
203.2 (80.0)
89.0 (196.2)
82.6 (182.2)
204.5 (80.5)
90.0 (198.6)
*Height in shoes with one inch 
heels
205.7 (81.0)
91.1 (200.9)
*Indoor clothing weighing 
5 pounds for men and 3 pounds 
for women
207.0 (81.5)
92.2 (203.3)
*Centimeters × 0.3937 = inches
208.3 (82.0)
93.3 (205.8)
*Pounds × 0.4535 = kilograms


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Appendix J.
70-Day Follow-Up Phone Call – Sample
Site Name/Number:  ____________________________
Subject Number:  __________________
Please contact subjects who discontinue adalimumab 70 days following study drug 
discontinuation.
Date of Call:  _____________________
Lost to Follow-up (Please check this box if subject was not willing to provide 
any follow-up information or you were unable to speak to the subject following 
at least one attempt.)
No Events Reported
N/A subject continued adalimumab therapy after the end of their study 
participation
List any Adverse Events (AE) and/or Serious Adverse Events (SAE) that occurred since the 
subject was last seen in clinic for this study.  If needed, provide AE/SAE details on the AE 
worksheet attached.  (Please report all SAEs to AbbVie within 24 hours of being made aware of 
the event.)
If events are listed above, your monitor will review and retrieve the appropriate eCRF pages during their 
next visit.
Please fax all completed forms to:
[Name] at XXX-XXX-XXXX


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Appendix K.
SES-CD Scoring




Adalimumab
M14-347 Protocol Amendment 2
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Appendix M.
Protocol Amendment:  List of Changes
Specific Protocol Changes:
The summary of changes is listed in Section 1.1.
Section 1.2  Synopsis
Subsection Methodology:
Second paragraph, last sentence previously read:
Subjects may be escalated to adalimumab 40 mg every week (ew) at or after Week 2 
should the subject meet the criteria for inadequate response:
Has been changed to read:
Subjects may be escalated to adalimumab 40 mg every week (ew) at or after Week 1 
should the subject meet the criteria for inadequate response:
Section 1.2  Synopsis
Subsection Methodology:
Heading "Inadequate Response:"
First paragraph, first sentence previously read:
Crohn's disease activity index (CDAI) ≥ 200 for two consecutive visits that are at least 
fourteen (14) days apart, and at least one of the following criteria is met:  an increase of at 
least 1 mg/L in level of high-sensitivity C-reactive protein (hs-CRP) from Baseline or a 
hs-CRP ≥5 mg/L.  
Has been changed to read:
Crohn's disease activity index (CDAI) ≥ 200 at any one visit and at least one of the 
following criteria is met:  an increase of at least 1 mg/L in level of high-sensitivity 
C-reactive protein (hs-CRP) from Baseline or an hs-CRP ≥ 5 mg/L.  The hs-CRP results 
used to determine inadequate response can be from the prior or current visit.


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Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
Subheading "Additional Efficacy Endpoints:"
Seventh bullet previously read:
●
Proportion of subjects who require weekly dosing at Week 2 of 
Study M14-347.
Has been changed to read:
●
Proportion of subjects who require weekly dosing at Week 1 of 
Study M14-347.
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph, last sentence previously read:
Subjects may be escalated to adalimumab 40 mg every week (ew) at or after Week 2 
should the subject meet the criteria for inadequate response (Table 1).
Has been changed to read:
Subjects may be escalated to adalimumab 40 mg every week (ew) at or after Week 1 
should the subject meet the criteria for inadequate response (Table 1).
Table 1.  Inadequate Response
Previously read:
Response Type
Definition
Inadequate response
Crohn's disease activity index (CDAI) of ≥ 200 for two consecutive visits that 
are at least fourteen (14) days apart, and at least one of the following criteria 
is met:  an increase of at least 1 mg/L in level of high-sensitivity C-reactive 
protein (hs-CRP) from Baseline or a hs-CRP ≥ 5 mg/L.  Assessment of 
inadequate response should include consideration by the Investigator to rule 
out symptoms caused by reasons other than Crohn's disease related 
inflammation.






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Table 2.  Study Activities
Row "Serological Biomarkers/mRNA" previously read:
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Serological Biomarkers/mRNA
Xa
X
X
X
Has been changed to read:
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Serological Biomarkers/mRNA
Xa
X
X
Table 2.  Study Activities
Row "Inflammatory Bowel disease Questionnaire (IBDQ)" through row "Abdominal Pain Rating Scale" previously read:
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Inflammatory Bowel disease Questionnaire (IBDQ)
Xa
X
X
X
X
European Quality of Life 5 dimensions (EQ-5D)
Xa
X
X
X
X
Work Productivity and Impairment Questionnaire 
(WPAI)
Xa
X
X
X
X
Abdominal Pain Rating Scale
Xa
X
X
X
X


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Has been changed to read:
Activity
Baseline
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Calll
Inflammatory Bowel disease Questionnaire (IBDQ)
Xa
X
X
X
European Quality of Life 5 dimensions (EQ-5D)
Xa
X
X
X
Work Productivity and Impairment Questionnaire 
(WPAI)
Xa
X
X
X
Abdominal Pain Rating Scale
Xa
X
X
X


Adalimumab
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Table 2.  Study Activities
Table note "g." last sentence previously read:
Stool samples for metagenomic analysis should be collected before any bowel preparation 
for endoscopy is started and returned to the site within 2 days of collection.
Has been changed to read:
Stool samples for metagenomic analysis should be collected before any bowel preparation 
for endoscopy is started and returned to the site within 3 days of collection.
Table 2.  Study Activities
Table note "k." previously read:
Visits for dispensing new study drug in case of temperature excursion, loss, or damage are 
not considered an Unscheduled Visit.  In addition, visits to retest a lab will not be 
considered an Unscheduled Visit.  Unscheduled visits can be used for situations including 
the following:  For evaluation and assessment of the subject, to dispense study drug, to 
evaluate a subject who meets criteria for inadequate response as outlined in Table 1, to 
collect samples to determine hs-CRP in those subjects, and to collect PK samples for a 
change in adalimumab dosing.
Has been changed to read:
Visits for dispensing new study drug in case of temperature excursion, loss, damage, or 
dose escalation are not considered an Unscheduled Visit.  In addition, visits to retest a lab 
will not be considered an Unscheduled Visit.  Unscheduled visits can be used for 
situations including the following:  For evaluation and assessment of the subject, to 
evaluate a subject who meets criteria for inadequate response as outlined in Table 1, to 
collect samples to determine hs-CRP in those subjects, and to collect PK samples for a 
change in adalimumab dosing.


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Section 5.3.1.1  Study Procedures
Subsection Informed Consent
Add:  new last sentence
Consent will be required for any optional testing.
Section 5.3.1.1  Study Procedures
Subsection Endoscopy
Second paragraph, first sentence previously read:
An ileocolonoscopy will be performed and recorded at the site in a video format.  
Has been changed to read:
An ileocolonoscopy will be performed and should be recorded at the site in a video 
format.
Section 5.3.1.1  Study Procedures
Subsection Urinalysis
Last sentence previously read:
Microscopic urinalysis will only be performed by the central laboratory if the dipstick UA 
results are abnormal, where abnormal is defined as a ketone, protein, blood or glucose 
value of greater than a trace.
Has been changed to read:
Microscopic urinalysis will only be performed by the central laboratory if the dipstick UA 
results are abnormal, where abnormal is defined as a protein, ketones or blood greater 
than negative or glucose greater than normal.


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Section 5.3.1.1  Study Procedures
Subsection Other Laboratory Assessments
Heading "Stool Sample (Fecal Calprotectin and Microbiota Metagenomic 
Analyses)"
Second paragraph, first sentence previously read: 
All stool samples should be collected before any bowel preparation for endoscopy is 
started and returned to the site within 2 days of collection.  
Has been changed to read:
All stool samples should be collected before any bowel preparation for endoscopy is 
started and returned to the site within 3 days of collection.  
Section 5.3.1.1  Study Procedures
Subsection Other Laboratory Assessments
Heading "Stool Sample (Fecal Calprotectin and Microbiota Metagenomic 
Analyses)"
Third paragraph, first sentence previously read:
Any remaining stool could be used for future exploratory analysis of non-genetic 
biomarkers related to the subject's disease and/or response to study drug or additional 
therapies, or development of AEs.
Has been changed to read:
Where allowed by local guidelines at the time of stool collection any remaining stool 
could be used for future exploratory analysis of non-genetic biomarkers related to the 
subject's disease and/or response to study drug or additional therapies, or development of 
AEs.
Section 5.3.3.2  Additional Efficacy Variables
Seventh bullet previously read:
●
Proportion of subjects who require weekly dosing at Week 2 of 
Study M14-347.


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Has been changed to read:
●
Proportion of subjects who require weekly dosing at Week 1 of 
Study M14-347.
Section 6.5  Adverse Event Reporting
"Primary Study Designated Physician:" contact information previously read:
Has been changed to read:


Adalimumab
M14-347 Protocol Amendment 2
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Section 6.5  Adverse Event Reporting
Fifth paragraph and contact information previously read:
Back-Up Study Designated Physician:
Has been changed to read:
Secondary Study Designated Physician:
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number: 
Phone:


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M14-347 Protocol Amendment 2
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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Statistics
Clinical
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical
Has been changed to read:
Name
Title
Functional Area
Statistics
Clinical
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical



SAP_001.pdf: 
Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
1
1.0
Title Page
Statistical Analysis Plan
Study M14-347
A Multicenter, Open-Label Study to Evaluate the 
Long Term Efficacy, Safety, and Tolerability of 
Repeated Administration of Adalimumab in Subjects 
with Crohn's Disease
Date:  13 Nov 2017
Version 1.0


Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 5
4.3
Sample Size.......................................................................................... 13
5.0
Analysis Populations ........................................................... 13
5.1
Definition for Analysis Populations ...................................................... 13
5.2
Variables Used for Stratification of Randomization .............................. 13
6.0
Analysis Conventions .......................................................... 13
6.1
Missing Dates Imputation..................................................................... 24
6.2
Dealing with Multiple Measurements Collected on the Same Day ........ 24
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............25
7.1
Demographic and Baseline Characteristics ........................................... 25
7.2
Medical/Surgical History...................................................................... 27
7.3
Prior and Concomitant Medications...................................................... 27
8.0
Patient Disposition............................................................... 28
9.0
Study Drug Exposure and Compliance.............................. 29
9.1
Study Drug Exposure ........................................................................... 29
9.2
Study Drug Compliance ....................................................................... 29
10.0
Efficacy Analysis .................................................................29
10.1
General Considerations......................................................................... 29
10.2
Primary Efficacy Analyses ................................................................... 30
10.3
Additional Efficacy Analyses ............................................................... 30
10.4
Handling of Multiplicity....................................................................... 35
10.5
Efficacy Subgroup Analysis ................................................................. 35
11.0
Safety Analysis.....................................................................36
11.1
General Considerations......................................................................... 36
11.2
Analysis of Adverse Events.................................................................. 36


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M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
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11.2.1
Treatment-Emergent Adverse Events.................................................... 37
11.2.2
Adverse Event Overview...................................................................... 37
11.2.2.1
Adverse Events by System Organ Class and Preferred Term ................ 38
11.2.2.2
Adverse Events by Maximum Severity................................................. 38
11.2.2.3
Adverse Events by Maximum Relationship .......................................... 38
11.2.2.4
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation................................................ 39
11.2.2.5
Frequent (≥ 5%) Adverse Events by Preferred Term in Decreasing 
Frequency............................................................................................. 39
11.2.2.6
Reasonably Possibly Related Adverse Events by System Organ 
Class and Preferred Term ..................................................................... 39
11.2.2.7
Reasonably Possibly Related Serious Adverse Events by System 
Organ Class and Preferred Term........................................................... 39
11.2.2.8
Adverse Events of Special Interests...................................................... 39
11.2.2.9
Adverse Events by 100 Patient Years ................................................... 41
11.2.2.10
Listing of Adverse Events..................................................................... 42
11.3
Analysis of Laboratory Data................................................................. 42
11.4
Analysis of Vital Signs and Weight ...................................................... 43
11.5
Analysis for Other Safety Variables...................................................... 44
11.6
Safety Subgroup Analysis..................................................................... 44
12.0
Summary of Changes .......................................................... 44
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 44
13.0
Appendix.............................................................................. 46
13.1
Crohn's Disease Activity Index (CDAI)................................................ 46
13.2
Simple Endoscopic Score – CD (SES-CD) ........................................... 48
13.3
Inflammatory Bowel Disease Questionnaire (IBDQ) ............................ 49
13.4
Work Productivity and Activity Impairment Questionnaire:  
Crohn's Disease (WPAI-CD)................................................................ 59
13.5
EQ-5D Questionnaires.......................................................................... 61
13.6
Abdominal Pain Rating Scale ............................................................... 63
14.0
References............................................................................64


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M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
4
List of Tables
Table 1.
Inadequate Response .............................................................................. 7
Table 2.
Study Activities.................................................................................... 10
Table 3.
Visit Windows for Analysis of Efficacy Variables (Except IBDQ, 
EQ-5D, WPAI, and SES-CD), Laboratory Parameters, and Vital 
Signs .................................................................................................... 15
Table 4.
Visit Windows for Analysis of IBDQ, EQ-5D, WPAI, and 
Abdominal Pain Rating Scale ............................................................... 15
Table 5.
Visit Windows for SES-CD.................................................................. 15
Table 6.
An EQ-5D-5L Value Set for England ................................................... 23
Table 7.
Criteria for Potentially Clinically Significant Vital Sign Findings......... 44
List of Figures
Figure 1.
Dose Adjustment Algorithm................................................................... 8


Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
5
3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Clinical Statistics Department for Study M14-347.
It provides details to further elaborate statistical methods as outlined in the protocol and 
describes analysis conventions to guide the statistical programming work.
This analysis plan describes the primary and secondary efficacy analyses as well as the 
safety analysis of data except pharmacokinetic, serological and mRNA biomarkers which 
will be analyzed separately.  It takes into account ICH Guidelines E3 and E9.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to evaluate the long-term efficacy, safety, and 
tolerability of repeated administration of adalimumab in subjects with Crohn's disease 
(CD) who participated in and successfully completed Study M14-115.
The secondary objective is to assess pharmacokinetics (PK) and immunogenicity of 
adalimumab following subcutaneous (SC) administration.
4.2
Design Diagram
This is a Phase 3, multicenter, open-label extension (OLE) study which comprises a 
40-week open-label period designed to evaluate the long-term efficacy, safety, and 
tolerability of adalimumab.  252 adult subjects who participated and successfully 
completed Study M14-115 Induction were enrolled into this study. 
Subjects were evaluated for entry into Study M14-347 at the final study visit (Week 12) of 
Study M14-115.  A subject's participation in the study was anticipated to be up to 


Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
6
40 weeks.  There was a ± 3-day window for all study visits.  An effort was made to bring 
the subject back to their original study visit (calculated from Week 0) if they were out of 
the visit window. 
Study visits for clinical and safety assessments were performed at Weeks 0, 8, 16, 24, 32 
and 40/Premature Discontinuation (PD).  All subjects were provided with a paper subject 
diary in which they could record CD-related symptoms (number of liquid or very soft 
stools, abdominal pain rating, and general well-being) and adalimumab dosing 
information throughout the study.  Blood samples were collected at various time points 
for routine labs, along with hs-CRP, adalimumab serum concentrations, anti-adalimumab 
antibody (AAA) levels and other biomarker analyses.  In addition, stool samples for 
calprotectin and microbiota were collected.  The stool samples were taken before starting 
bowel preparations for endoscopy.  Endoscopic evaluation were performed at 
Week 40/PD, if the PD occurred after Week 24.  CDAI evaluations were calculated based 
on entries recorded into the subject's diary at all study visits.  The SFPS 
(Stool [liquid/soft] Frequency + Abdominal Pain Score) were calculated using the 
weighted values for the CDAI components "Number of liquid or very soft stools" and 
"Abdominal pain."
All subjects received open-label adalimumab 40 mg every other week (eow) beginning at 
Week 0.  No dose was administered at Week 40.  Subjects might be escalated to 
adalimumab 40 mg every week (ew) at or after Week 1 should the subject met the criteria 
for inadequate response (Table 1).


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M14-347 – Statistical Analysis Plan
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7
Table 1.
Inadequate Response
Response Type
Definition
Inadequate response
Crohn's disease activity index (CDAI) of ≥ 200 at any one visit and at least 
one of the following criteria is met:  an increase of at least 1 mg/L in level of 
high-sensitivity C-reactive protein (hs-CRP) from Baseline or an hs-CRP 
≥5 mg/L.  The hs-CRP results used to determine inadequate response can be 
from the prior or current visit.  Assessment of inadequate response should 
include consideration by the Investigator to rule out symptoms caused by 
reasons other than Crohn's disease related inflammation.
For subjects taking corticosteroids at Baseline of Study M14-115 adalimumab dose 
escalation was considered in lieu of increases in steroid dose.  Subjects who continued to 
experience inadequate response on 40 mg ew who were taking corticosteroids at Baseline 
of Study M14-115 might have their steroid dose increased, per the Investigator's 
discretion, in order to manage the subject's symptoms.  Any subject who continued to 
experience inadequate response on 40 mg ew might be discontinued from the study at the 
investigator's discretion after discussion with the study designated physician (SDP).
Subjects who dose escalated to adalimumab 40 mg ew, had one opportunity to de-escalate 
adalimumab dose to 40 mg eow provided the following criteria had been met:  CDAI 
< 200 and high-sensitivity C-reactive protein (hs-CRP) value equal to or lower than that 
observed at the time of dose escalation.  Subjects who experienced inadequate response 
after dose de-escalation (using the same criteria outlined above), might again be escalated 
to 40 mg ew.  A subject had only one opportunity to dose de-escalate and one opportunity 
to re-escalate to ew adalimumab dosing.
Changes in adalimumab dosing might only occur when the above criteria were met but 
were not mandatory.  A schematic for dose adjustments is presented in Figure 1. 


Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
8
Figure 1.
Dose Adjustment Algorithm
Subjects might discontinue adalimumab treatment at any time during study participation 
(Section 5.4).  Subjects would be discontinued from the study if they withdraw consent or 
if they were deemed unsuitable to continue for any reason by the Investigator.  Subjects 
who ended study participation early would have a PD visit.  All subjects were to have a 
follow-up phone call approximately 70 days after the last administration of study drug to 
obtain information on any new or ongoing adverse events (AEs).  The 70-day follow-up 
phone call would not be required for any subject who initiated commercial adalimumab.


Adalimumab
M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
9
Clinical evaluation was completed at each study visit.  See activities outlined in Table 2.
Throughout the study, subjects were only allowed to change the dosage of CD-specific 
concomitant medications as specified below:
●
Immunosuppressant doses might be decreased or terminated in the event of 
moderate-to-severe treatment-related toxicities.
●
Subjects who were taking corticosteroid therapy at Baseline of Study M14-115 
should continue the steroid taper initiated during Study M14-115.  Increases in 
steroid doses back to the dose used at Baseline of Study M14-115 to manage 
inadequately controlled CD-related symptoms might be undertaken at the 
Investigator's discretion in subjects who were receiving adalimumab 40 mg 
ew.
For subjects taking adalimumab 40 mg eow, adalimumab dose escalation (for 
subjects who meet inadequate response criteria) were to be considered in lieu 
of increases in the steroid dose.


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M14-347 – Statistical Analysis Plan
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Table 2.
Study Activities
Activity
Baseline 
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Call1
Informed Consent
X
Inclusion/Exclusionb
X
Medical/Surgery History Updateb
X
Previous and Concomitant Medication Updateb
X
X
X
X
X
X
X
Vital Signs
Xa
X
X
X
X
X
X
Endoscopyc
Xa
X
SES-CD Score
Xa
X
Physical Examinationd
Xa
X
X
X
X
X
X
Urinalysise
Xa
X
X
X
X
X
X
Pregnancy Testsf
Xa
X
Chemistry and Hematologyh
Xa
X
X
X
X
X
X
hs-CRP
Xa
X
X
X
X
X
X
Provide Stool Kitg
X
X
X
X
X
X
Stool Sample (fecal calprotectin)g
Xa
X
X
X
X
X
X
Stool Sample (microbiota metagenomic analyses)g
Xa
X
X
Bristol Stool Scale for Metagenomic Analysisg
Xa
X
X
Adalimumab Concentrationh
Xa
X
X
X
X
X
X
AAA Concentrationh
Xa
X
X
X
Serological Biomarkers/mRNA
Xa
X
X
Crohn's Disease Activity Index (CDAI)
Xa
X
X
X
X
X
X


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M14-347 – Statistical Analysis Plan
Version 1.0 – 13 Nov 2017
11
Table 2.
Study Activities (Continued)
Activity
Baseline 
(Week 0)a
Week 8
Week 16
Week 24
Week 32
Week 40/ 
Premature 
Discontinuation
Unscheduled 
Visitk
70-Day 
Follow-Up 
Call1
Inflammatory Bowel disease Questionnaire (IBDQ)
Xa
X
X
X
European Quality of Life 5 dimensions (EQ-5D)
Xa
X
X
X
Work Productivity and Impairment Questionnaire
(WPAI)
Xa
X
X
X
Abdominal Pain Rating Scale
Xa
X
X
X
Monitor Adverse Eventsi
Xa
X
X
X
X
X
X
X
Study Drug Dispensing/Administrationj
X
X
X
X
X
Subject Diary Review
Xm
X
X
X
X
X
X
Chest X-Ray (for patients in Ukraine only)n
X
a.
Information from the activities completed at Week 12 of Study M14-115 will be carried over to the Baseline visit and will serve as the reference for all subsequent visits.  A 
± 3-day window is permitted around scheduled study visits.
b.
Inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information will be assessed to assure subject eligibility.
c.
An ileocolonoscopy will be performed at Week 40/PD, if the PD occurs after Week 24.  A biopsy will be performed at Week 40/PD if a suspicious lesion or suspected 
malignancy, in the assessment of the Investigator, is observed, and evaluated by the local pathologist.  Biopsies to evaluate suspicious lesions and to rule out malignancy may 
be taken during any study endoscopy per the Investigator's discretion and evaluated by the local pathologist.
d.
Physical examination performed at Week 40/Premature Discontinuation Visit is a full physical examination which must include an assessment of extra-intestinal 
manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations performed at all other visits are symptom based and must include a count of the 
number of cutaneous fistulas.
e.
Dipstick urinalysis will be completed by the sites at all required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results 
show protein, ketones or blood greater than negative or glucose greater than normal.


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Table 2.
Study Activities (Continued)
f.
Urine pregnancy test results from Week 12 of Study M14-115 will be carried over to the Baseline Visit.  Urine pregnancy test will be performed at Week 40/PD for all 
women of childbearing potential.  The frequency can be increased up to every visit as per local regulations.  If any urine pregnancy test is positive, a serum pregnancy test will 
be performed by the central laboratory.
g.
A stool sample will be collected for fecal calprotectin and metagenomic analysis at each time points indicated.  Subjects will be sent home with instructions and a stool 
sample supply kit (supplies will be provided at the time points indicated).  The stool from which these samples are prepared should be scored using the Bristol stool scale by 
site.  Stool samples for metagenomic analysis should be collected before any bowel preparation for endoscopy is started and returned to the site within 3 days of collection.
h.
Blood samples for the measurement of adalimumab and anti-adalimumab antibody (AAA) concentrations will be collected prior to dosing. If the subject is dose escalating or 
de-escalating, blood samples will be taken prior to dosing for the measurement of adalimumab and AAA concentrations which may occur at an unscheduled visit.
i.
Collection of serious adverse events (SAEs) begins the day the subject signs the informed consent.
j.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
k.
Visits for dispensing new study drug in case of temperature excursion, loss, damage, or dose escalation are not considered an Unscheduled Visit. In addition, visits to retest a 
lab will not be considered an Unscheduled Visit.  Unscheduled visits can be used for situations including the following:  For evaluation and assessment of the subject, to 
evaluate a subject who meets criteria for inadequate response as outlined in Table 1, to collect samples to determine hs-CRP in those subjects, and to collect PK samples for a 
change in adalimumab dosing.
l.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who continue on commercial 
adalimumab therapy after the end of study participation.
m.
Sites will review the electronic diary utilized and collected from Week 12 of Study M14-115 to obtain the number of liquid or very soft stools, abdominal pain rating, general 
well-being and adalimumab dosing information.  A new paper subject diary will be dispensed to subjects at Baseline.  All subjects should complete their subject diary on a 
daily basis throughout the entire study, including if and when hospitalized whenever possible.  The diary will be reviewed by site personnel with the subject at each visit and 
collected at the Final/PD visit.
n.
For patients in Ukraine only. Chest x-ray should be performed up to two weeks prior to the Week 24 visit, as a screening measure for newly developed/reactivated TB.  In 
case diagnosis of TB is established following further assessments, such patients should be immediately discontinued from the study (as a consequence of diagnosis of TB).  
Procedures as per Section 5.4.1 "Discontinuation of Individual Subjects" should be applied in such cases.


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4.3
Sample Size
No sample was calculated for this study.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The following populations will be used for analyses in the study:
Intent-to-Treat Analysis Set
The Intent-to-treat (ITT) analysis set consists of all subjects who enrolled into the study 
and received at least one injection of study drug.
Safety Analysis Set
The Safety analysis set will include all subjects who receive at least one injection of study 
drug during the study.  
For analysis purpose, these two populations are same.
5.2
Variables Used for Stratification of Randomization
There is no randomization for this open-label study.
6.0
Analysis Conventions
Definition of Week 0
The Week 0 visit date is the date when the first dose of Study M14-347 study drug is 
received and referred to as Day 1 or Week 0.  The Week 0 value for a variable is defined 
as the last non-missing value on or before the date of the first dose of Study M14-347 
study drug.


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Definition of Rx Days (Days Relative to the First Dose of Study Drug)
The Rx Day is calculated as the event date minus the date of first dose of study drug 
plus 1 when the time point of interest is after the date of first dose of study drug, or the 
event date minus the date of first dose of study drug when the time point of interest is 
prior to the date of first dose of study drug.  It provides a quantitative measure of days 
between the time point of interest and the first dose date.  The day of the first dose of 
study drug is defined as Rx Day 1, while the day prior to the first study drug dose is 
defined as Rx Day –1 (there is no Rx Day 0).
Dealing with Multiple Measurements Collected on the Same Day
For efficacy related analyses, if multiple measurements for a particular parameter are 
collected on the same day for the same subject, the average of those measurements will be 
used.
For safety related analyses, if multiple measurements are made for a particular laboratory 
or vital sign parameter on the same day for the same subjects, the later time one will be 
used if there is time or the average of the values will be used in the analyses of change 
from Baseline.  For summaries and listings for shift from baseline and potentially 
significant values, all collected values within the pre-specified treatment window will be 
used.
Definition of Analysis Windows
Since subjects do not always adhere to the study visit schedule, the following rules will be 
applied to assign actual visits to protocol-specified visits including early termination 
visits.  For each study visit mentioned in the protocol, a nominal or target day will be 
selected to represent the corresponding visit along with a window around the target day.  
Windows will be selected in a non-overlapping fashion so that a date collected on the case 
report form (CRF) does not correspond to multiple visit windows.  Moreover, windows 
will not discard any post-baseline measurement recorded on the CRF.  If a subject had 
2 or more actual visits in one visit window, the visit closest to the target will be used as 


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the study visit for that window.  If two visits are equidistant from the target day, then the 
later visit will be used for reporting. 
The visit windows and the nominal (target) day for each study visit are shown in the 
following tables.
Table 3.
Visit Windows for Analysis of Efficacy Variables (Except IBDQ, 
EQ-5D, WPAI, and SES-CD), Laboratory Parameters, and Vital 
Signs
Protocol Specified Visit 
Week
Lower Bound
Nominal Day
Upper Bound
0
–999
1
1
8
2
57
85
16
86
113
141
24
142
169
197
32
198
225
253
40
254
281
309
Table 4.
Visit Windows for Analysis of IBDQ, EQ-5D, WPAI, and 
Abdominal Pain Rating Scale 
Protocol Specified Visit 
Week
Lower Bound
Nominal Day
Upper Bound
0
–999
1
1
16
2
113
169
32
170
225
253
40
254
281
309
Table 5.
Visit Windows for SES-CD
Protocol Specified Visit 
Week
Lower Bound
Nominal Day
Upper Bound
0
–999
1
1
40
2
281
561
Note:
If an endoscopy was done within 7 days after first dose of Study M14-347, the SES-CD will still be used as 
Study M14-347 Baseline value.


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CD-Related Concomitant Therapy
Subjects in whom systemic corticosteroids that were not being taken at Baseline of 
Study M14-347 and are initiated during the study or who have dosages of corticosteroids 
increased to greater than the dose taken at Baseline of Study M14-115 will be censored 
for efficacy assessments (i.e., will be considered non-responders for categorical endpoints 
and will have Study M14-115 Baseline values carried forward for non-categorical 
assessments) from that point through the end of the study.  These subjects will continue to 
be evaluated in the safety population.
The equivalent steroid dose will be determined based on the table below:
Corticosteroid
Equivalent Dose (mg)
Cortisone
25
Hydrocortisone
20
Prednisone
5
Prednisolone
5
Triamcinolone
4.0
Methylprednisolone
4.0
Betamethasone
0.75
Dexamethasone
0.75
Budesonide
1
Beclomethasone
5
Beclometasone
5
If a subject met the censoring criteria for CD related concomitant therapy during 
Study M14-115, all binary efficacy endpoints will be No in Study M14-347, all observed 
values in Study M14-347 will be replaced by Study M14-115 Baseline values.
Dose Escalation
Subjects who had dose escalated to 40 mg ew will be censored for efficacy assessments 
(i.e., will be considered non-responders for categorical endpoints and will have 


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Study M14-115 Baseline values carried forward for non-categorical assessments) from 
that point through the end of the study.  
Definition of Missing Data Imputation
Missing data imputation will be done only for efficacy variables (categorical and 
continuous variables).  For the analysis other than efficacy, no imputation will be done for 
missing values.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy data.  These variables can take values of 
'Achieved' or 'Not Achieved' or may be missing for any reason including discontinuation 
from study.  According to the NRI imputation approach, all missing values will be 
considered as 'Not Achieved.' 
Observed Case (OC)
Observed case analysis will be performed such that missing values will not be imputed.  
However, all observed values will be replaced by Study M14-115 Baseline value once 
subjects met the censoring criteria for CD-related concomitant therapy or dose escalation, 
whichever is earlier.
Last Observation Carried Forward (LOCF)
For all variables (categorical variables and continuous variables), the following rules will 
be used for the LOCF approach:
1.
Baseline and Pre-Baseline values will not be used to impute the missing 
Post-Baseline values.
2.
Missing values after Study Day 1 will be imputed using the latest non-missing 
values after Day 1 and prior to the missing value.  If there are no non-missing 
values after Baseline, then the LOCF value will be missing.


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Rule for CDAI Calculation
Up to 14 days of diary entries will be evaluated for the CDAI calculation for each visit.  
The diary entries on the days the subjects receive endoscopy preparation medications, the 
day of endoscopy procedure, and 2 days after endoscopy procedure will be excluded.  For 
each CDAI subscore, the available scores from the most recent diary days (at least 4 days, 
up to 7 days) prior to actual day of the study visit will be summed, and then multiplied by 
the corresponding multiplier to get subtotal score.  If available diary entries are fewer than 
7 days, the subtotal score will be calculated as (summed total available score/number of 
days) × 7 × corresponding multiplier.  The three subtotal scores (number of liquid/very 
soft stools, abdominal pain rating, and general well-being) will then be rounded to 
one decimal.  The final CDAI is rounded to a whole number.
If a subject has less than 4 days of diary data, the total CDAI score will not be calculated 
and will be considered missing.
SFPS
SFPS is the CDAI components "Number of liquid or very soft stools" and "Abdominal 
pain" (Stool [liquid/soft] Frequency + Abdominal Pain Score).  The sub-total score for 
each component is calculated as the sum of the 7 day diary score multiplied by the 
corresponding multiplier using the same rule for CDAI calculation.
If a subject has less than 4 days of diary data, the SFPS will not be calculated and will be 
considered missing.
SES-CD Scoring
All colonoscopies shall be performed and recorded in video format.  Investigators shall 
provide their SES-CD assessment on the SES-CD sheet for the baseline and 
Week 40/Premature Discontinuation visits.  The investigator SES-CD are to be entered in 
the appropriate eCRF, however neither the Investigator's Induction Baseline nor Week 40 
SES-CD will be used for the study's efficacy analyses.


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Two primary central reviewers will evaluate the videotaped colonoscopies separately and 
provide their SES-CD to Parexel.  A third central reviewer will adjudicate between the 
two initial reviewers' SES-CD if there is discrepancy in any SES-CD variable.  The 
adjudicator will select the final SES-CD that he/she most agrees with from those provided 
by the two primary reviewers, and this final SES-CD will be entered into the study 
database and be used for the study's efficacy analyses.  If there is no discrepancy between 
the two primary central reviewers, that score will be entered into the study database and 
serve as the SES CD to be used for the study's efficacy analyses.
If there is a missing SES-CD individual variable in the SES-CD that serves as the SES-
CD for the study's efficacy analyses, the following imputation rules will be applied:
The missing SES-CD individual variables at Study M14-115 Baseline will be imputed 
as 0.  Study M14-115 Baseline SES-CD will be used to determine endoscopic 
improvement.
The missing SES-CD individual variables for Study M14-347 Week 0 or Study M14-347 
Week 40 will be imputed as 0 if there are 8 or fewer missing individual variables.  If more 
than 8 individual variables are missing, the total SES-CD will be missing for that visit.
Hs-CRP
From November 2014 to December 2015, Roche hs-CRP kit lot 604450 was in use at 
ICON.  In December 2015 ICON altered the study team of a bias in the lot of the Roche 
Diagnostic C-creative protein high sensitive reagent.  ICON then informed the study team 
of the extent of the under recovery in March 2016.  This lot was "retrospectively expired" 
as the low standard beads agglutinated causing specimen results that are below 5 mg/L to 
be up to 25% lower than the accurate value.  ICON later determined with Roche that the 
affected samples were those tested from May 18, 2015 to December 2015.
In the Study M14-347 approximately 146 samples were affected according to ICON.  
AbbVie obtained the final listing of affected samples/results from ICON on 
August 10, 2016.  A correction factor developed by Roche and ICON will be applied to 


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all affected specimens with a concentration between 0.51 to 4.99 mg/L and will replace 
the initially provided hs-CRP values in the study database.  
For Study M14-347, both Roche and Abbott platform are used to measure hs-CRP.  The 
study team has decided to use Abbott platform for CSR analysis.  If hs-CRP was 
measured by Roche platform only, the value will be converted to Abbott equivalent by a 
conversion factor.
Definition of Endoscopic Improvement
SES-CD ≤ 4 and at least two point reduction from Study M14-115 Baseline and no 
subscore > 1 in any individual variable.
Definition of CDAI Remission
CDAI < 150
Definition of SFPS Remission
SFPS < 50
Definition of CDAI Response
Decrease in CDAI ≥ 70 points from Study M14-115 Baseline
Definition of Enhanced CDAI Response
Decrease in CDAI ≥ 100 points from Study M14-115 Baseline
Definition of Endoscopic Response
Decrease in SES-CD > 50% from Study M14-115 Baseline
Definition of IBDQ Response
Increase in IBDQ ≥ 16 from Study M14-115 Baseline


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Definition of IBDQ Remission
IBDQ ≥ 170
Definition of Symptomatic Remission
Average daily stool frequency ≤ 1.5 and not worse than Study M14-115 Induction 
baseline AND average daily abdominal pain ≤ 1.0 and not worse than Study M14-115 
Induction baseline.
Definition of Symptomatic Response
Average daily stool frequency at least 30% reduction from Study M14-115 Induction 
baseline and average daily abdominal pain not worse than Study M14-115 Induction 
baseline OR average daily abdominal pain at least 30% reduction from Study M14-115 
Induction baseline and average daily stool frequency not worse than Study M14-115 
Induction baseline.
Discontinued Corticosteroid Use at Each Visit Among Subjects Who Used 
Corticosteroids at Week 0 of Study M14-347
Discontinued steroid use at each visit is based on the steroid use on the date of CDAI 
measurement for that visit.  If the subject has no CDAI for the visit, the steroid use on the 
nominal day for that visit (Table 3) will be evaluated.
If a subject discontinued the study, 'discontinued corticosteroid use' will be classified as 
No from that point through the end of the study.
If a subject met censoring criteria for CD-related concomitant therapy or dose escalation, 
whichever is earlier, 'discontinued steroid use' will be classified as No from that point 
through the end of the study.
EuroQol-5D-5L (EQ-5D)
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  


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The EQ-5D consists of 2 pages.  The first page measures 5 dimensions of the health status 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with 
5 levels per dimension (no problems, slight problems, moderate problems, severe 
problems, and unable corresponding to Level 1 to Level 5 respectively).  The second page 
is an EQ Visual Analogue Scale (EQ VAS).  EQ-5D health states, defined by the 
EQ-5D-5L descriptive system on the first page, may be converted into a single index 
value.  The change from baseline of the index value and EQ VAS will be analyzed and 
reported.  UK scoring algorithm will be used (Table 7).


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Table 6.
An EQ-5D-5L Value Set for England
Central Estimate
Value for Health State 23245
Mobility
No Problem
Slight
Moderate
Severe
Unable
0
0.051
0.063
0.212
0.275
0.051
Self-Care
No Problem
Slight
Moderate
Severe
Unable
0
0.057
0.076
0.181
0.217
0.076
Usual Activities
No Problem
Slight
Moderate
Severe
Unable
0
0.051
0.067
0.174
0.190
0.051
Pain/Discomfort
No
Slight
Moderate
Severe
Unable
0
0.060
0.075
0.276
0.341
0.276
Anxiety/Depression
Not
Slight
Moderate
Severe
Unable
0
0.079
0.104
0.296
0.301
0.301
The value for health state 23245:
1 – 0.9675 × (sum of the subscores)
1 – 0.9675 × (0.051 + 0.076 
+ 0.051 + 0.276 + 0.301) = 0.270
The index value is 1 – 0.9675 × sum of 5 components based on central estimates.
The minimum index value is – 0.281 (health state 55555), and the maximum index value 
is 1 (health state 11111).  (Reference:  Devlin N, Shah KK, Feng Y, et al.  Valuing health-
related quality of life:  an EQ-5D-5L value set for England.  Health Econ.  2017.).


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If one of the 5 dimensions is missing, the EQ-5D index value will be missing.
CD Related Hospitalizations and Major CD Related Events
CD related hospitalizations and major CD related events will be adjudicated according to 
the hospitalization adjudication charter.
6.1
Missing Dates Imputation
For Baseline, efficacy, and safety parameters, if the day and/or month are missing, the 
following conventions will be used to impute the missing dates:
●
01 for missing start day
●
End of month for missing end day
●
January 1st for missing start month
●
December 31st for missing end month
In case of partially missing AE start and stop dates, the dates will be imputed by 
comparing to first dose date of study medication so that the corresponding AEs will be 
made treatment-emergent whenever possible.  If the start date of an AE is partially 
missing and the month is the same as the start date of a new therapy, the AE will be made 
treatment emergent to the new therapy.
In case of missing or partially missing study drug dosing dates, the dates will not be 
imputed and subjects will be treated as not receiving dose on that date. 
6.2
Dealing with Multiple Measurements Collected on the Same 
Day
For efficacy related analyses other than imaging endpoints, if multiple measurements for a 
particular parameter are collected on the same day for the same subject, the average of 
those measurements will be used.


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For safety related analyses, if multiple measurements are made for a particular laboratory 
or vital sign parameter on the same day for the same subjects, the average of the values 
will be used in the analyses of change from Baseline.  For summaries and listings for shift 
from baseline and potentially significant values, all collected values within the pre-
specified treatment window will be used.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
The following demographic and Study M14-115 baseline characteristics will be 
summarized by treatment group. 
Continuous Variables:
●
Age (years)
●
Body weight (kg)
●
Height (cm)
●
Body Mass Index (kg/m2)
●
Blood Pressure (systolic/diastolic) (mmHg)
●
Pulse (bpm)
●
Respiratory Rate (RPM)
●
Temperature (°C)
●
CDAI
●
SFPS
●
Total SES-CD
●
Crohn's Disease Duration (years)
●
IBDQ score
●
WPAI and its components
●
EQ-5D
●
Abdominal Pain Rating Scale


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●
hs-CRP mg/L
●
Fecal calprotectin μg/g
Categorical Variables:
The baseline used for the following categorical variables is defined as the baseline in 
Study M14-115.
●
Sex (male, female)
●
Race
●
Ethnicity
●
Age (≤ median, > median)
●
Age (< 40, 40 to < 65, 65 to < 75, ≥ 75)
●
Baseline fecal calprotectin (≤ median, > median)
●
Baseline fecal calprotectin (≤ 250 μg/g, > 250 μg/g)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
hs-CRP at Baseline (≤ median, > median)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline
●
Baseline CDAI (≤ median, > median)
●
Baseline SES-CD (≤ median, > median)
●
Prior infliximab use (yes, no)
●
Weight (≤ median, > median)
●
Baseline albumin (≤ median, > median)
●
Disease duration (≤ median, > median)
●
Disease duration (≤ 3 years, > 3 years)
●
Tobacco use (user, ex-user, never used, unknown)
●
Alcohol use (drinker, ex-drinker, non-drinker, unknown)
●
Region (US, ex-US)


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●
Study M14-115 induction dose (higher, standard) [will be performed after 
Study M14-115 database lock.]
Demographic and Baseline characteristics will be summarized with descriptive statistics 
for the ITT analysis set.  The number of non-missing observations, mean, standard 
deviation, median, minimum and maximum will be summarized for continuous variables.  
The counts and percentages will be summarized for categorical variables. 
7.2
Medical/Surgical History
Medical/Surgical history data will be summarized using body systems and 
conditions/diagnoses as captured on the CRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  Subjects reporting more than one condition/diagnosis within a 
body system will be counted only once for that body system.
7.3
Prior and Concomitant Medications
The number and percent of subjects who received a prior or concomitant medication will 
be tabulated by the generic name assigned by the most current version of the World 
Health Organization (WHO) Drug Dictionary in alphabetical order for prior and 
concomitant medications, respectively.   
A prior medication is defined as any medication taken prior to the first dose of study drug 
of Study M14-115 and collected in the CRF.  A concomitant medication is defined as any 
medication other than study drug that (1) was started prior to the first dose of study drug 
of Study M14-347 and continued to be taken after the first dose of study drug or (2) was 
started after the first dose of study drug, but was not started after the last dose of study 
drug.  A particular medication may be classified as "prior" or "concomitant" or "both."
The prior and concomitant medications will be summarized for ITT analysis set.


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Concomitant medications at baseline include prior medications that have a start date 
before first dose of study drug and are ongoing or have a stop date after first dose of study 
drug.
The number and percent of subjects using Crohn's disease specific medications (including 
corticosteroids [0, ≤ 10 mg, ≤ 20 mg, or ≤ 30 mg prednisone equivalents], 
aminosalicylates, immunomodulators [defined as azathioprine, mercaptopurine, or 
methotrexate], and antibiotics) prior to Study M14-115 Baseline, and at Study M14-115 
Baseline will be tabulated.  In addition, the number and percent of subjects using 
infliximab at any time prior to Study M14-115 Baseline will be tabulated.
8.0
Patient Disposition
The number of subjects will be tabulated by country, investigator site and overall for the 
following sets:  
●
ITT analysis set 
●
Safety analysis set 
●
Subjects who completed study 
●
Subjects who prematurely discontinued study drug
In addition, the number and percentage of subjects who discontinued study drug will be 
summarized by primary reason and by any reason as recorded on the eCRF:   
●
Adverse event (AE) 
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Requires alternative (or prohibited) therapy
●
Subject non-compliance
●
Other


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Subjects may have more than one reason for discontinuing study drug, but they will be 
counted once for the total number of discontinuations.  Subjects have only one primary 
reason for discontinuing study drug or discontinuing from the study.
9.0
Study Drug Exposure and Compliance
9.1
Study Drug Exposure
The duration of exposure to study drug will be summarized using the mean, standard 
deviation, minimum, median, and maximum for the safety population.  Duration of 
exposure is defined for each subject as number of days since first dose of study drug 
through the last study drug dose date + 70 days.  Study drug dose date refers to recorded 
dates of injections of study drug. 
9.2
Study Drug Compliance
The treatment compliance (%) of study drug will be summarized using the mean, standard 
deviation, minimum, median, and maximum for safety population.  The compliance rate 
will be calculated as follows:
Compliance rate (%) = the total number of injection received/the total number of injection 
expected * 100
10.0
Efficacy Analysis
10.1
General Considerations
For all efficacy endpoints, the descriptive statistics including number of observations, 
mean, standard deviation, minimum, median, and maximum for continuous variables; and 
number and percent for discrete variables, will be summarized for ITT analysis set.  No 
statistical tests will be performed. 


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10.2
Primary Efficacy Analyses
The primary efficacy variable is the proportion of subjects with endoscopic improvement 
at Week 40 among subjects with endoscopic improvement at Week 0 of Study M14-347. 
A two-sided 95% confidence interval will be calculated for ITT analysis set.  Missing 
SES-CD at Week 40 will be imputed using non-responder imputation (NRI) approach.  
The LOCF method will be used as the sensitivity analyses.
10.3
Additional Efficacy Analyses
For additional efficacy endpoints, the baseline is defined as the Baseline in 
Study M14-115.  The additional efficacy variables are listed as below.
●
Proportion of subjects with CDAI remission (CDAI < 150) over time among 
subjects with CDAI remission at Week 0 of Study M14-347.
●
Proportion of subjects with endoscopic improvement, defined as an SES-CD 
≤4 and at least 2 point reduction versus Study M14-115 Baseline and no 
subscore greater than 1 in any individual variable at Week 40.
●
Proportion of subjects with CDAI remission (CDAI < 150) over time.
●
Proportion of subjects with CDAI < 150 at Week 40 and SES-CD ≤ 4 and at 
least a 2 point reduction versus Study M14-115 Baseline and no subscore 
greater than 1 in any individual variable at Week 40 among subjects with 
CDAI < 150 at Week 0 and SES-CD ≤ 4 and at least a 2 point reduction versus 
Study M14-115 Baseline and no subscore greater than 1 in any individual 
variable at Week 0 of Study M14-347.
●
Proportion of subjects with CDAI < 150 at Week 40 and SES-CD ≤ 4 and at 
least a 2 point reduction versus Study M14-115 Baseline and no subscore 
greater than 1 in any individual variable at Week 40.
●
Proportion of subjects with endoscopic response at Week 40 among subjects 
with endoscopic response at Week 0 of Study M14-347.
●
Proportion of subjects with endoscopic response at Week 40.
●
Change from Study M14-115 Baseline in fecal calprotectin level over time.


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●
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g 
over time among subjects with hs-CRP < 5 mg/L and fecal calprotectin 
< 250 μg/g at Week 0 of Study M14-347.
●
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g 
over time.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal 
calprotectin < 250 μg/g over time among subjects with CDAI < 150, hs-CRP 
< 5 mg/L, and fecal calprotectin < 250 μg/g at Week 0 of Study M14-347.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal 
calprotectin < 250 μg/g over time.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and 
at least 2 point reduction versus Study M14-115 Baseline and no subscore 
greater than 1 in any individual variable, and fecal calprotectin < 250 μg/g at 
Week 40 among subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 
and at least 2 point reduction versus Study M14-115 Baseline and no subscore 
greater than 1 in any individual variable, and fecal calprotectin < 250 μg/g at 
Week 0 of Study M14-347.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and 
at least 2 point reduction versus Study M14-115 Baseline and no subscore 
greater than 1 in any individual variable, and fecal calprotectin < 250 μg/g at 
Week 40.
●
Proportion of subjects with SES-CD ≤ 2 at Week 40 among subjects with 
SESCD ≤ 2 at Week 0 of Study M14-347.
●
Proportion of subjects with SES-CD ≤ 2 at Week 40.
●
Proportion of subjects with CDAI response (decrease in CDAI ≥ 70 points 
from Study M14-115 Baseline) over time among subjects with CDAI response 
at Week 0 of Study M14-347.
●
Proportion of subjects with CDAI response (decrease in CDAI ≥ 70 points 
from Study M14-115 Baseline) over time.
●
Proportion of subjects with enhanced CDAI response (decrease in CDAI 
≥100 points from Study M14-115 Baseline) over time among subjects with 
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●
Proportion of subjects with enhanced CDAI response (decrease in CDAI 
≥100 points from Study M14-115 Baseline) over time.
●
Change in IBDQ from Study M14-115 Baseline over time.
●
Proportion of subjects who discontinue corticosteroid use at each visit among 
subjects who used corticosteroids at Week 0 of Study M14-347.
●
Proportion of subjects who achieve CDAI remission and discontinue 
corticosteroid use at each visit among subjects who used corticosteroids at 
Week 0 of Study M14-347.
●
Proportion of subjects with a SFPS remission (SFPS < 50) over time among 
subjects with SFPS remission at Week 0 of Study M14-347.
●
Proportion of subjects with a SFPS remission (SFPS < 50) over time.
●
Proportion of subjects with a SFPS remission (SFPS < 50) over time among 
subjects with SFPS ≥ 100 at Week 0 of Study M14-347.
●
Proportion of subjects with SES-CD ≤ 3 and at least 2 point reduction versus 
Study M14-115 Baseline and no subscore greater than 1 in any individual 
variable at Week 40 among subjects with SES-CD ≤ 3 and at least 2 point 
reduction versus Study M14-115 Baseline and no subscore greater than 1 in 
any individual variable at Week 0 of Study M14-347.
●
Proportion of subjects with SES-CD ≤ 3 and at least 2 point reduction versus 
Study M14-115 Baseline and no subscore greater than 1 in any individual 
variable at Week 40 
●
Proportion of subjects with SES-CD = 0 at Week 40 among subjects with 
SESCD = 0 at Week 0 of Study M14-347.
●
Proportion of subjects with SES-CD = 0 at Week 40.
●
Proportion of subjects with a decrease of SES-CD ≥ 3 points from 
Study M14-115 Baseline at Week 40 among subjects with a decrease of SES-
CD ≥ 3 points from Study M14-115 Baseline at Week 0 of Study M14-347.
●
Proportion of subjects with a decrease of SES-CD ≥ 3 points from 
Study M14-115 Baseline at Week 40.
●
Proportion of subjects with a decrease in SES-CD > 50% from Study M14-115 
Baseline (or for subjects with an SES-CD of 4 at Study M14-115 Baseline, at 
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subjects with a decrease in SES-CD > 50% from Study M14-115 Baseline (or 
for subjects with an SES-CD of 4 at Study M14-115 Baseline, at least a 
2-point reduction from Study M14-115 Baseline) at Week 0 of 
Study M14-347.
●
Proportion of subjects with a decrease in SES-CD > 50% from Study M14-115 
Baseline (or for subjects with an SES-CD of 4 at Study M14-115 Baseline, at 
least a 2-point reduction from Study M14-115 Baseline) at Week 40. 
●
Change from Study M14-115 Baseline in hs-CRP level over time.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (decrease ≥ 16 points from Study M14-115 Baseline) over 
time among subjects with Inflammatory Bowel Disease Questionnaire (IBDQ) 
response (decrease ≥ 16 points from Study M14-115 Baseline) at Week 0 of 
Study M14-347.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (decrease ≥ 16 points from Study M14-115 Baseline) over 
time.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) over time 
among subjects with IBDQ remission (IBDQ ≥ 170 points) at Week 0 of 
Study M14-347.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) over time.
●
Change in WPAI from Study M14-115 Baseline over time.
●
Change in European Quality of Life 5 Dimensions (EQ-5D) from 
Study M14-115 Baseline over time.
●
Change in CDAI from Study M14-115 Baseline over time.
●
Change in SFPS from Study M14-115 Baseline over time.
●
Change in Abdominal Pain Rating Scale score from Study M14-115 Baseline 
over time.
●
Change in each CDAI component subscore (number of liquid or very soft 
stools, abdominal pain rating, general well-being, CD related complications, 
anti-diarrhea use, abdominal mass, hematocrit, body weight) from 
Study M14-115 Baseline over time.
●
Time to first dose escalation.


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●
Proportion of subjects who require weekly dosing at Week 1 of 
Study M14-347.
●
Proportion of subjects with major CD related event (e.g., hospitalization, 
bowel surgery, abscess drainage).
●
Proportion of subjects with CD related hospitalization.
●
Proportion of subjects with CD related surgery.
●
Proportion of subjects requiring dose escalation to weekly dosing during this 
study.
●
Proportion of subjects with no draining fistulas over time among subjects with 
draining fistula at Study M14-115 Baseline.
●
Proportion of subjects in each treatment group with > 50% reduction from 
Baseline of Study M14-115 in the number of draining fistulas over time among 
subjects with draining fistula at Study M14-115 Baseline.
●
Resolution of extraintestinal manifestations over time.
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 1.5 (and not worse than Study M14-115 Baseline) and 
average daily abdominal pain ≤ 1.0 (and not worse than Study M14-115 
Baseline) over time among subjects with Study M14-115 Baseline average 
daily stool frequency ≥ 2.5 or average daily abdominal pain ≥ 2.0.
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than Study M14-115 Baseline) and 
average daily abdominal pain ≤ 1.0 (and not worse than Study M14-115 
Baseline) over time among subjects with Study M14-115 Baseline average 
daily stool frequency ≥ 4.0 or average daily abdominal pain ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from Study M14-115 Baseline 
and average daily abdominal pain not worse than Study M14-115 Baseline or 
average daily abdominal pain at least 30% reduction from Study M14-115 
Baseline and average daily stool frequency not worse than Study M14-115 
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For categorical additional efficacy endpoints, the two-sided 95% confidence interval for 
the proportions will be provided.  The NRI method will be used for subjects with missing 
data at the time point evaluated.  The LOCF method will also be used as the sensitivity 
analyses.
For continuous additional efficacy endpoints, change from Study M14-115 Baseline will 
be summarized by descriptive statistics using mean, standard deviation, minimum, median 
and maximum.  Both LOCF and observed case analyses will be performed.
For time to event additional efficacy endpoints, the number of event and the 25th, median, 
and 75th percentiles of time to event will be estimated by the product limit method.  The 
95% CI for the median time-to-event will also be provided if applicable.
The time to first occurrence of event will be calculated as (first occurrence of event date 
or censoring date – date of first dose of the treatment during this study + 1).  Subjects who 
did not experience the event prior to discontinue or complete the study will be censored at 
the date the last assessment was taken.  For the endpoint of time to dose escalation, 
subjects without experiencing an event will be censored at the last available dose date. 
10.4
Handling of Multiplicity
Not applicable. 
10.5
Efficacy Subgroup Analysis
The subgroups listed below will be used in subgroup analyses of the primary endpoint.  
The baseline used for the subgroups below is defined as the Study M14-115 Baseline.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline fecal calprotectin [≤ median, > median]
●
Baseline fecal calprotectin [≤ 250 μg/g, > 250 μg/g]
●
Baseline corticosteroid use (yes, no)


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●
Baseline immunosuppressant use (yes, no)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
hs-CRP at Baseline (≤ median, > median)
●
Crohn's disease activity (CDAI ≤ 300, > 300) at Baseline
●
Baseline CDAI (≤ median, > median)
●
Baseline SES-CD [≤ median, > median]
●
Prior infliximab use (yes, no)
●
Weight (≤ median, > median)
●
Baseline albumin (≤ median, > median)
●
Disease duration (< 3 years, > 3 years)
●
Disease duration (≤ median, > median)
●
Study M14-115 induction dose (higher, standard) [will be performed after 
Study M14-115 database lock.]
11.0
Safety Analysis
11.1
General Considerations
Laboratory data, AEs, and vital signs are the primary safety parameters in this study.  All 
safety analyses will be performed for Safety population.
The continuous data will be summarized using descriptive statistics, including mean, 
standard deviation, and median for subjects who have both baseline and post-baseline 
values by visit.  Categorical data will be summarized using frequencies and percentages.  
The number of non-missing values will also be given.
11.2
Analysis of Adverse Events
The adverse event (AE) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary version 20.0 or later.  The analyses of adverse events will 
be descriptive in nature.  All analyses of AEs will be based on the number of patients with 
AEs (not the number of AEs).  Unless otherwise specified, the adverse event will be 


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summarized by system organ classes (SOCs) and preferred terms (PTs), and presented in 
the alphabetical order.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAE) are defined as events that begin or worsen either on or 
after the first dose of the study medication and within 70 days after the last dose of the 
study drug.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the adverse event start time are 
collected and the adverse event start time is prior to the study drug start time.  If an 
incomplete onset date was collected for an adverse event, the event will be assumed to be 
treatment-emergent unless there is other evidence that confirms that the event was not 
treatment-emergent (e.g., the event end date was prior to the study drug start date).
11.2.2
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized for the 
following AE categories:
●
Any treatment-emergent adverse event
●
Any treatment-emergent adverse event that was rated as related (Reasonable 
Possibility) to study drug by the investigator
●
Any treatment-emergent severe adverse event
●
Any treatment-emergent serious adverse event
●
Any treatment-emergent adverse event leading to discontinuation of study drug
●
Any treatment-emergent adverse event leading to death
●
Any treatment-emergent adverse event of special interest 


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11.2.2.1
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing TEAEs will be tabulated by SOC 
and PT.  The SOCs will be presented in alphabetical order, and the PTs will be presented 
in the alphabetical order within each SOC.
A subject who reports more than one AE in different SOCs will be counted only once in 
the overall total.  A subject who reports two or more different PTs within the same SOC 
will be counted only once in the SOC total.  Subjects reporting more than one AE for a 
given PT will be counted only once for that PT using the most extreme incident (i.e., most 
"severe" for the severity tables and most "related" for the relationship tables).  
11.2.2.2
Adverse Events by Maximum Severity
TEAEs will also be summarized by maximum severity.  If a subject has an AE with an 
unknown severity, then the subject will be counted in the severity category of unknown, 
even if the subject has another occurrence of the same event with a severity present.  The 
only exception is if the subject has another occurrence of the same AE with the most 
extreme severity – severe.  In this case, the subject will be counted under the severe 
category.
11.2.2.3
Adverse Events by Maximum Relationship
TEAEs will also be summarized by maximum relationship as assessed by the investigator.  
If a subject has an AE with an unknown relationship, then the subject will be counted in 
the relationship category of "unknown," even if the subject has another occurrence of the 
same event with a relationship present.  The only exception is if the subject has another 
occurrence of the same AE with a relationship assessment of "Reasonable Possibility.  In 
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11.2.2.4
Serious Adverse Events (Including Deaths) and Adverse 
Events Leading to Study Drug Discontinuation
All pre- and post-treatment serious adverse events (TESAEs), deaths, and AEs leading to 
discontinuation of study drug will be listed.  The number and percentage of subjects 
experiencing SAEs (including deaths) and AEs leading to discontinuation of study drug 
will be tabulated.
11.2.2.5
Frequent (≥ 5%) Adverse Events by Preferred Term in 
Decreasing Frequency
TEAEs occurring 5% or more of the subjects will be only summarized by PT in the 
decreasing frequency.
11.2.2.6
Reasonably Possibly Related Adverse Events by System 
Organ Class and Preferred Term 
Reasonable Possibility TEAEs will be summarized by SOC and PT.
11.2.2.7
Reasonably Possibly Related Serious Adverse Events by 
System Organ Class and Preferred Term 
Reasonable Possibility serious TEAEs will be summarized by SOC and PT.
11.2.2.8
Adverse Events of Special Interests
The following AEs of special interest will be summarized by number and percentage of 
subjects experiencing an AE of interest.  The AEs of interest will be summarized and 
presented using primary MedDRA system organ classes (SOCs) and preferred terms 
(PTs) for the following AE categories:
●
Any Infections AE
●
Any Serious Infection AE
●
Any Legionella Infection AE
●
Any Diverticulitis AE
●
Any Opportunistic Infection AE (Excluding Oral Candidiasis and TB)


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●
Any Oral Candidiasis
●
Any Tuberculosis AE
●
Any Active Tuberculosis
●
Any Latent Tuberculosis
●
Any Parasitic Infection AE
●
Any Reactivation of Hepatitis B
●
Any Progressive Multifocal Leukoencephalopathy (PML) AE
●
Any Malignancy AE
●
Any Lymphoma AE
●
Any Hepatosplenic T-Cell Lymphoma AE (HSTCL)
●
Any Non-Melanoma Skin Cancer (NMSC) AE
●
Any Melanoma AE
●
Any Leukemia AE
●
Any Other Malignant AE (Excluding NMSC, Melanoma, Lymphoma, 
HSTCL, and Leukemia)
●
Any Allergic Reaction (Including Angioedema/Anaphylaxis)
●
Any Lupus-Like Reactions and Systemic Lupus Erythematosus
●
Any Vasculitis AE
●
Any Cutaneous Vasculitis AE
●
Any Non-Cutaneous Vasculitis AE
●
Any Sarcoidosis AE
●
Any Autoimmune Hepatitis
●
Any Myocardial Infarction Related AE
●
Any Cerebrovascular Accident Related AE
●
Any Congestive Heart Failure Related AE
●
Any Pulmonary Embolism Related AE
●
Any Interstitial Lung Disease AE
●
Any Intestinal Perforation AE
●
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●
Any Pancreatitis AE
●
Any Stevens-Johnson Syndrome AE
●
Any Erythema Multiforme Related AE
●
Any Worsening/New Onset of Psoriasis
●
Any Demyelinating Disorder
●
Any Amyotrophic Lateral Sclerosis AE
●
Any Reversible Posterior Leukoencephalopathy Syndrome (RPLS) AE
●
Any Hematologic Disorders AE (Including Pancytopenia)
●
Any Liver Failure and Other Liver Event AE (Except Gall Bladder Related 
Events)
●
Any Humira Administration Related Medication Errors AE
●
Any Injection Site Reaction AE
●
Any AE Leading to Death
●
Any AE Leading to Discontinuation of Study Drug
●
Any Deaths
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
11.2.2.9
Adverse Events by 100 Patient Years
The event rates per 100 patient years of exposure to study drug will be presented for 
TEAE overviews and for TEAEs SOC and PT where the number of events will be used as 
the numerator.
100
!
Years
Patient
Total
TEAEs
of
Number
where total patient years is defined as the sum of the study drug exposure of all subjects, 
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11.2.2.10
Listing of Adverse Events
The following additional summaries of AEs will be prepared.
●
Listing of Subjects with Treatment-Emergent Adverse Event of Special 
Interests
●
Listing of Subjects with Pretreatment Serious Adverse Events
●
Listing of Subjects with Treatment-Emergent Serious Adverse Events
●
Listing of all adverse events that led to discontinuation of study drug
●
Listing of all deaths
11.3
Analysis of Laboratory Data
The summary statistics, including Study M14-115 Baseline mean, the mean at each visit, 
mean change from baseline, standard deviation, and median will be presented. 
Shift tables from Study M14-115 Baseline to minimum, maximum, and the final value 
according to the normal range will be provided for each hematology, clinical chemistry 
parameter and urinalysis parameter.  The laboratory data will be categorized as low, 
normal, or high based on the normal ranges of the laboratory used in this study.  The shift 
tables will tabulate the number and percentage of subjects with Baseline values 
below/within/above the normal range versus minimum, maximum, final values 
below/within/above the normal range.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 4.0 (or later) of 
Grade ≥ 3 will be provided.  For each of these subjects, the whole course of the parameter 
will be listed.  For subjects with laboratory values with CTC ≥ 3, all of the laboratory 
parameters for those subjects will be listed.
The liver-specific laboratory tests include the serum glutamic-pyruvic transaminase 
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline 


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phosphatase, and total bilirubin.  Each of these laboratory values will be categorized as 
follows:
●
< 1.5 × ULN,
●
≥ 1.5 × ULN TO < 3 × ULN,
●
≥ 3 × ULN TO < 5 × ULN,
●
≥ 5 × ULN TO < 8 × ULN, and
●
≥ 8 × ULN,
where ULN is the upper normal limit.
Shift tables showing shift from Baseline to maximum and final values will be presented 
using these five categories.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
Alkaline phosphatase ≥ 2.5 × ULN, or
●
Total bilirubin ≥ 1.5 × ULN
11.4
Analysis of Vital Signs and Weight
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure 
and heart rate.  The criteria for potentially clinically significant vital sign findings are 
presented in Table 8.


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Table 7.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure (mmHg)
Value ≤ 90 mmHg and/or decrease ≥ 20 mmHg from Baseline
Value ≥ 180 mmHg and/or increase ≥ 20 mmHg from Baseline
Diastolic blood pressure (mmHg)
Value ≤ 50 mmHg and/or decrease ≥ 15 mmHg from Baseline
Value ≥ 100 mmHg and/or increase ≥ 15 mmHg from Baseline
Heart rate (bpm)
Value ≤ 50 bpm and/or decrease ≥ 15 bpm from Baseline
Value ≥ 120 bpm and/or increase ≥ 15 bpm from Baseline
The summary statistics, including Study M14-115 Baseline mean, the mean at each visit, 
mean change from baseline, standard deviation, and median will be presented.  The 
number and percentage of subjects meeting the criteria for potentially clinically 
significant (PCS) vital sign values will also be summarized. 
Vital sign results meeting the criteria for PCS findings will be identified in a listing.
11.5
Analysis for Other Safety Variables
Not applicable for the current planned analysis.
11.6
Safety Subgroup Analysis
Not applicable.
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The following efficacy variables are mentioned in the protocol but will not be summarized 
as they were removed from Study M14-115 protocol:
Proportion of subjects with predicted endoscopic improvement at Week 40, using the 
3 definitions and equations.


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Correlation between actual SES-CD and Predicted SES-CD: 
In addition, change in Bristol Stool Scale score from Baseline over time will not be 
summarized as Bristol Stool Chart data in ePRO was not collected in Study M14-347.
The following efficacy variables are not mentioned in the protocol but are added to the 
SAP:
Proportion of subjects with CD related hospitalization:  CD related hospitalization is a 
component of major CD related event.
Proportion of subjects with CD related surgery:  CD related surgery is a component of 
major CD related event.
The following efficacy endpoints are added because they are used in new CD studies.
Proportion of subjects who achieve symptomatic remission, defined as average daily stool 
frequency ≤ 2.8 (and not worse than Study M14-115 Baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than Study M14-115 Baseline) over time among 
subjects with Study M14-115 Baseline average daily stool frequency ≥ 4.0 or average 
daily abdominal pain ≥ 2.0:  This endpoint is used for new CD studies as a primary 
efficacy endpoint.
Proportion of subjects with a decrease in SES-CD > 50% from Study M14-115 Baseline 
(or for subjects with an SES-CD of 4 at Study M14-115 Baseline, at least a 2-point 
reduction from Study M14-115 Baseline) at Week 40.


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13.0
Appendix
13.1
Crohn's Disease Activity Index (CDAI) 


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13.2
Simple Endoscopic Score – CD (SES-CD) 


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13.3
Inflammatory Bowel Disease Questionnaire (IBDQ) 


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13.5
EQ-5D Questionnaires


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14.0
References
1.
Devlin N, Shah KK, Feng Y, et al.  Valuing health-related quality of life:  an EQ-
5D-5L value set for England.  Health Econ.  2017.