Conditions: Crohn's Disease
Keywords: Crohn's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 514
Healthy volunteers: no

Brief summary:
This study will evaluate higher versus standard adalimumab dosing regimens for induction and maintenance therapy in subjects with moderately to severely active Crohn's Disease and evidence of mucosal ulceration.

Detailed description:

Arms:
arm 1: Participants randomized to receive received blinded adalimumab 160 mg at Baseline and matching placebo at Week 1, adalimumab 80 mg and matching placebo at Week 2, matching placebo at Week 3, and then adalimumab 40 mg every other week (eow) starting at Week 4 through Week 12. arm 2: Participants randomized to receive blinded adalimumab 160 mg at Baseline, Week 1, Week 2, and Week 3. At Week 4, participants receive adalimumab 40 mg eow through Week 12. arm 3: Participants randomized to the CA regimen receive adalimumab 40 mg eow beginning at Week 12. The adalimumab dose will be escalated to every week (ew) starting as early as Week 14 and up to Week 54 based on Crohn's Disease Activity Index (CDAI) or high-sensitivity C-reactive protein (hs-CRP) values, using results from the prior or current study visit. Once participants in the CA regimen are escalated, they remain on adalimumab 40 mg ew dosing. arm 4: At Weeks 14, 28 and 42, the adalimumab dose for participants randomized to the TDM will be determined by protocol-established dose adjustment criteria. Doses will be determined using blinded serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI or hs-CRP values from the current or prior study visit. Participants who meet criteria for dose escalation at Weeks 14, 28 or 42 will receive 40 mg ew.

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

Protocol document:
Prot_000.pdf: 
NCT02065570


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
25 October 2013
Administrative Change 1
07 March 2014
Administrative Change 2
11 March 2014
Administrative Change 3
18 March 2014
Amendment 1
21 May 2014
Administrative Change 4
04 December 2014
Amendment 2
21 May 2015
Amendment 3
14 December 2015
Amendment 4
28 March 2016
Amendment 5
20 March 2017
The purpose of this amendment is to:
●
Section 1.2, Synopsis: Clarify that all endpoints for the Exploratory 
Maintenance Study are non-ranked and correct error.
Rationale:  To be consistent with existing methodology section within synopsis 
and Sections 5.3.3.2 and 5.3.3.3
●
Section 1.2, Synopsis, Section 4.0, Study Objective, Section 5.1, Overall Study 
Design and Plan: Description, Section 8.2, Determination of Sample Size:  
Update study sample size to 500, related power calculations and sample 
language.
Rationale:  Sample size was updated based on adequacy of power assumed for 
updated endoscopic co-primary variable.
●
Section 1.2, Synopsis, Section 4.0, Study Objective, Section 5.3.3.1, Co-
Primary Variables for Induction Study:  Replace endoscopic co-primary 
variable.  
Rationale:  Update change in primary endoscopic endpoint.


Adalimumab
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●
Section 1.2, Synopsis, Section 5.3.3.2, Secondary Variables for Induction 
Study, ranked, Section 5.3.3.3, Endpoints for Exploratory Maintenance Study:  
Modify endoscopic portion of ranked secondary endpoint #2 and add an 
Exploratory Maintenance Study endpoint relating to endoscopic response. 
Rationale:  Update secondary and exploratory maintenance endpoints to 
reflect change in primary endoscopic endpoint.
●
Section 1.2, Synopsis, Section 5.3.3.2 Secondary Variables for Induction 
Study, ranked, Section 5.3.3.3, Endpoints for Exploratory Maintenance Study:  
Replace ranked secondary endpoint #5, and modify Exploratory Maintenance 
Study endpoint from endoscopic improvement to endoscopic remission. 
Rationale:  Update secondary and exploratory maintenance endpoints to 
reflect change in primary endoscopic endpoint.
●
Section 1.2 Synopsis, Section 4.0 Study Objective, Section 5.1 Overall Study 
Design and Plan:  Description, Section 5.3.3.1, Co-Primary Variables for 
Induction Study, Section 5.3.3.2 Secondary Variables for Induction Study, 
Section 5.3.3.3 Endpoints for Exploratory Maintenance Study, Section 5.5.1
Treatments Administered, Section 8.1.4.1 Primary Efficacy Variable for 
Induction Study, Section 8.2 Determination of Sample Size, Section 8.3
Randomization Methods:  Change instances of term endoscopic improvement, 
response, and remission throughout protocol and synopsis to reflect relevant 
endpoints.
Rationale:  Align with study changes.
●
Section 1.2, Synopsis, Section 5.3.3.2 Secondary Variables for Induction 
Study, ranked:  Modify ranked secondary endpoints #13 & #14 related to 
IBDQ.
Rationale:  To focus on evaluation of bowel symptom domain of IBDQ that is 
directly related to the disease and relevant to IBD patients.
●
Section 1.2, Synopsis, Section 5.3.3.2 Secondary Variables for Induction 
Study, ranked:  Add ranked secondary endpoint #15, proportion of subjects 
achieving response in IBDQ fatigue item at Week 12.
Rationale: To include fatigue in the evaluation as it is considered relevant to 
IBD patients and may provide information complimentary to the primary 
endpoint.


Adalimumab
M14-115 Protocol Amendment 6
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●
Section 1.2, Synopsis, Section 5.3.3.2 Secondary Variables for Induction 
Study, non-ranked, Section 5.3.3.3 Endpoints for Exploratory Maintenance 
Study:  Add and modify non-ranked secondary endpoints related to IBDQ in 
Induction and Exploratory Maintenance, and delete a duplicate endpoint in 
Exploratory Maintenance.
Rationale:  To examine the effect of treatment on various aspects of patients' 
life as measured by IBDQ total score and domain scores, as well as the fatigue 
item in IBDQ.
●
Section 5.3.3.2 Secondary Variables for Induction Study, non-ranked, 
Section 5.3.3.3 Endpoints for Exploratory Maintenance Study:  Clarify name 
of score in non-ranked additional efficacy endpoints from "Bristol Stool Scale" 
to "Bristol Stool Chart score."
Rationale:  To provide better clarity and consistency with the SAP.
●
Section 5.3.3.2 Secondary Variables for Induction Study, non-ranked:  Add 
non-ranked efficacy endpoint regarding Bristol Stool Chart Score.
Rationale:  Add second method to measure subjects who have response in 
stool consistency.
●
Section 5.3.3.2 Secondary Variables for Induction Study, non-ranked, 
Section 5.3.3.3 Endpoints for Exploratory Maintenance Study:  Modify non-
ranked additional efficacy endpoint definition of symptomatic remission and 
specify the Baseline stool frequency and abdominal pain score for 
symptomatic remission and response analyses at each scheduled visit in 
Induction and Maintenance Study respectively.
Rationale:  Modify non-ranked efficacy endpoint definition for symptomatic 
remission and response to align with current AbbVie IBD registrational trials.
●
Section 5.3.3.3 Endpoints for Exploratory Maintenance Study: Add additional 
non-ranked efficacy endpoints at Week 56 related to subjects requiring dose 
escalation to weekly dosing during Maintenance Study.
Rationale:  To assess the effect of dose escalation.
●
Section 5.2.3.2, Concomitant Therapy:  Update Prior and Concomitant
Therapy section to specify details regarding concomitant medications and 
censoring.  


Adalimumab
M14-115 Protocol Amendment 6
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Rationale:  Align censoring rules according to current AbbVie conventions.
●
Section 5.3.1 Table 3.  Corrected error in Study Activities Table, for activity 
Study Drug Dispensing/Administration"s"
Rationale:  Clarify that the "s" in Study Drug Dispensing/Administration"s" 
should be a superscript "s" and correspond to footnote "s."
●
Section 5.5.2.2, Storage and Disposition of Study Drug:  Clarify that only 
temperature excursions greater than 30 minutes need to be reported to the 
sponsor.
Rationale:  Align with new AbbVie guidance developed following a cross-
functional risk evaluation.
●
Section 7.0, Protocol Deviations:  Update alternate contact.
Rationale:  Update to include current study contact information.
●
Section 8.1.7, Interim Analysis:  Information added to describe Interim 
Analysis which may be performed via a database cut
Rationale:  To reflect a possibility to perform an interim analysis for the 
induction study and clarify the process.
An itemized list of all changes made to this protocol amendment can be found in 
Appendix N.


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-115
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  27 November 2018
Protocol Title:  A Multicenter, Randomized, Double-Blind Study to Evaluate Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Crohn's Disease and Evidence of Mucosal Ulceration
Objectives:
The objective of Study M14-115 is to evaluate efficacy and safety of higher induction and maintenance 
dosing regimens in subjects with moderately to severely active Crohn's disease.
Investigators:  Multicenter
Study Sites:  Approximately 150 sites worldwide.
Study Population:  Males and females ≥ 18 and ≤ 75 years of age with a diagnosis of moderately to 
severely active Crohn's disease, CDAI ≥ 220 and ≤ 450, and evidence of mucosal ulceration by Simple 
Endoscopic Score (SES-CD) ≥ 6, excluding the presence of narrowing component, or SES-CD ≥ 4, 
excluding the presence of narrowing component, for patients with disease limited to the ileum, on 
screening endoscopy (or endoscopy performed within 45 days before Baseline), confirmed by a central 
reader.
Number of Subjects to be Enrolled:  Approximately 500 (300 in higher induction regimen group and 
200 in standard induction regimen group) subjects with moderately to severely active Crohn's Disease, 
CDAI of ≥ 220 and ≤ 450 and evidence of mucosal ulceration, confirmed by centrally read endoscopy.
Methodology:
This Phase 3 study design includes the Screening Period followed by a 12-Week double-blind Induction 
Study and 44-Week double-blind Maintenance Study.  The Induction Study will assess the efficacy and 
safety of two adalimumab induction regimens in achieving clinical remission, defined as Crohn's Disease 
Activity Index (CDAI) < 150 at Week 4, and endoscopic response, defined as a decrease in Simplified 
Endoscopic Score for Crohn's Disease (SES-CD) > 50% from Baseline (or for a Baseline SES-CD of 4, 
at least a 2 point reduction from Baseline), as scored by central reviewer, at Week 12; in subjects with 
moderately to severely active Crohn's disease and evidence of mucosal ulceration at Baseline.
The Maintenance Study will assess the efficacy and safety of two adalimumab maintenance regimens in 
maintaining clinical and endoscopic improvements at Week 56.  Analyses of the outcomes from the 
maintenance regimens are considered exploratory.
During both the Induction Study and the Maintenance Study, visit week designations will represent 
weeks since first dose in the Induction Study.  Week 0 (Baseline) will reflect the date of first adalimumab 
dosing in the Induction Study.  Week 12 will represent the final assessment in the Induction Study.  
Week 56 will represent the final assessment in the Maintenance Study (representing 44 weeks of 
maintenance treatment in the Maintenance Study).  


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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Methodology (Continued):
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
study and randomized in a 3:2 ratio at Baseline to receive a higher induction adalimumab regimen or 
standard induction adalimumab regimen during the double-blind Induction Study.  Up to 25% of subjects 
with previous infliximab exposure may be enrolled.  All subjects who complete the Induction Study 
(regardless of achievement of response at Week 12) will continue into the Maintenance Study.  Assuming 
the Week 4 clinical remission rate will be approximately 50% for the higher induction dose regimen and 
approximately 30% for the standard dose regimen, a sample size of 500 (300 higher dose and 
200 standard dose) will be adequate to detect at least a 20% treatment difference in clinical remission 
rates at Week 4 between the dosing regimens using Fisher's exact test with 99% power at a 
0.05 two-sided significant level.
Since exposure/endoscopic relationships are not currently available for adalimumab, clinical remission 
will be based on PK/PD modeling which predicts an expected ~50% increase in the proportion of 
subjects with endoscopic response compared to the standard adalimumab induction regimen.  The 
observed rate of endoscopic response in Study M05-769 was 44% at Week 12 with the currently 
approved dosing regimen.  Thus, by extrapolation, the expected rate for endoscopic response at Week 12 
using the higher induction regimen is 66%.  A sample size of 500 subjects (300 higher induction regimen 
and 200 standard induction regimen) will be adequate to detect at least a 22% treatment difference in 
endoscopic response rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 99% power at a 0.05 two-sided significance level.
Since clinical remission at the Week 4 endpoint and the endoscopic response at the Week 12 endpoint are 
not likely to be independent of each other, the power for the co-primary endpoints for the Induction Study 
is expected to be > 98% (see protocol for detailed assumptions of the sample size calculation).
The randomization of subjects for the Induction Study will be stratified by high-sensitivity C-Reactive 
Protein (hs-CRP) at Baseline (< 10 and ≥ 10 mg/L), using the Screening hs-CRP value, prior infliximab 
use, and Crohn's disease activity (CDAI ≤ 300, > 300) at Baseline.  Subjects with prior infliximab 
experience will be limited to 25% of the study population.  Subjects assigned to the higher induction 
regimen will receive blinded adalimumab 160 mg at Baseline, Week 1, Week 2, and Week 3.  At Week 4, 
subjects will receive adalimumab 40 mg every other week (eow) through Week 12.  Subjects assigned to 
the standard induction regimen will receive blinded adalimumab 160 mg at Baseline and matching 
placebo at Week 1, adalimumab 80 mg at Week 2 and matching placebo at Week 3.  At Week 4, subjects 
will receive adalimumab 40 mg every other week through Week 12.
Maintenance Study:
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-blinded exploratory 
treatment regimens (adalimumab clinically adjusted [CA] regimen and adalimumab therapeutic drug 
monitoring [TDM] regimen).  The re-randomization at Week 12 will be stratified by induction treatment 
regimen, clinical response (CR-70) status at Week 12 and decrease in SES-CD > 50% from Baseline per 
the site investigator reading at Week 12.  Among subjects achieving SES-CD > 50% from Baseline at 
Week 12, the randomization will be further stratified by SES-CD ≤ 4 and at least a 2 point reduction 
versus baseline and no subscore greater than 1 in any individual variable using the Week 12 SES-CD 
value provided by the site.


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Methodology (Continued):
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab every other week 
beginning at Week 12.  The adalimumab dose will be escalated to every week (ew) as early as Week 14 if 
the subject's CDAI ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or current visit) as shown by 
the dose adjustment criteria below.  These subjects will also be allowed to escalate at unscheduled visits 
that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 54.  Once subjects in the 
clinically adjusted regimen are escalated, they will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will be determined 
by the dose adjustment criteria referenced in the table below.  Doses will be determined using blinded 
serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI or hs-
CRP values from the current or prior visit.  For subjects who meet criteria for dose escalation at Weeks 
14, 28 or 42, subjects will receive 40 mg weekly.
The goal of the TDM regimen is to attain and maintain serum adalimumab levels above a reasonably high 
concentration levels in subjects for mucosal healing.  Since exposure-endoscopic relationships are not 
currently available for adalimumab, clinical remission was used for selection of concentration threshold 
to be used in TDM arm.  Based on the PK analyses of concentrations in Studies M02-403, M04-691 and 
M02-433, no concentration level could be identified as significant and reliable predictor of remission in 
adult CD.  Therefore, the TDM regimen will be based on two concentration thresholds in conjunction 
with clinical response criteria as expected to occur in clinical setting.  About 75% of the subjects who 
were in remission at Week 56 in Study M02-433 had serum concentration above 5 μg/mL.  Therefore, the 
lower concentration threshold for the TDM regimen was selected as 5 μg/mL and any subject below 
5 μg/mL concentration will be escalated to ew dosing.  The second threshold was selected as 10 μg/mL, 
which is similar to the median concentrations (9.4 μg/mL at Week 56) observed in subjects who were in 
remission.  The subjects with concentration above 5 and below 10 μg/mL may be dose escalated based on 
clinical response as outlined in the table below.  The subjects with serum concentration above 10 μg/mL 
will not be dose escalated.


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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Methodology (Continued):
Adalimumab Dose Adjustment Criteriaa
ADA Serum Concentrationb (ug/mL)
CDAIc
hs-CRPd (mg/L)
Dose Change?
Clinically Adjusted Regimen
any
< 220
< 10
no
any
any
≥ 10
yes; dose escalate to ew
any
≥ 220
any
yes; dose escalate to ew
Therapeutic Drug Monitoring Regimen
< 5
any
any
yes; dose escalate to ew
5 – 10
< 220
< 10
no
5 – 10
any
≥ 10
yes; dose escalate to ew
5 – 10
≥ 220
any
yes; dose escalate to ew
> 10
any
any
no
a.
For subjects experiencing an active infection or those for whom the investigator feels dose escalation is not 
advisable, the investigator should contact the Study Designated Physician.
b.
Measured from the serum concentration taken at the prior study visit.
c.
Measured using hematocrit taken from prior study visit for CDAI calculation.
d.
Measured using hs-CRP from the prior or current study visit.
   
The duration of the study could be up to 60 weeks which includes a Screening Period (1 – 4 weeks), a 
12-week double-blind Induction Study and a 44-week Maintenance Study.  The Screening Period may be 
extended as necessary after consultation with and approval by the AbbVie Study Designated Physician 
(SDP) for subjects who require initiation of prophylactic anti-tuberculosis (TB) therapy, or in case of 
external, not subject-related circumstances (e.g., due to delay of availability of screening test results).  
There will also be a 70-day follow-up phone call for subjects who complete Week 56 or discontinue from 
the study prematurely.
Clinical evaluation will occur at Baseline, Weeks 2, 4, 6, 8, 12, 14, 20, 26, 28, 34, 40, 42, 48, and 
56/Premature Discontinuation (PD) visits.  An electronic diary will be dispensed at the Screening visit.  
In addition to routine physical examination, CDAI calculation, diary review, laboratory, adverse event, 
concomitant medication and vital sign assessments, the following will be collected:
!
Results of study questionnaires (IBDQ, EQ-5D, WPAI) at Baseline, Week 4, Week 8, Week 12, 
Week 26, Week 40 and Week 56/PD.
!
Calculation of the SFPS at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 14, 
Week 20, Week 26, Week 28, Week 34, Week 40, Week 42, Week 48 and Week 56/PD.  The 
Screening visit results will serve as the Baseline value.
!
Results of daily Bristol Stool Form Scale beginning at Baseline through Week 56/PD.
!
Results of 11-point Abdominal Pain Rating Scale beginning at Baseline, Week 2, Week 4, 
Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of adalimumab concentrations just prior to dosing at Baseline, Week 2, 
Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.


Adalimumab
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Methodology (Continued):
!
Serum for measurement of Anti-Adalimumab Antibodies (AAA) just prior to dosing at Baseline,
Week 4, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of infliximab serum levels and Human Anti-Chimeric Antibodies 
(HACA) just prior to dosing at Baseline.
!
Serum biomarkers/mRNA at Baseline, Week 2, Week 4, Week 8, Week 12, Week 26, Week 40, 
and Week 56/PD.
!
Stool samples for analysis of fecal calprotectin during Screening, at Week 4, Week 12, Week 26, 
and Week 56/PD.
!
Stool samples for microbiota metagenomic analyses during Screening, at Week 4, Week 12, 
Week 26, and Week 56/PD.
!
Endoscopic evaluations, confirmed by central reader, will be done at Screening, Week 12, and 
Week 56/PD.
!
An optional pharmacogenetic sample should be drawn at Baseline and Week 12.
Throughout the study, subjects will only be allowed to change the dosage of CD-specific concomitant 
medications as specified below:
!
At Week 4, subjects who are taking corticosteroid therapy at Baseline will have their 
corticosteroid therapy tapered according to a tapering schedule specified in the clinical study 
protocol.  If the Investigator feels that the steroid taper is not advisable for a particular subject at 
Week 4, the Study Designated Physician (SDP) should be consulted for evaluation and approval.
!
Subjects taking corticosteroids at Baseline who have a loss of satisfactory clinical response per 
the Investigator's judgment after the steroid taper has been initiated may have their 
corticosteroid dose increased per the Investigator's discretion during the study.  Subjects in 
whom the maximum equivalent steroid dose exceeds the dose used at Baseline will be censored 
for efficacy assessments (i.e., they will be considered non-responders for categorical endpoints 
and will have the last non-missing values carried forward for non-categorical assessments) from 
that point forward.  These subjects will continue to be evaluated in the safety population.
!
Immunosuppressant doses may be decreased or terminated in the event of moderate-to-severe 
treatment-related toxicities.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion
1.
Males and females ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of colonic, ileocolonic, or ileal Crohn's disease for ≥ 3 months prior to Baseline and 
confirmed by endoscopy during the Screening period or endoscopy performed within 45 days before 
Baseline, with exclusion of current infection, dysplasia, and/or malignancy.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the 
Investigator, must be available.
3.
Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6, excluding the presence of 
narrowing component, or SES-CD ≥ 4, excluding the presence of narrowing component, for patients 
with disease limited to the ileum, on a screening endoscopy or endoscopy performed within 45 days
before Baseline, confirmed by a central reader.


Adalimumab
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued)
4.
Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450 at Baseline despite concurrent or prior 
treatment with a full and adequate course, in the opinion of the Investigator, of at least one of the 
following (oral corticosteroids and/or immunosuppressants or both as defined below):
!
Subject taking oral corticosteroids, excluding budesonide:
o
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
!
For subjects with a dose > 10 and ≤ 40 mg/day, dose has been stable for at least 7 days 
prior to Baseline and the duration of the current steroid course has been at least 14 days 
prior to Baseline.
!
For subjects with a dose ≤ 10 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior to 
Baseline.
!
Subject taking oral budesonide:
o
Dose must not exceed 9 mg/day;
!
For subjects with a dose ≥ 6 mg/day, dose has been stable for at least 7 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
!
For subjects with a dose < 6 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
or,
!
At least a consecutive 42-day course of azathioprine, 6-MP or injectable MTX prior to Baseline, 
with a stable dose for at least 28 days prior to Baseline of azathioprine ≥1.5 mg/kg/day or 6-MP 
≥ 1 mg/kg/day (rounded to the nearest available tablet or half tablet formulation) or a 
documented 6-TGN level of at least 230 pmol/8 × 108 RBC to clarify a therapeutic level was 
achieved on the current dosing regimen or MTX ≥15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the subject (e.g., due to 
leukopenia, elevated liver enzymes, nausea) during that time.
Note:  If a subject is taking both an oral corticosteroid and an immunosuppressant listed above, 
BOTH of the drugs need to meet the above criteria.  Oral MTX use is allowed during the study 
(at a stable dose for 28 days prior to Baseline) however current or prior use of oral MTX is not 
sufficient for inclusion into the study.
or,
!
Concurrent therapy with oral corticosteroids or immunosuppressants (azathioprine, 6-MP or 
SC/IM MTX) is not required for subjects not currently taking these medications who were 
previously treated during the past 1 year and have confirmed documentation of failure to 
respond, or were previously treated during the past 5 years and have confirmed documentation 
indicating lack of tolerability, see Section 10.1.


Adalimumab
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Subject may be included if they have previously experienced a benefit from infliximab and 
discontinued its use due to a subsequent loss of response (judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of CD-related symptoms) or intolerance (in the opinion of the Investigator therapy was 
discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication) to the agent.  Confirmed documentation indicating loss of response or lack of tolerability 
will be required.
6.
Subject has a negative TB Screening Assessment (including a PPD test or QuantiFERON TB Gold 
test [or equivalent]) and negative chest x-ray (CXR – PA and lateral view) at Screening.  If the 
subject has evidence of a latent TB infection; the subject must initiate and complete a minimum of 
2 weeks of an ongoing TB prophylaxis or have documented completion of a full course of anti-TB 
prophylaxis, prior to Baseline.
7.
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.
8.
Subject must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.
9.
Subject is judged to be in otherwise good health as determined by the Principal Investigator based 
upon the results of medical history, laboratory profile, physical examination, CXR, and a 12-lead 
electrocardiogram (ECG) performed during Screening.
10. Subject must be able and willing to self-administer subcutaneous (SC) injections or have a qualified 
person available to administer SC injections.
Main Exclusion:
1.
Subject with a current diagnosis of ulcerative colitis (UC) or indeterminate colitis.
2.
Subject on azathioprine, 6-mercaptopurine (6-MP), methotrexate (MTX), or another 
immunosuppressant (e.g., thalidomide) who:
!
Has not been on these medications for at least 42 days prior to Baseline; or
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or 
!
Has discontinued these medications within 14 days of Baseline.


Adalimumab
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
3.
Subject on oral aminosalicylates who:
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or
!
Has discontinued use of aminosalicylates within 14 days of Baseline.
4.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subjects on budesonide 
> 9 mg/day; or
!
Subject taking an oral corticosteroid (excluding budesonide):
o
dose > 10 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose > 10 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose ≤ 10 mg/day or equivalent, but has not been on a stable dose for at least 10 days prior 
to Baseline; or
o
dose ≤ 10 mg/day or equivalent but has not been on a current steroid course of at least 
14 days in duration prior to Baseline, or
!
Subject taking budesonide:
o
dose ≥ 6 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose ≥ 6 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose < 6 mg/day dose but has not been on a stable dose of at least 10 days prior to Baseline; 
or
o
dose < 6 mg/day but the current course has not been at least 14 days in duration prior to 
Baseline; or
Has been taking both oral budesonide and prednisone (or equivalent) simultaneously, with the 
exception of inhalers.
5.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
6.
Subject who has had surgical bowel resections within the past 6 months or is planning any resection 
at any time point while enrolled in the study.
7.
Subject with a symptomatic bowel stricture.
8.
Subject with an abdominal or peri-anal abscess.
9.
Subject with an ostomy or ileoanal pouch.
10. Subject who has short bowel syndrome.
11. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 
14 days prior to Screening and/or during the Screening period.
12. Subject with prior exposure to medications that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML) including participation in a clinical trial of 
investigational agents targeting white cell trafficking (e.g., natalizumab [Tysabri®], rituximab 
[Rituxan®], efalizumab [Raptiva®]).  Prior exposure to any anti-tumor necrosis factor (TNF) agent 
other than infliximab (including etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).


Adalimumab
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
13. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to 
Baseline, whichever is longer.
14. Subject who previously received treatment with adalimumab or previously participated in an 
adalimumab clinical study.
15. Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 60 days prior to 
Baseline.
16. Subject who previously received stem cell transplantation.
17. Subject who previously received fecal microbial transplantation.
18. Subject that received non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to 
Screening and during the Screening Visit, except low-dose aspirin for prevention of heart attacks, 
unstable angina or transient ischemic attacks or topical NSAIDs.
19. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives for non-Crohn's disease related infections within 14 days prior 
to the Baseline Visit.
20. Subjects on Crohn's disease related antibiotics that have not been on stable doses for at least 28 days 
prior to Baseline.  Subjects on Crohn's disease related antibiotics that have discontinued these 
medications within 28 days of Baseline are excluded.
21. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during 
the course of the study.
22. Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the Screening period.
23. Screening laboratory and other analyses show any of the following abnormal results:
!
AST, ALT > 1.75 × upper limit of the reference range;
!
WBC count < 3.0 × 109/L;
!
Electrocardiogram (ECG) – with clinically significant abnormalities;
!
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert syndrome;
!
Serum creatinine > 1.6 mg/dL.
24. Known hypersensitivity to adalimumab or its excipients.
25. Subject who has previously used infliximab:
!
and had not clinically responded at any time ("primary non-responder") unless subject 
experienced a treatment limiting reaction;
or
!
who used infliximab within 56 days of Baseline.
26. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
27. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency 
syndrome (HIV).
28. 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.


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
29. Subjects with a positive result for the Hepatitis B surface antigen (HBs Ag) will be excluded.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core 
antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab Total (+) require 
PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection 
sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require HBV DNA 
PCR qualitative testing:
!
HBc Ab Total (–) and HBs Ab* (–)  
!
HBc Ab Total (–) and HBs Ab* (+) 
!
HBc Ab Total (+) and HBs Ab* (+)
*
For HBs Ab test results, a (–) result is equivalent to nonreactive and a (+) result is 
equivalent to reactive.
30. Chronic recurring infections.
31. Subject with active TB.
32. Subject with latent TB infection unless there is evidence the subject initiated and completed a 
minimum of 2 weeks of an ongoing TB prophylaxis or have documented completion of a full course 
of anti-TB prophylaxis, prior to Baseline.
33. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular 
accident and any other condition which, in the opinion of the Investigator, would put the subject at 
risk by participation in the study.
34. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in 
any biopsy performed during the Screening endoscopy or endoscopy performed within 45 days 
before Baseline.
35. Positive pregnancy test at Screening (serum) or Baseline (urine).
36. Female subjects who are breastfeeding or considering becoming pregnant during the study.
37. History of clinically significant drug or alcohol abuse in the last 12 months.
38. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
39. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other 
than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or 
localized carcinoma in situ of the cervix.
40. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.


Adalimumab
M14-115 Protocol Amendment 6
EudraCT 2013-001746-33
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Investigational Products:
Adalimumab (40 mg/0.8 mL)
Double-Blind Induction
Subjects will be randomized to receive one of 2 double-blind 
adalimumab Induction Study regimens.
Doses:
(Higher Induction Regimen)
160 mg at Baseline, Weeks 1, 2, and 3, and 40 mg at Week 4, continuing 
at 40 mg every other week through Week 12.
(Standard Induction Regimen)
160 mg at Baseline and matching placebo at Week 1, 80 mg at Week 2 
and matching placebo at Week 3 and 40 mg every other week beginning 
at Week 4 through Week 12.
Double-Blind Maintenance
Subjects will receive one of two double-blind adalimumab Maintenance 
Study regimens.
Doses:
NOTE:  In order to retain 
blinding across regimens, all 
subjects who do not meet the 
criteria for dose escalation in 
either maintenance regimen 
will receive matching placebo 
injections in addition to the 
adalimumab injection.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 
40 mg adalimumab every other week beginning at Week 12.  The 
adalimumab dose will be escalated to every week starting at Week 14 if 
CDAI is ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or 
current visit) as shown by the dose adjustment criteria table.  These 
subjects will also be allowed to escalate at unscheduled visits that may 
occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 
54.  Once subjects in the clinically adjusted regimen are escalated, they 
will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized 
to the TDM regimen will be determined by the dose adjustment criteria 
table.  Doses will be determined using blinded serum concentrations at 
the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI 
or hs-CRP values from the current or prior visit.  For subjects who meet 
criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 
40 mg weekly.
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:
The study will include a Screening Period of 1 – 4 weeks, a double-blind Induction Study of 12 weeks,
and a double-blind Maintenance Study of 44 weeks.  There will also be a 70-day follow-up phone call for 
subjects who complete the study or discontinue from the study prematurely.


Adalimumab
M14-115 Protocol Amendment 6
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Criteria for Evaluation:
Efficacy Endpoints:
Subjects participating in the Induction Study randomized to the higher adalimumab induction dose 
regimen will be compared to those subjects randomized to the standard adalimumab induction regimen.  
Subject data from the Maintenance Study will be used for exploratory analyses.
Induction Study Co-Primary Efficacy Endpoints:
!
Proportion of subjects who achieve a CDAI < 150 at Week 4.
!
Proportion of subjects with decrease in SES-CD > 50% from Baseline (or for a Baseline SES-
CD of 4, at least a 2 point reduction from Baseline) at Week 12.
Induction Study Ranked Secondary Endpoints:
1.
Proportion of subjects with sustained clinical remission (CDAI < 150) at both Weeks 4 and 12.
2.
Proportion of subjects with CDAI < 150 at Week 4 and decrease in SES-CD > 50% from Baseline 
(or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline) at Week 12.
3.
Proportion of subjects with clinical remission (CDAI < 150) at Week 12.
4.
Proportion of subjects who discontinued corticosteroid use and achieved clinical remission (CDAI 
< 150) at Week 12 among subjects taking corticosteroids at Baseline.
5.
Proportion of subjects with endoscopic remission (SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable) at Week 12.
6.
Change from Baseline in fecal calprotectin level at Week 4.
7.
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g at Week 4.
8.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal calprotectin < 250 μg/g at 
Week 4.
9.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore > 1 in any individual variable, and fecal calprotectin 
< 250 μg/g at Week 12.
10. Proportion of subjects who achieve an SES-CD ≤ 2 at Week 12.
11. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 4.
12. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 12.
13. Proportion of subjects achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 8) at Week 4.
14. Proportion of subjects achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 8) at Week 12.
15. Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ fatigue item score 
≥ 1) at Week 12.
All other efficacy and exploratory endpoints will be non-ranked.


Adalimumab
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Criteria for Evaluation (Continued):
All endpoints for the Exploratory Maintenance Study will be non-ranked. 
Pharmacokinetic:
Blood samples will be collected for measurement of serum adalimumab concentration just prior to dosing 
at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/Premature 
Discontinuation and anti-adalimumab antibody (AAA) just prior to dosing at Baseline, Week 4, Week 12, 
Week 26, Week 40, and Week 56PD.
Blood samples will also be collected for measurement of infliximab serum levels and Human 
Anti-Chimeric Antibodies (HACA) just prior to dosing at Baseline.
Exploratory Research Using Intestinal Mucosal Biopsy Samples (Optional):
Optional intestinal biopsies will be collected with consent at Screening, Week 12, and Week 56 or at 
premature discontinuation.  The purpose of these samples is to test potential biomarker signatures and 
new drug targets for IBD.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of study drug.  Incidence 
of adverse events, changes in vital signs, physical examination results, and clinical laboratory data will be 
assessed.
Statistical Methods:
Efficacy:
The co-primary efficacy variables for the Induction Study are proportion of subjects with moderately to 
severely active CD that have achieved clinical remission, defined as CDAI < 150, at Week 4 and 
proportion of subjects with moderately to severely active CD that have achieved a decrease in SES-CD 
> 50% from Baseline (or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), at 
Week 12. The comparison between treatment groups for the two co-primary efficacy variables will be 
performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by hs-CRP at Baseline 
(< 10 and ≥ 10 mg/L) (the Screening hs-CRP will serve as the Baseline value), prior infliximab use, and 
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline.  A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated.  The ITT set includes all subjects 
who were randomized at baseline.  For the evaluation of co-primary endpoints, missing data of CDAI at 
Week 4 or missing SES-CD at Week 12 will be imputed using the non-responder imputation (NRI) 
approach.  For Week 4 clinical remission, LOCF, OC and multiple imputation methods will be used as 
sensitivity analyses.  For Week 12 endoscopic response (decrease in SES-CD > 50% from Baseline [or 
for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline]), OC will be used as sensitivity 
analysis.


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Statistical Methods (Continued):
Efficacy (Continued):
Secondary efficacy variables for the Induction Study are divided into two groups.  The first group 
includes ranked secondary endpoints, which are ranked by clinical importance.  Statistical significance is 
assessed at significance level of 0.050 (2-sided) in ranked endpoint order until the significance level 
exceeds 0.05.  No additional statistically significant treatment differences may be declared after the first 
ranked endpoint fails to achieve statistical significance at a two-sided significance level of 0.05.  The 
second group includes all other secondary variables.
In general, continuous secondary efficacy variables, including all efficacy variables for Maintenance 
Study, will be analyzed using Analysis of Covariance (ANCOVA) model including factor for treatment 
group, stratification factors and Baseline values, whereas CMH test stratified by stratification factors is 
used for categorical endpoints.  NRI for missing data will be used for categorical endpoints.  Both last 
observation carried forward (LOCF) and observed case (OC) analyses will be performed for continuous 
endpoints.  The LOCF analysis is considered primary for inferential purposes.  In addition, Mixed-Effect 
Model Repeated Measure (MMRM) will be applied, wherever appropriate, as a sensitivity analysis for 
the longitudinal continuous endpoints.
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 regimen, and rates of AAA positive will be calculated.  
As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment 
emergent adverse events may be evaluated.
Safety:
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  
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 for subjects who do not participate in 
the OLE or until first dose of study drug in the OLE study if the subject is a study completer and is 
enrolled in the OLE.  Treatment-emergent AEs will be summarized separately for:  a) Baseline to 
Week 12; b) Week 12 to Week 56; c) Baseline to Week 56 (overall study duration).  An overview of 
treatment-emergent AEs, including AEs of special interest, adverse events leading to death and adverse 
events leading to premature discontinuation (see details in the SAP), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version 20.1 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 and compared 
between-treatment groups will be performed using a one-way Analysis of Variance (ANOVA).  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
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-mercaptopurine 
6-TGN
6-thioguanine
AAA
Anti-adalimumab antibody 
ADA
Adalimumab 
AE
Adverse event 
ALT
Alanine transaminase 
ANA
Antinuclear antibody 
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase 
BCG
Bacillus Calmette-Guérin 
BUN
Blood urea nitrogen 
CA
Clinically Adjusted
CD
Crohn's disease 
CDAI
Crohn's disease activity index
CDC
Centers for Disease Control and Prevention 
CMH
Cochran-Mantel-Haenszel
CRA
Clinical Research Associate 
CRF
Case report form 
CRP
C-Reactive Protein 
CXR
Chest x-ray 
DNA
Deoxyribonucleic acid 
dsDNA
Double-stranded DNA 
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EIM
Extra-Intestinal Manifestations
eow
Every other week 
ePRO
Electronic Patient Reported Outcome
EQ-5D
European Quality of Life 5 Dimensions
ew
Every Week
FDA
Food and Drug Administration 


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GCP
Good Clinical Practice 
HACA
Human Anti-Chimeric Antibody
HBV
Hepatitis B virus
HBc Ab
Hepatitis B core antibodies
Hbs Ab
Hepatitis B surface antibodies
Hbs Ag
Hepatitis B surface antigen 
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 
IGRA
Interferon-Gamma Release Assay
IL
Interleukin 
IRB
Institutional Review Board 
ITT
Intent-to-treat
IVRS
Interactive Voice Response System 
IWRS
Interactive Web Response System
LOCF
Last observation carried forward 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed-Effect Model Repeated Measure
MTX
Methotrexate 
NRI
Non-responder imputation
NSAID
Non-steroidal anti-inflammatory drug
OC
Observed Case
OLE
Open-Label Extension
PA
Posteroanterior 
PD
Premature Discontinuation
PK
Pharmacokinetics
PML
Progressive Multifocal Leukoencephalopathy
POR
Proof of Receipt 
PPD
Purified protein derivative 
RA
Rheumatoid arthritis 
RBC
Red blood cell 


Adalimumab
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SAE
Serious adverse event 
SC
Subcutaneous 
SDP
Study designated physician
SES-CD
Simplified endoscopic score for Crohn's disease
SFPS
CDAI components "Number of liquid or very soft stools" and "Abdominal 
pain" (Stool [liquid/soft] Frequency + Abdominal Pain Score; SFPS)
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis 
TDM
Therapeutic Drug Monitoring
TNF
Tumor Necrosis Factor 
TPN
Total Parenteral Nutrition 
UC
Ulcerative Colitis
WBC
White blood cell


Adalimumab
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 6
1.3
List of Abbreviations and Definition of Terms...................................... 20
2.0
Table of Contents ................................................................ 23
3.0
Introduction......................................................................... 28
3.1
Differences Statement .......................................................................... 30
3.2
Benefits and Risks................................................................................ 30
3.3
Adalimumab Overview......................................................................... 30
3.4
Safety information................................................................................ 31
4.0
Study Objective ................................................................... 32
5.0
Investigational Plan.............................................................32
5.1
Overall Study Design and Plan:  Description ........................................ 32
5.2
Selection of Study Population............................................................... 41
5.2.1
Inclusion Criteria.................................................................................. 41
5.2.2
Exclusion Criteria................................................................................. 44
5.2.3
Prior and Concomitant Therapy............................................................ 50
5.2.3.1
Prior Therapy ....................................................................................... 50
5.2.3.2
Concomitant Therapy........................................................................... 51
5.2.3.3
Prohibited Therapy............................................................................... 53
5.3
Efficacy, Pharmacokinetic and Safety Assessments/Variables .............. 54
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 54
5.3.1.1
Study Procedures.................................................................................. 61
5.3.1.2
Blood Sample for Pharmacogenetic Analysis........................................ 79
5.3.1.3
Blood Samples for Biomarkers Analysis............................................... 80
5.3.1.4
Collection and Handling of Optional Intestinal Biopsy Samples 
for Exploratory Research...................................................................... 80
5.3.2
Drug Concentration Measurements....................................................... 82
5.3.2.1
Collection of Samples for Analysis....................................................... 82
5.3.2.2
Handling/Processing of Samples........................................................... 83
5.3.2.3
Disposition of Samples......................................................................... 83


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5.3.2.4
Measurement Methods ......................................................................... 83
5.3.3
Efficacy Variables................................................................................ 84
5.3.3.1
Co-Primary Variables for Induction Study............................................ 84
5.3.3.2
Secondary Variables for Induction Study.............................................. 84
5.3.3.3
Endpoints for Exploratory Maintenance Study...................................... 87
5.3.4
Safety Variables ................................................................................... 91
5.3.5
Pharmacokinetic Variables ................................................................... 91
5.3.6
Pharmacogenetic and Serologic Variables ............................................ 92
5.3.6.1
Pharmacogenetic Variables................................................................... 92
5.3.6.2
Serologic Variables .............................................................................. 92
5.3.7
Exploratory Research Variables............................................................ 93
5.4
Removal of Subjects from Therapy or Assessment ............................... 93
5.4.1
Discontinuation of Individual Subjects ................................................. 93
5.4.2
Discontinuation of Entire Study............................................................ 95
5.5
Treatments ........................................................................................... 95
5.5.1
Treatments Administered...................................................................... 95
5.5.2
Identity of Investigational Products ...................................................... 97
5.5.2.1
Packaging and Labeling........................................................................ 97
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 98
5.5.3
Method of Assigning Subjects to Treatment Groups............................. 98
5.5.4
Selection and Timing of Dose for Each Subject.................................... 99
5.5.5
Blinding ............................................................................................... 99
5.5.5.1
Blinding of Investigational Product ...................................................... 99
5.5.6
Treatment Compliance ........................................................................100
5.5.7
Drug Accountability............................................................................100
5.6
Discussion and Justification of Study Design.......................................101
5.6.1
Discussion of Study Design and Choice of Control Groups .................101
5.6.2
Appropriateness of Measurements.......................................................102
5.6.3
Suitability of Subject Population .........................................................102
5.6.4
Selection of Doses in the Study ...........................................................102
6.0
Complaints......................................................................... 103
6.1
Medical Complaints ............................................................................104
6.1.1
Definitions ..........................................................................................104


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6.1.1.1
Adverse Event.....................................................................................104
6.1.1.2
Serious Adverse Events.......................................................................105
6.1.2
Adverse Event Severity .......................................................................106
6.1.3
Relationship to Study Drug..................................................................107
6.1.4
Adverse Event Collection Period.........................................................107
6.1.5
Adverse Event Reporting.....................................................................108
6.1.6
Pregnancy............................................................................................110
6.1.7
Toxicity Management..........................................................................110
6.2
Product Complaint...............................................................................111
6.2.1
Definition............................................................................................111
6.2.2
Reporting ............................................................................................112
7.0
Protocol Deviations ........................................................... 112
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 113
8.1
Statistical and Analytical Plans............................................................113
8.1.1
Analyzable Population.........................................................................113
8.1.2
Planned Methods of Statistical Analysis ..............................................114
8.1.3
Demographics and Baseline Characteristics.........................................114
8.1.4
Statistical Analyses of Efficacy ...........................................................115
8.1.4.1
Primary Efficacy Variable for Induction Study....................................115
8.1.4.2
Secondary Efficacy Variables for Induction Study...............................115
8.1.4.3
Efficacy Variables for Maintenance Study...........................................116
8.1.5
Statistical Analyses of Safety...............................................................117
8.1.6
Other Statistical Analyses of Efficacy..................................................117
8.1.7
Interim Analysis..................................................................................118
8.1.8
Pharmacokinetic Analyses...................................................................119
8.2
Determination of Sample Size .............................................................119
8.3
Randomization Methods......................................................................120
9.0
Ethics.................................................................................. 121
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................121
9.2
Ethical Conduct of the Study...............................................................121
9.3
Subject Information and Consent.........................................................122


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10.0
Source Documents and Case Report Form 
Completion ........................................................................ 123
10.1
Source Documents...............................................................................123
10.2
Case Report Forms ..............................................................................123
10.3
Electronic Patient Reported Outcomes (ePRO)....................................125
10.4
Data Collection Process.......................................................................126
11.0
Data Quality Assurance .................................................... 126
12.0
Use of Information ............................................................ 126
13.0
Completion of the Study ................................................... 128
14.0
Investigator's Agreement.................................................. 129
15.0
Reference List.................................................................... 130
List of Tables
Table 1.
Efficacy Rates at Week 12 (ITT) of the M05-769 Study ....................... 29
Table 2.
Adalimumab Dose Adjustment Criteria ................................................ 37
Table 3.
Study Activities.................................................................................... 55
Table 4.
Clinical Laboratory Tests ..................................................................... 69
Table 5.
Study Drugs ......................................................................................... 97
List of Figures
Figure 1.
Therapeutic Drug Monitoring (TDM) Regimen Schematic ................... 36
Figure 2.
Study Schematic................................................................................... 38
Figure 3.
Adverse Event Collection....................................................................108
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................131
Appendix B.
List of Protocol Signatories .................................................................133
Appendix C.
Sample Work Productivity and Activity Impairment 
Questionnaire:  Crohn's Disease V2.0 (WPAI:CD) ..............................134
Appendix D.
Sample EQ-5D Questionnaires ............................................................136


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Appendix E.
Sample Quality of Life in Inflammatory Bowel Disease 
Questionnaire (IBDQ) .........................................................................138
Appendix F.
Abdominal Pain Rating Scale ..............................................................148
Appendix G.
Injection Instructions – Sample Pre-Filled Syringe ..............................149
Appendix H.
Crohn's Disease Activity Index (CDAI)...............................................156
Appendix I.
Standard Weights ................................................................................157
Appendix J.
70-Day Follow-Up Phone Call – Sample .............................................160
Appendix K.
Guidelines to Evaluate Loss of Response and Intolerance to 
Infliximab............................................................................................161
Appendix L.
Bristol Stool Form Scale......................................................................162
Appendix M.
SES-CD Scoring..................................................................................163
Appendix N.
Protocol Amendment:  List of Changes ...............................................164


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3.0
Introduction
Crohn's disease 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 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.  
A new endpoint for efficacy of therapy was discussed at the Organization for the Study of 
Inflammatory Bowel Disease (IOIBD); the achievement of mucosal remission measured 
as SES-CD of ≤ 2.0.9  This endpoint was added to the Induction Study and as an 
exploratory endpoint in the Maintenance study.


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Comparison of various efficacy endpoints assessed in the EXTEND study 
(Study M05-769) suggests that when raising the efficacy standard from one that is driven 
by symptoms to one that is more objective (i.e., assessment of improvement in the 
condition of the intestinal mucosa), there is an overall decrease in both efficacy rate and 
effect size for adalimumab.7
Table 1.
Efficacy Rates at Week 12 (ITT) of the M05-769 Study
Placebo
ADA 160/80
Effect Size
P Value
Clinical Remissiona n/N (%)
18/65 (28)
30/64 (47)
19
0.021
Mucosal Healingb n/N (%)
8/61 (13)
17/62 (27)
14
0.056
ITT = intent-to-treat
a.
Defined as CDAI < 150.
b.
Defined as absence of mucosal ulceration as confirmed by central reader's visual assessment of the 
ileocolonoscopy.
Note:
Four patients randomized to placebo and 2 patients randomized to ADA were excluded from the mucosal 
healing analysis as they had absence of mucosal ulceration at screening (as judged by the review committee).
Exposure-response analyses based on adalimumab trough serum concentration and 
Crohn's disease activity index (CDAI)-based efficacy (remission, CR-70 and CR-100) at 
Week 4 conducted with data from previous adalimumab induction studies (CLASSIC 
[Study M02-403] and GAIN [Study M04-691]) have shown that higher Week 4 efficacy 
rates corresponded to higher adalimumab trough serum concentrations in both anti-TNF 
naïve and anti-TNF experienced subjects.  Therefore, to improve the likelihood of 
achieving more stringent efficacy endpoints, such as endoscopic improvement of the 
intestinal mucosa, more intensive treatment with adalimumab may be required.
For the reasons described above, this study is designed to investigate the efficacy and 
safety of two adalimumab induction regimens (higher and standard) in adult subjects with 
moderately to severely active CD and evidence of mucosal ulceration.  Additionally, the 
study will evaluate the sustained efficacy of the standard maintenance therapy of 40 mg 
adalimumab dosing every other week with subjects whose dosing is either guided by 
trough adalimumab concentrations (Therapeutic Drug Monitoring regimen) or by clinical 
assessment without adalimumab concentrations (Clinically Adjusted regimen).


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3.1
Differences Statement
The primary difference between Study M14-115 and the other CD studies, are the 
inclusion of subjects with evidence of mucosal ulceration defined as SES-CD ≥ 6, 
excluding the presence of narrowing component, or SES-CD ≥4, excluding the presence 
of narrowing component, for patients with disease limited to the ileum on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
central reader.  Subjects would be required to have presence of ulceration confirmed by 
central reader prior to Baseline.  An additional difference is the inclusion of an induction 
regimen higher than has previously been studied in CD in the 12 week Induction Study.  
For the first time in a blinded study, the Maintenance Study of this protocol presents the 
option to adjust adalimumab dosing from eow to ew based on trough adalimumab 
concentrations as compared to adjustment based on clinical assessment of hs-CRP and 
CDAI.  
3.2
Benefits and Risks
Extensive clinical and post marketing experience exists with adalimumab in a wide range 
of disease states including Crohn's disease 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 current 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, Crohn's Disease, 
ulcerative colitis, polyarticular Juvenile Idiopathic Arthritis, pediatric Crohn's Disease, 
pediatric psoriasis as well as pediatric enthesitis related arthritis and non-radiographic 
axial spondyloarthritis in EU only and intestinal Beçhet's Disease in Japan.  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 rheumatoid arthritis.  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 Food and Drug Administration (FDA)-requested, TNF inhibitor class 


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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 reporting requirements needed in this unlikely event, outlined in 
Section 6.1.5 under Adverse Event Reporting.
4.0
Study Objective
The primary objective of this study is to assess the efficacy and safety of two adalimumab 
induction regimens in achieving clinical remission (CDAI < 150) at Week 4 and 
endoscopic response defined as decrease in SES-CD > 50% from Baseline (or for a 
Baseline SES-CD of 4, at least a 2 point reduction from Baseline) at Week 12, in subjects 
with moderately to severely active Crohn's disease and evidence of mucosal ulceration at 
Baseline.
Additional objectives include:
●
Assessing the efficacy and safety of two adalimumab induction regimens in 
reducing signs and symptoms of Crohn's disease at Week 12.
●
Assessing the efficacy and safety of two adalimumab maintenance regimens in 
reducing signs and symptoms of Crohn's disease at Week 56.
●
Assessing pharmacokinetics (PK) and immunogenicity of two adalimumab 
induction regimens following subcutaneous (SC) administration.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a randomized, double-blind multicenter study of two adalimumab induction and 
maintenance regimens in subjects with moderately to severely active CD with evidence of 
mucosal ulceration confirmed by central reading.  No placebo arm is planned since there 
is well-documented efficacy of adalimumab in CD and because the purpose of this study 
is to achieve better efficacy than the standard induction and maintenance regimens in 


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terms of clinical remission and endoscopic response.  Additionally, since subjects will be 
required to have failed or been intolerant of standard therapies and have evidence of 
endoscopic damage confirmed by a central reader, it would be not medically acceptable to 
deny those subjects effective treatment or feasible to enroll subjects in the trial when 
adalimumab is available to be prescribed for CD.
Approximately 500 adult subjects with active Crohn's disease, defined as having a CDAI 
of ≥ 220 and ≤ 450 and evidence of mucosal ulceration defined as SES-CD ≥ 6, excluding 
the presence of narrowing component, or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
centrally read endoscopy, will be enrolled at approximately 150 sites worldwide.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the study and randomized in a 3:2 ratio at Baseline to receive a higher 
induction adalimumab regimen or standard induction adalimumab regimen during the 
double-blind Induction Study.  Assuming the Week 4 clinical remission rate will be 
approximately 50% for the higher induction dose regimen and approximately 30% for the 
standard dose regimen, a sample size of 500 (300 higher dose and 200 standard dose) will 
be adequate to detect at least a 20% treatment difference in clinical remission rates at 
Week 4 between the dosing regimens using Fisher's exact test with 99% power at a 0.05 
two-sided significant level.
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts an expected ~50% 
increase in the proportion of subjects with endoscopic response compared to the standard 
adalimumab induction regimen.  The observed rate of endoscopic response (decrease 
> 50% SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction 
from Baseline]) in Study M05-769 was 44% at Week 12 with the currently approved 
dosing regimen.  Thus, by extrapolation, the expected rate for endoscopic response at 
Week 12 using the higher induction regimen is 66%.  A sample size of 500 subjects 
(300 higher induction regimen and 200 standard induction regimen) will be adequate to 


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detect at least a 22% treatment difference in endoscopic response (decrease >50% SES-
CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 99% power at a 0.05 two-sided significance level.
Since the clinical remission at Week 4 endpoint and the endoscopic response at Week 12 
endpoint are likely not independent of each other, the power for the co-primary endpoints 
for the study is expected to be > 98% (see Section 8.2 for detailed assumptions of the 
sample size calculation).
The randomization of subjects for the Induction Study will be stratified by hs-CRP at 
Baseline (< 10 and ≥ 10 mg/L), using the Screening hs-CRP value, prior infliximab use, 
and Crohn's disease activity (CDAI ≤ 300, > 300), at Baseline.  Enrollment of subjects 
with prior infliximab use will be limited to 25% of the total study population.
Subjects assigned to the higher induction regimen will receive blinded adalimumab 
160 mg at Baseline, Week 1, Week 2, and Week 3.  At Week 4, subjects will receive 
40 mg every other week (eow) through Week 12.  Subjects assigned to the standard 
adalimumab induction regimen will receive blinded adalimumab 160 mg at Baseline and 
matching placebo at Week 1.  Subjects will receive 80 mg and matching placebo at 
Week 2, and then matching placebo at Week 3.  At Week 4, subjects will receive 40 mg 
every other week through Week 12.
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-
blinded exploratory treatment regimens (adalimumab clinically adjusted [CA] regimen 
and adalimumab therapeutic drug monitoring [TDM] regimen).  The re-randomization at 
Week 12 will be stratified by induction treatment regimen, clinical response (CR-70) 
status at Week 12 and decrease in SES-CD > 50% from Baseline per the site investigator 
reading at Week 12.  Among subjects achieving SES-CD > 50% from Baseline at 
Week 12, the randomization will be further stratified by achievement of an SES-CD ≤ 4 
and at least a 2 point reduction versus Baseline and no subscore greater than 1 in any 


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individual variable using the Week 12 SES-CD value provided by the site.  No study drug 
will be administered or injected at the final visit.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab 
every other week beginning at Week 12.  The adalimumab dose will be escalated to every 
week starting as early as Week 14 if the subject's CDAI is ≥ 220 or hs-CRP ≥10 mg/L 
(using results from the prior or current visit).  These subjects will also be allowed to 
escalate at unscheduled visits that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 
44, 46, 50, 52 and 54.  Once subjects in the CA regimen are escalated, they will remain on 
40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will 
be determined by the dose adjustment criteria table (Table 2).  Doses will be determined 
using blinded serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) 
as well as the CDAI or hs-CRP values from the current or prior visit.  For subjects who 
meet criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 40 mg 
weekly.


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Figure 1.
Therapeutic Drug Monitoring (TDM) Regimen Schematic


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Table 2.
Adalimumab Dose Adjustment Criteria
Adalimumab Dose Adjustment Criteriaa
ADA Serum Concentrationb (ug/mL)
CDAIc
hs-CRPd (mg/L)
Dose Change?
Clinically Adjusted Regimen
any
< 220
< 10
no
any
any
≥ 10
yes; dose escalate to ew
any
≥ 220
any
yes; dose escalate to ew
Therapeutic Drug Monitoring Regimen
< 5 
any
any
yes; dose escalate to ew
5 – 10
< 220
< 10
no
5 – 10
any
≥ 10
yes; dose escalate to ew
5 – 10
≥ 220
any
yes; dose escalate to ew
> 10
any
any
no
a.
For subjects experiencing an active infection or those for whom the investigator feels dose escalation is not 
advisable, the investigator should contact the Study Designated Physician.
b.
Measured from the serum concentration taken at the prior study visit.
c.
Measured using hematocrit taken from prior study visit for CDAI calculation.
d.
Measure using hs-CRP from the prior or current study visit.
The duration of the study could be up to 60 weeks which includes a Screening Period
(1 – 4 weeks, ± 3 days which is granted around all study visits), a 12 week double-blind 
period Induction Study, and a double-blind 44-week Maintenance Study.  The Screening 
Period may be extended as necessary after consultation and approval with the AbbVie 
Study Designated Physician (SDP) for subjects who require initiation of prophylactic anti-
tuberculosis (TB) therapy, or in case of external, not subject-related circumstances 
(e.g., due to delay of availability of screening test results).  There will also be a 70-day 
follow-up phone call for subjects who complete Week 56 or discontinue from the study 
prematurely.
A schematic of the study design is presented in Figure 2.


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Figure 2.
Study Schematic
Clinical evaluation will be at visits occurring at Baseline, Weeks 2, 4, 6, 8, 12, 14, 20, 26, 
28, 34, 40, 42, 48, and 56/PD.  An electronic diary will be dispensed at the Screening 
visit.  In addition to routine physical examination, CDAI calculation, diary review, 
laboratory, adverse event, concomitant medication and vital sign assessments, the 
following will be collected:
●
Results of study questionnaires (inflammatory bowel disease questionnaire 
[IBDQ], European Quality of Life 5 dimensions [EQ-5D], work productivity 
and impairment [WPAI]) at Baseline, Week 4, Week 8, Week 12, Week 26, 
Week 40 and Week 56/PD.
●
Calculation of the SFPS at Baseline, Week 2, Week 4, Week 6, Week 8, 
Week 12, Week 14, Week 20, Week 26, Week 28, Week 34, Week 40, 
Week 42, Week 48 and Week 56/PD.  The Screening results will serve as the 
Baseline value.
●
Results of daily Bristol Stool Form Scale beginning at Baseline through 
Week 56/PD.
●
Results of 11-point Abdominal Pain Rating Scale beginning at Baseline, 
Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and 
Week 56/PD.


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●
Serum for measurement of adalimumab concentrations just prior to dosing at 
Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, 
and Week 56/PD.
●
Serum for measurement of Anti-Adalimumab Antibodies (AAA) just prior to 
dosing at Baseline, Week 4, Week 12, Week 26, Week 40, and Week 56/PD.
●
Serum for measurement of infliximab serum levels and Human Anti-Chimeric 
Antibodies (HACA) just prior to dosing at Baseline.
●
Serological biomarkers/mRNA at Baseline, Week 2, Week 4, Week 8,
Week 12, Week 26, Week 40, and Week 56/PD.
●
Stool samples for analysis of fecal calprotectin during Screening, at Week 4, 
Week 12, Week 26, and Week 56/PD.
●
Stool samples for microbiota metagenomic analyses during Screening, at 
Week 4, Week 12, Week 26, and Week 56/PD.  The stool samples should be 
taken before starting bowel preparations for endoscopy.
●
Endoscopic evaluations, eligibility confirmed by central reader, will be done at 
Screening, Week 12, and Week 56/PD.
●
An optional pharmacogenetic sample should be drawn at Baseline and 
Week 12.
Throughout the study, subjects will only be allowed to change the dosage of CD-specific 
concomitant medications as specified below:
●
At Week 4, subjects who are taking corticosteroid therapy at Baseline will 
have their corticosteroid therapy tapered according to a tapering schedule 
specified in the clinical study protocol.  If the Investigator feels that the steroid 
taper is not advisable for a particular subject at Week 4, the Study Designated 
Physician (SDP) should be consulted for evaluation and approval.
●
Subjects taking corticosteroids at Baseline who have a loss of satisfactory 
clinical response per the Investigator's judgment after the steroid taper has 
been initiated may have their corticosteroid dose increased per the 
Investigator's discretion during the study.  Subjects in whom the maximum 
steroid dose equivalent exceeds the dose used at Baseline will be censored for 
efficacy assessments (i.e., will be considered non-responders for categorical 


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endpoints and will have the last non-missing values carried forward for non-
categorical assessments) from that point forward.  These subjects will continue 
to be evaluated in the safety population.
●
Immunosuppressant doses may be decreased or terminated in the event of 
moderate-to-severe treatment-related toxicities.
The study was designed to enroll 500 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target number of subjects has been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.
Re-Screening
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  All screening procedures with the possible exceptions noted below will be 
repeated.  The subject must meet all inclusion and none of the exclusion criteria at the 
time of re-screening in order to qualify for the study.  There is no minimum period of time 
a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon Gamma Release Assay (IGRA; QuantiFERON-TB Gold 
In-Tube test or T SPOT TB test) chest x-ray (if applicable) and electrocardiogram (ECG), 
these tests will not be required to be repeated for re-screening provided the conditions 
noted in Section 5.3.1.1 are met and no more than 90 days have passed.  If an endoscopy 
was performed, this will not be required to be repeated for re-screening provided the 
conditions noted in Section 5.3.1.1 are met and no more than 45 days have passed 
between the endoscopy date and the Baseline date.  As appropriate, sites are encouraged 
to contact the AbbVie Study Designated Physician (SDP) to confirm if subjects should or 
should not be re-screened.
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have a Premature Discontinuation Visit.  
All subjects who discontinue from the study prematurely will have a follow-up phone call 


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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 will not be 
required for any subject that initiates commercial adalimumab.
5.2
Selection of Study Population
5.2.1
Inclusion Criteria
1.
Males and females ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of colonic, ileocolonic, or ileal Crohn's disease for ≥ 3 months prior to 
Baseline and confirmed by endoscopy during the Screening period or endoscopy 
performed within 45 days before Baseline with exclusion of current infection, 
dysplasia, and/or malignancy.  Appropriate documentation of biopsy results 
consistent with the diagnosis of CD, in the assessment of the Investigator, must be 
available.
3.
Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6, excluding the 
presence of narrowing component, or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum, on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
central reader.
4.
Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450 at Baseline despite 
concurrent or prior treatment with a full and adequate course, in the opinion of the 
Investigator, of at least one of the following (oral corticosteroids and/or 
immunosuppressants or both as defined below):
●
Subject taking oral corticosteroids, excluding budesonide:
○
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
●
For subjects with a dose > 10 and ≤ 40 mg/day, dose has been stable 
for at least 7 days prior to Baseline and the duration of the current 
steroid course has been at least 14 days prior to Baseline.


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●
For subjects with a dose ≤ 10 mg/day, dose has been stable for at least 
10 days prior to Baseline and the duration of the current steroid course 
has been at least 14 days prior to Baseline.
●
Subject taking oral budesonide:
○
Dose must not exceed 9 mg/day;
●
For subjects with a dose ≥ 6 mg/day, dose has been stable for at least 
7 days prior to Baseline and the duration of the current steroid course 
has been at least 14 days prior to Baseline.
●
For subjects with a dose < 6 mg/day, dose has been stable for at least 
10 days prior to Baseline and the duration of the current steroid course 
has been at least 14 days prior to Baseline.
or,
●
At least a consecutive 42-day course of azathioprine, 6-MP, or injectable MTX 
prior to Baseline, with a stable dose for at least 28 days prior to Baseline of 
azathioprine ≥1.5 mg/kg/day or 6-MP ≥ 1 mg/kg/day (rounded to the nearest 
available tablet or half tablet formulation) or a documented 6-TGN level of at 
least 230 pmol/8 × 108 RBC to clarify a therapeutic level was achieved on the 
current dosing regimen or MTX ≥15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the subject 
(e.g., due to leukopenia, elevated liver enzymes, nausea) during that time.
Note:  If a subject is taking both an oral corticosteroid and an 
immunosuppressant listed above, BOTH of the drugs need to meet the above 
criteria.  Oral MTX use is allowed during the study (at a stable dose for 
28 days prior to Baseline) however current or prior use of oral MTX is not 
sufficient for inclusion into the study.
or
●
Concurrent therapy with oral corticosteroids or immunosuppressants 
(azathioprine, 6-MP or SC/IM MTX) is not required for subjects not currently 
taking these medications who were previously treated during the past 1 year 
and have confirmed documentation of failure to respond, or were previously 
treated during the past 5 years and have confirmed documentation indicating 
lack of tolerability, see Section 10.1.


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5.
Subject may be included if they have previously experienced a benefit from 
infliximab and discontinued its use due to a subsequent loss of response (judged by 
the Investigator to have responded to infliximab in the past and subsequently 
experienced an overall lack of improvement or worsening of CD-related 
symptoms) or intolerance (in the opinion of the Investigator therapy was 
discontinued as a result of a significant acute or delayed infusion/administration 
reaction to the medication) to the agent.  Confirmed documentation indicating loss 
of response or lack of tolerability will be required.
6.
Subject has a negative TB Screening Assessment (including a PPD test or 
QuantiFERON TB Gold test [or equivalent]) and negative chest x-ray (CXR – PA 
and lateral view) at Screening.  If the subject has evidence of a latent TB infection; 
the subject must initiate and complete a minimum of 2 weeks of an ongoing TB 
prophylaxis or have documented completion of a full course of anti TB 
prophylaxis, prior to Baseline.
7.
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


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●
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.
8.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.
9.
Subject is judged to be in otherwise good health as determined by the Principal 
Investigator based upon the results of medical history, laboratory profile, physical 
examination, CXR, and a 12-lead electrocardiogram (ECG) performed during 
Screening.
10.
Subject must be able and willing to self-administer subcutaneous (SC) injections or 
have a qualified person available to administer SC injections.
Criteria
Rationale
1
In accordance with good clinical practice (GCP)
2 – 9
In order to select the appropriate subject population with a disease status representative of 
the target population for evaluation.
10
In order to select subjects who will comply with study procedures for adequate evaluation.
5.2.2
Exclusion Criteria
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
2.
Subject on azathioprine, 6-mercaptopurine (6-MP), methotrexate (MTX), or 
another immunosuppressant (e.g., thalidomide) who:
●
Has not been on these medications for at least 42 days prior to Baseline; or
●
Has not been on stable doses of these medications for at least 28 days prior to 
Baseline; or 
●
Has discontinued these medications within 14 days of Baseline.
3.
Subject on oral aminosalicylates who:


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●
Has not been on stable doses of these medications for at least 28 days prior to 
Baseline; or
●
Has discontinued use of aminosalicylates within 14 days of Baseline.
4.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subjects 
on budesonide > 9 mg/day; or
●
Subject taking an oral corticosteroid (excluding budesonide):
○
dose > 10 mg/day, but has not been on a stable dose for at least 7 days 
prior to Baseline; or
○
dose > 10 mg/day, but has not been on a current steroid course for at least 
14 days prior to Baseline; or
○
dose ≤ 10 mg/day or equivalent, but has not been on a stable dose for at 
least 10 days prior to Baseline; or
○
dose ≤ 10 mg/day or equivalent but has not been on a current steroid 
course of at least 14 days in duration prior to Baseline, or
●
Subject taking budesonide:
○
dose ≥ 6 mg/day, but has not been on a stable dose for at least 7 days prior 
to Baseline; or
○
dose ≥ 6 mg/day, but has not been on a current steroid course for at least 
14 days prior to Baseline; or
○
dose < 6 mg/day dose but has not been on a stable dose of at least 10 days 
prior to Baseline; or
○
dose < 6 mg/day but the current course has not been at least 14 days in 
duration prior to Baseline; or
Has been taking both oral budesonide and prednisone (or equivalent) 
simultaneously, with the exception of inhalers.
5.
Received intravenous corticosteroids within 14 days prior to Screening or during 
the Screening Period.
6.
Subject who has had surgical bowel resections within the past 6 months or is 
planning any resection at any time point while enrolled in the study.
7.
Subject with a symptomatic bowel stricture.


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8.
Subject with an abdominal or peri-anal abscess.
9.
Subject with an ostomy or ileoanal pouch.
10.
Subject who has short bowel syndrome.
11.
Subject has received therapeutic enema or suppository, other than required for 
endoscopy, within 14 days prior to Screening and/or during the Screening period.
12.
Prior exposure to medications that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML), including participation in a 
clinical trial of investigational agents targeting white cell trafficking 
(e.g., natalizumab [Tysabri®], rituximab [Rituxan®], efalizumab [Raptiva®]).  Prior 
exposure to any anti-TNF agent other than infliximab (including etanercept 
[Enbrel®], golimumab [Simponi®] or certolizumab pegol [Cimzia®]).  Prior 
exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).
13.
Subject who received any investigational agent or procedure within 30 days or 
5 half-lives prior to the Baseline, whichever is longer.
14.
Subject who previously received treated with adalimumab or previously 
participated in an adalimumab clinical study.
15.
Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 
60 days prior to Baseline.
16.
Subject who previously received stem cell transplantation.
17.
Subject who previously received fecal microbial transplantation.
18.
Subject that received non-steroidal anti-inflammatory drugs (NSAIDs) within 
14 days prior to Screening and during the Screening visit, except low-dose aspirin 
for prevention of heart attacks, unstable angina or transient ischemic attacks or 
topical NSAIDs.


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19.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral anti-infectives for non-Crohn's disease 
related infections within 14 days prior to the Baseline Visit.
20.
Subjects on Crohn's disease related antibiotics that have not been on stable doses 
for at least 4 weeks prior to Baseline.  Subjects on Crohn's disease related 
antibiotics that have discontinued these medications within 4 weeks of Baseline are 
excluded.
21.
Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN 
at any time during the course of the study.
22.
Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the 
Screening period.
23.
Screening laboratory and other analyses show any of the following abnormal 
results:
●
AST, ALT > 1.75 × upper limit of the reference range;
●
WBC count < 3.0 × 109/L;
●
Electrocardiogram (ECG) – with clinically significant abnormalities;
●
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of 
indirect bilirubin relating to Gilbert syndrome;
●
Serum creatinine > 1.6 mg/dL.
24.
Known hypersensitivity to adalimumab or its excipients.
25.
Subject who has previously used infliximab:
●
and has not clinically responded at any time ("primary non-responder") unless 
subject experienced a treatment limiting reaction;
or
●
who used infliximab within 56 days of Baseline.
26.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.


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27.
History of invasive infection (e.g., listeriosis and histoplasmosis) or human 
immunodeficiency syndrome (HIV).
28.
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.
29.
Subjects with a positive result for the Hepatitis B surface antigen (HBs Ag) will be 
excluded.  Samples that are negative for HBs Ag will be tested for surface 
antibodies (HBs Ab) and core antibodies (HBc Ab Total).  Subjects with 
HBs Ag (–), HBs Ab* (–), and HBc Ab Total (+) require PCR qualitative testing 
for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection 
sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not 
require HBV DNA PCR qualitative testing:
●
HBc Ab Total (–) and HBs Ab* (–)
●
HBc Ab Total (–) and HBs Ab* (+)
●
HBc Ab Total (+) and HBs Ab* (+)
*
For HBs Ab test results, a (–) result is equivalent to nonreactive and a (+) 
result is equivalent to reactive.
30.
Chronic recurring infections.
31.
Subject with active TB.
32.
Subject with latent TB infection unless there is evidence the subject initiated and 
completed a minimum of 2 weeks of an ongoing TB prophylaxis or has 
documented completion of a full course of anti-TB prophylaxis, prior to Baseline.
33.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and any other condition which, in the opinion of 
the Investigator, would put the subject at risk by participation in the study.


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34.
Subject with a previous history of dysplasia of the gastrointestinal tract, or found to 
have dysplasia in any biopsy performed during the Screening endoscopy or 
endoscopy performed within 45 days before Baseline.
35.
Positive pregnancy test at Screening (serum) or Baseline (urine).
36.
Female subjects who are breastfeeding or considering becoming pregnant during 
the study.
37.
History of clinically significant drug or alcohol abuse in the last 12 months.
38.
Clinically significant abnormal screening laboratory results as evaluated by the 
Investigator.
39.
Current evidence of dysplasia or history of malignancy (including lymphoma and 
leukemia) other than a successfully treated non-metastatic cutaneous squamous cell 
or basal cell carcinoma or localized carcinoma in situ of the cervix.
40.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
Criteria
Rationale
1
To avoid medical conditions that may compromise the ability to identify subjects 
with the correct diagnosis or to interpret medical importance of clinical results.
2 – 5
To exclude subjects who have not been treated with conventional therapies.
19 – 20, 22, 
24 – 36, 39
To reduce the risk to subjects or others and/or to exclude underlying conditions 
that would compromise the subject's safety.
40
To maintain the integrity of other aspects of study conduct, including, subject 
sampling, treatment procedures, etc.
6 – 10, 11 – 18, 21, 
23
To avoid bias for the evaluation of efficacy and safety by concomitant use of other 
medications or treatments.
37, 38
To exclude subjects who maybe at increased risk for protocol non-adherence or 
premature discontinuation.


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5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any non CD-related medication or vaccine (including over-the-counter or prescription 
medicines, vitamins and/or herbal supplements) that the subject has received within 
30 days prior to Baseline, is receiving at the time of enrollment, 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).
Crohn's disease specific medications (including but not limited to corticosteroids, 
aminosalicylates, immunosuppressant agents, and CD-related antibiotics) that the subject 
has received within 90 days of Baseline should be recorded on the appropriate page of the 
eCRF and should include the dates of administration and dosages.  Antibiotics taken for 
any reason other than Crohn's disease within 90 days of Baseline should be recorded on 
the appropriate page of the eCRF and should include the reason for use, dates of 
administration and dosages.
Subjects who failed to respond to corticosteroids or immunosuppressants (azathioprine, 
6-MP or MTX) within the past 1 year require a confirmed documentation of failure.  The 
dates (start and end dates) of the most recent course of treatment and the maximum daily 
dosage of the most recent course of treatment and reasons for discontinuation is to be 
recorded in the appropriate eCRF.  In addition the highest known dose taken within the 
past 1 year will be recorded.  For subjects who were intolerant to treatment with 
corticosteroids or immunosuppressants (azathioprine, 6-MP or MTX) within the past 
5 years confirmed documentation of intolerance is required.  The highest known dose 
taken will be recorded in appropriate eCRF.
Subjects who previously experienced a benefit from infliximab and discontinued its use 
due to a subsequent loss of response (judged by the Investigator to have responded to 
infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of CD related symptoms) or intolerance (in the opinion of the investigator 


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therapy was discontinued as a result of a significant acute or delayed 
infusion/administration reaction to the medication) to the agent will have the highest 
known dose taken recorded in the appropriate eCRF (Appendix K).
In addition, for subjects age ≤ 30 with a reported malignancy adverse event, 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 eCRF pages.  At the 
time of the reported malignancy adverse event, 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, 
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.
The AbbVie study designated physician identified in Section 6.1.5 should be contacted if 
there are any questions regarding concomitant or prior therapy(ies).
5.2.3.2
Concomitant Therapy
Doses of immunosuppressants (including but not limited to) azathioprine, 6-MP, and 
methotrexate and aminosalicylates taken at Baseline 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.
Doses of Crohn's disease related antibiotics taken at Baseline will be continued.  Change 
in dose of Crohn's disease related antibiotics during the study will not be allowed except 
for treatment related toxicities or concerns about development of antibiotic resistance.  
Newly prescribed CD related antibiotics is not allowed during the study.
Doses of corticosteroids taken at Baseline, as outlined in inclusion criterion 4 in 
Section 5.2.1, will be continued.  Subjects are not allowed to change the corticosteroid 


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dose during the first 4 weeks of the study except in the event of treatment-related 
toxicities considered moderate to severe in the opinion of the Investigator.  At Week 4, all 
subjects who are taking corticosteroid therapy at Baseline will have their corticosteroid 
therapy tapered according to a tapering schedule specified below and in Section 5.3.1.1.
If the Investigator feels that the steroid taper is not advisable for a particular subject at 
Week 4, the SDP should be consulted for evaluation and approval.
A proposed regimen to taper prednisone dose starts with a weekly decrease by 5 mg/day 
prednisone (or equivalent) for doses > 10 mg/day of prednisone (or equivalent) until a 
10 mg/day (or equivalent) dose is reached, then a weekly decrease by 2.5 mg/day (or 
equivalent) until discontinuation.  A proposed regimen to taper budesonide dose starts 
with a weekly decrease by 3 mg/day budesonide until discontinuation.
Subjects taking corticosteroids at Baseline who have a loss of satisfactory clinical 
response per the Investigator's judgment after the steroid taper has been initiated may 
have their corticosteroid dose increased per the Investigator's discretion during the study.  
Subjects in whom the maximum equivalent steroid dose exceeds the dose used at Baseline 
will be censored for efficacy assessments (i.e., they will be considered non-responders for 
categorical endpoints and will have the last non-missing values carried forward for non-
categorical assessments) from that point forward.  These subjects will continue to be 
evaluated in the safety population.  In addition, subjects in whom the CD-related 
corticosteroids that were not being taken at Baseline and are initiated during the study will 
be censored for efficacy assessments (i.e., they will be considered non-responders for 
categorical endpoints and will have the last non-missing values carried forward for non-
categorical assessments) from that point forward.  These subjects will continue to be 
evaluated in the safety population.
Subjects may not be on both budesonide and prednisone (or equivalent) simultaneously.
Subjects who enter the study on probiotics may continue this therapy provided doses 
remain stable from Baseline throughout the duration of the study.


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Subjects in whom the following CD-related medications (oral or rectal aminosalicylates, 
thiopurines and MTX) that were not being taken at Baseline and are initiated during the 
study or who have dosages of these medications increased to greater than the dose taken at 
Baseline is prohibited during the study, except in the event of moderate-to-severe 
treatment related toxicities and after discussion with the AbbVie TA MD.
Changes in all concomitant medications will be assessed at each study visit from Baseline 
(Week 0) through Week 56/PD Visits.  Any changes will be documented in the source 
documents and captured on the appropriate eCRF page.
The AbbVie Study Designated Physician identified in Section 6.1.5 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:
●
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®);
○
Infliximab (Remicade®);
○
Certolizumab pegol (Cimzia®);
○
Golimumab (Simponi®);
○
Vedolizumab (Entyvio®).


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●
Tofacitinib (Xeljanz®)
●
NSAIDs (excluding low-dose aspirin for prevention of heart attacks, unstable 
angina or transient ischemic attacks and topical NSAIDs).
●
Live vaccines (during the study and for 70 days after the last dose of study 
drug).
●
Cyclosporine, tacrolimus, or mycophenolate mofetil (within 60 days prior to 
Baseline and during the study).
●
Recreational or medical marijuana use 14 day prior to Baseline or during the 
study.
Rectal therapy with any therapeutic enemas or suppositories, with the exception of those 
required for endoscopy, is prohibited within 14 days prior to Screening endoscopy, during 
the remainder of the Screening Period and during the study.
Intravenous corticosteroid use is prohibited within 14 days prior to Screening, during the 
Screening Period and during the study.
Investigational drugs of a chemical or biologic nature are prohibited within 30 days or 
5 half-lives (whichever is longer) of the drug prior to the Baseline and during the study.
The AbbVie study designated physician identified in Section 6.1.5 should be contacted if 
there are any questions regarding prohibited therapy.
5.3
Efficacy, Pharmacokinetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures will be performed as summarized in Section 5.3.1.1.  All subjects must 
meet the study selection criteria outlined in Section 5.2.1 and Section 5.2.2 in order to be 
randomized in to the study.


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Table 3.
Study Activities
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/ Premature 
Discontinuation
Informed Consent
X
Inclusion/Exclusionb
X
X
Medical/Surgery Historyb
X
X
Previous and Concomitant Medicationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopyd
X
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB Screeningf
X
Chest X-Rayg
X
ECGh
X
Chemistry and Hematologyi
X
X
X
X
X
X
X
X
X
X
Urinalysisi,j
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testsk
Xk
X
X
X
Hepatitis B Screen and HIVl
X


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Table 3.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/ Premature 
Discontinuation
hs-CRP
X
X
X
X
X
X
X
X
X
X
C. difficile toxin
X
Antinuclear antibody (ANA)/Anti-double-
stranded DNA (anti dsDNA)m
X
Stool Sample (microbiota metagenomic 
analyses and fecal calprotectin)n
X
X
X
X
X
X
Human Antichimeric Antibodies 
(HACA)/Infliximab Concentrations
X
Adalimumab Concentrationo
X
X
X
X
X
X
X
X
X
X
AAA Concentrationo
X
X
X
X
X
X
X
Pharmacogenetic Markerp
X
X
Serological Biomarkers/mRNA
X
X
X
X
X
X
X
X


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Table 3.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/ Premature 
Discontinuation
Crohn's Disease Activity Index (CDAI) 
CDAI components "Number of liquid or 
very soft stools" and "Abdominal pain" 
(Stool [liquid/soft] Frequency + 
Abdominal Pain Score; SFPS)
X
Xu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SES-CD Score
X
X
X
Inflammatory Bowel disease 
Questionnaire (IBDQ)
X
X
X
X
X
X
X
European Quality of Life 5 dimensions 
(EQ‑5D)
X
X
X
X
X
X
X
Work Productivity and Impairment 
Questionnaire (WPAI)
X
X
X
X
X
X
X
Abdominal Pain Rating Scale
X
X
X
X
X
X
X
X
X
Corticosteroid Taperq
X
X
X
X
X
Monitor Adverse Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing/Administrations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 3.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/ Premature 
Discontinuation
Dispense Subject Diary
X
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intestinal Biopsiesp
X
X
X
a.
The Screening period will be a minimum of 7 days for CDAI calculation.  The CDAI calculated at Screening will serve as the Baseline CDAI.  Baseline visit date will serve 
as the reference for all subsequent visits.  A ± 3-day window is permitted around all study visits.
b.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
c.
Height will be measured at Screening only (with shoes off, and then adding 1 inch or 2.5cm).
d.
An ileocolonoscopy will be performed during Screening or one performed within 45 days before Baseline, Week 12, and at Week 56/PD.  A biopsy will be performed at 
Screening, Week 12, and Week 56/PD if a suspicious lesion or suspected malignancy, in the assessment of the Investigator, is observed, and evaluated by the local 
pathologist.  Site staff should schedule the Week 12 Endoscopy during the Baseline visit, if possible.  Appropriate documentation of biopsy results consistent with the 
diagnosis of CD, in the assessment of the Investigator, must be available in order to confirm the subject's eligibility for the study.  If this documentation is not available, a 
diagnostic biopsy from the most affected observed area of the ileum/colon must be performed during the Screening endoscopy and evaluated by a qualified local pathologist 
and the results reviewed by the Investigator.  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.


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Table 3.
Study Activities (Continued)
e.
Physical examination performed at Screening, Week 12 and Week 56/Premature Discontinuation Visits are full physical examinations which must include an assessment of 
extra-intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations at all other visits are symptom based and must include a count 
of the number of cutaneous fistulas.
f.
Subjects with negative PPD test and/or QuantiFERON-TB Gold test within 90 days of Screening will not require a repeat skin test, if documentation is available.  PPD skin 
test is to be read 48 to 72 hours after placement.
g.
Chest x-ray includes posterior-anterior (PA) and lateral views.  Subjects with normal chest x-ray within 3 months of Screening would not require a repeat chest x-ray, if 
documentation is available.
h.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.
i.
Lab assessments will only need to be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if the subject's health status has changed to 
warrant a repeat test.
j.
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.  Further explanations of these tests are provided in the laboratory manual.
k.
Serum pregnancy test will be performed on all women of childbearing potential at Screening.  Urine pregnancy test will be performed locally at Baseline Visit, and at the 
Week 12 and Week 56/PD for all women of child-bearing 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.
l.
Subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  A positive result for the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Please refer to hepatitis procedures for details on testing requirements.  If required by country regulatory authorities to confirm eligibility, subjects will be tested for HIV and 
documented that the test has been performed.  This testing is to be done at a local laboratory.  A subject will not be eligible for study participation if test results indicate a 
positive HIV infection.  AbbVie will not receive results from the testing and not be made aware of any positive result.
m.
Anti-dsDNA performed if ANA result is positive.
n.
If a sample cannot be obtained during the site visit, the site will give 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 chart by ePRO.  All stool samples for metagenomic analysis should be collected before 
any bowel preparation for endoscopy is started and should be returned to the site within 3 days of collection.
Note:
The Screening stool sample may be taken anytime during the Screening period but should be collected prior to any bowel prep.
o.
Blood samples for the measurement of adalimumab and AAA concentrations will be collected prior to dosing.  Testing of the adalimumab and AAA concentrations must not 
be performed locally.  All pharmacokinetic results will remain blinded to the investigator, study site personnel and the subject throughout the study.


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Table 3.
Study Activities (Continued)
p.
Pharmacogenetic Marker and intestinal biopsy samples are optional.  Separate consents must be signed prior to the sample draw.  If the pharmacogenetic sample is not 
collected at Baseline, preferably it should be collected at the next study visit.
q.
Subject will begin corticosteroid taper at Week 4.  If the Investigator feels that the steroid taper is not advisable for a particular subject at Week 4, the SDP should be 
consulted for evaluation and approval.
r.
Collection of SAEs begins the day the subject signs the informed consent.
s.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
t.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects that continue on adalimumab 
therapy after the end of study participation.
u.
The Screening results of the SFPS will serve as the Baseline value.
v.
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 according to this table are for purposes when the subject is coming in for a visit for evaluation, assessment and 
potential dose escalation.


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5.3.1.1
Study Procedures
The following study procedures are identical for the Induction Study (Weeks 0 – 12) and 
the Maintenance Study (Weeks 12 – 56).  The study procedures outlined in Table 3 are 
discussed in detail in this section, with the exception of drug concentration measurements 
and antibody measurements (discussed in Section 5.3.2), pharmacogenetic and serologic 
marker/mRNA samples (discussed in Section 5.3.1.2 and Section 5.3.6.2 respectively), 
pharmacokinetics (discussed in Section 5.3.2) and the collection of adverse event (AE) 
information (discussed in Section 6.1.4).  All study data will be recorded in source 
documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, 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 both the Screening and Baseline Visits.
Medical, Surgical, and Medication History
A complete medical and surgical history, as well as a history of tobacco and alcohol use, 
will be obtained from each subject during the Screening Period.  An updated medical 
history will be obtained at the Baseline Visit to ensure that the subject still qualifies.
The location of the subject's Crohn's disease should be recorded in the source documents 
and on the appropriate eCRFs (anal, perianal, rectum, gastroduodenal, ileum, colon, 


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and/or jejunum).  History should also include onset date, and history of complications 
related to the disease.
Prior azathioprine or 6-MP use or methotrexate (since birth) will be asked.  If subjects 
have/had ever treated with azathioprine or 6-MP or methotrexate, the duration of therapy, 
maximum dose, reason for use and reason(s) for termination of treatment with 
azathioprine and/or 6-MP and/or methotrexate will be recorded in appropriated eCRF.
A detailed medical history with respect to Loss of Response and/or Intolerance to 
infliximab must be documented in the subject's source documents.  Documentation must 
include the investigator's judgment based on the conditions defined in Appendix K.
A detailed medical history with respect to TB exposure needs to be documented.  This 
information needs to include Bacille Calmette-Guérin (BCG) vaccination, cohabitation 
with individuals who have had TB, and/or who reside or work in TB endemic locations.
Physical Examination
A full physical examination will be performed at Screening, Week 12 and 
Week 56/Premature Discontinuation Visits and must include an assessment of extra-
intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas as in 
Table 3.  All other visits are symptom based but must include a count of the number of 
cutaneous fistulas.  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 
Baseline (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.
Additionally physical examination findings that are related to or part of each subject's 
medical history will be captured on the appropriate medical history eCRFs.


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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.  Height will be measured at the Screening Visit only (with shoes off, and 
then adding 1 inch or 2.5 cm).  All measurements will be recorded in metric units if 
possible.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the designated study visits in Table 3.  A 
qualified physician will interpret the clinical significance of any abnormal finding, sign, 
and date each ECG.  Any clinically significant findings will be documented in the source 
documents and later transcribed on to the appropriate eCRF.  Each signed original ECG 
will be monitored by the responsible CRA and kept with subject's source documents 
onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided all protocol required documentation is available.  
If there are other findings that are clinically significant, the Principal Investigator must 
contact the SDP before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the Investigator.
Chest X-Ray (CXR)
All subjects will undergo a standard CXR (posterior-anterior [PA] and lateral views) at 
the Screening Visit to rule out the presence of TB or other clinically relevant findings.  
The CXR will not be required if the subject had a previous normal chest x-ray within 
90 days of Screening, provided all protocol required documentation is available at the site 
(as outlined below).


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Subjects can have a repeat CXR at any time during the study as warranted based on the 
opinion of the Investigator.
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 
1) calcified granulomas, 2) pleural scarring/thickening, and 3) signs of active TB.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.  The CXR reports require the signature of both the radiologist who 
read the films and the Principal Investigator.  If it is the site's policy that the radiologist 
does not sign the final report, the report must include the date of the procedure, the name 
of the interpreting radiologist and at a minimum must be signed and dated by the Principal 
Investigator.
TB Screening
A PPD skin test (alternatively, also known as tuberculin skin test) must be placed or a 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test or 
T-SPOT TB test) must be performed during the Screening Period for all subjects 
including those with a prior history of BCG administration.  If a subject had a negative 
PPD or IGRA test within 90 days prior to Screening, and all protocol required 
documentation is available, this test does not need to be repeated, provided nothing has 
changed in the subject's medical history to warrant a repeat test.  These cases must be 
discussed with the AbbVie SDP.
For the PPD test:
The subject will be required to have the PPD test read by a licensed healthcare 
professional 48 to 72 hours (or according to manufacturer's guide) after placement when 
the induration is maximal.  An induration (not erythema) of 5 mm or greater will be 
considered as PPD positive, irrespective of BCG status or local guidelines.  The 
induration must be recorded in mm not as positive or negative.  The absence of induration 
should be recorded as "0 mm," not "negative."  (If required by specific countries a 
two-step test may be performed per local guidelines.  The result of the second test should 
be recorded.  An induration of 5 mm or greater will be considered as PPD positive.)


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Subjects who have had an ulcerating reaction to a PPD skin test in the past should not be 
re-exposed and should not be tested at Screening but will be considered PPD positive.
If there are sites where the accepted testing materials are not available an alternative may 
be substituted, but the method must be submitted and approved by AbbVie prior to use 
with study subjects.
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 1) 
calcified granulomas, 2) pleural scarring/thickening, and 3) signs of active TB.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.  If the CXR demonstrates changes suggestive of previous TB 
(e.g., calcified nodule, fibrotic scar, apical or basilar pleural thickening) or other findings 
that are clinically significant, the Principal Investigator must contact the AbbVie SDP 
before enrolling the subject.
If the PPD or the IGRA test is positive or the subject has a CXR indicative of latent TB, 
the subject will be required to initiate and have taken at least 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing course of Center for Disease Control 
(CDC) recommended prophylaxis or prophylaxis per local guidelines prior to starting 
study therapy.
Subjects with a prior history of latent TB that have a documented completion of the CDC 
recommended or local guideline recommended prophylaxis may be permitted to enroll.  If 
the subject has a prior history of latent TB but has not completed or received prophylaxis, 
prophylaxis must be initiated for at least 2 weeks (or per local guidelines, whichever is 
longer) before enrolling into the study.
If the subject has a prior history of active TB they must have documentation of 
completion of CDC recommended or local guideline recommended treatment and 
documentation of resolution of the infection.
Subjects should be screened for TB using either PPD or IGRA.  In the event both a PPD 
test and an IGRA test are performed, if either one is positive, the subject will be 


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considered to be positive and should initiate TB prophylaxis.  If the IGRA test is 
indeterminate, the site should repeat the test.  If the second IGRA test is also 
indeterminate, the subject is considered to be positive and should initiate TB prophylaxis.  
If the IGRA test is indeterminate, the site should repeat the test with another blood sample 
or perform a PPD test.  If the second IGRA test or PPD is also indeterminate, the subject 
is considered to be positive and should initiate TB prophylaxis.
Prior, ongoing and newly initiated TB prophylactic treatment should be captured on the 
concomitant medications page in the eCRF and in the source documents.  Known history 
of latent/active TB should be captured on the medical history eCRF page.
For sites participating in the Czech Republic, the following local requirements will 
also be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure.  This information needs to include BCG vaccination, 
cohabitation with individuals who have had TB, and/or reside or work in TB 
endemic locations.  The information obtained by the pulmonologist must be 
documented in the subject's source note, dated and signed by the 
pulmonologist.
●
A pulmonologist must review the results of the PPD skin test or the IGRA test 
and the chest x-ray and provide his/her opinion about the eligibility of each 
subject to be enrolled to the study.  This opinion must be documented in 
writing in the subject's source documents.
●
All subjects with a positive PPD or IGRA test need to be approved for entry 
into the trial by both the Czech pulmonologist and the AbbVie SDP and all 
such subjects need to receive prophylaxis for latent TB.  Under no 
circumstances can a subject with a positive PPD or IGRA test result and no 
prior history of treatment for active or latent TB be allowed into this trial.
Pregnancy Tests
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential.  At the Baseline Visit, Week 12, and Week 56/PD, subjects of 


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childbearing potential will have a urine pregnancy test performed locally by designated 
study personnel.  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.
All women of childbearing potential will have a repeat urine pregnancy test at the final 
Study Visit (PD) performed locally by designated study personnel.
Hepatitis B Testing
All subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  
A positive result for the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and 
core antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab* (–), and HBc Ab 
Total (+) require PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that 
meets or exceeds detection sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require 
HBV DNA PCR qualitative testing: 
●
HBc Ab Total (–) and HBs Ab* (–)
●
HBc Ab Total (–) and HBs Ab* (+)
●
HBc Ab Total (+) and HBs Ab* (+)
*
For HBs Ab test results, a (–) result for HBs Ab is equivalent to 
nonreactive and a (+) result is equivalent to reactive.
Clinical Laboratory Tests
Blood samples will be obtained for the laboratory tests listed in Table 4.  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.


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Chemistry/hematology and urinalysis assessments will only need to be repeated at 
Baseline if the time between Screening and Baseline is greater than 14 days, or if the 
subject's health status has changed to warrant a repeat test.
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.
If required by country regulatory authorities to confirm eligibility, subjects will be tested 
for antibodies to the Human Immunodeficiency Virus (HIV) at Screening and documented 
that the test has been performed.  This testing is to be done at a local lab.  A subject will 
not be eligible for study participation if test results indicate a positive HIV infection.  
AbbVie will not receive results from the testing and not be made aware of any positive 
result.


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Table 4.
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
C. difficile toxin
Fecal calprotectin
Microbiota metagenomic 
analyses
Additional Blood Samples Collected
High-Sensitivity C-Reactive Protein (hs-CRP)
Antinuclear antibody (ANA)
Anti–double-stranded DNA (anti-dsDNA) – if ANA positive
β-HCG
HBV
Pharmacokinetic
Pharmacogenetic and intestinal biopsies (optional)
mRNA
HACA
Infliximab
Serologic Biomarkers
HIV, if applicable (testing to be conducted at local lab)
*
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.
Urinalysis
Dipstick urinalysis will be completed by the sites at all required visits as listed in Table 3.  
Microscopic urinalysis will be performed by the central laboratory in the event the 


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dipstick UA results show protein, ketones or blood greater than negative or glucose 
greater than normal.
Other Laboratory Assessments
ANA/anti-dsDNA
Blood samples for antinuclear antibody (ANA) will be obtained per Table 3.  
Anti-double-stranded DNA (anti-dsDNA) assessments will be performed if ANA is 
positive.
In the event that subject develops lupus-like symptoms, ANA sample will be obtained.
hs-CRP
Blood samples for high-sensitivity C-Reactive Protein (hs-CRP) will be obtained per 
Table 3.  The Screening hs-CRP will serve as the Baseline value.  The hs-CRP results in 
the Induction Study starting from Baseline to Week 8 will remain blinded to Investigator, 
study site personnel and the subject.  The hs-CRP results in the Maintenance Study 
starting at Week 12 to Week 56 will be unblinded to the Investigator, study site personnel 
and the subject.
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.
Stool Samples Collected
Fecal Calprotectin
Fecal calprotectin will be performed for all subjects as indicated in Table 3.  If subjects 
are unable to provide a sample at the site visit, subjects will be sent home with a stool 
sample supply kit and the site will give instructions to assist with collection procedures.  
The fecal calprotectin sample collected during the Screening Period will be used as the 


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baseline.  All stool samples should be collected before any bowel preparation for 
endoscopy is started and returned to the site within 3 days of collection.
The fecal calprotectin results will remain blinded to Investigator, study site personnel and 
the subject throughout the study.
The central laboratory will be utilized to process and provide results for these laboratory 
tests.
C. Difficile Stool Testing
During the Screening Period a stool sample will be collected and sent to the central 
laboratory for testing.  The sample will be assessed for the presence of C. difficile toxin.
The sample must be shipped to the central laboratory using dry ice.  Additional 
information is available in the Investigator Manual provided by the central laboratory.
Subjects who are positive for C. difficile toxin may be treated appropriately and 
re-screened.
Microbiota Metagenomic Analysis
An additional stool microbiota metagenomic analyses will be performed as indicated in 
Table 3.  Subjects will be asked to provide a stool sample at the visit, if possible.  Or, 
subjects will be sent home with stool sample supplies and the site will give instructions 
with collection procedures.  At Screening, Week 12, and Week 56/PD, the stool sample 
should be collected prior to the bowel preparation for endoscopy has started (if possible) 
and returned to the site within 3 days of collection.  A central laboratory(s) will be utilized 
to process these laboratory tests.
Where allowed by local requirements at the time of the stool sample 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 adverse events.  These samples may also be used for the development of 


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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 requirements) 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 Screening.  The Screening period will be 
a minimum of 7 days to calculate the CDAI score.  The CDAI calculated at Screening will 
serve as the Baseline CDAI.
Beginning with the Week 2 through Week 56 visits and 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 2
Baseline
Week 4
Week 2
Week 6
Week 4
Week 8
Week 4
Week 12
Week 8
Week 26
Week 12
Week 40
Week 26
Week 56
Week 40
For calculating CDAI at Screening through Week 56/Premature Discontinuation, 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 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 


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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.
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 at Screening should be used when selecting the standard weight in 
Appendix H, and this standard weight should be used for calculating every CDAI 
throughout subject participation in the study.
Standard height is calculated by using the height obtained at Screening (without shoes) 
plus one inch. 
If the body weight obtained at the time of assessment is not captured in kilograms (kg), 
then when converting into kg, 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 and 97.687 would be captured as 97.7).
The subtotal of box 8 should not be rounded to a whole number.


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The calculation of the CDAI score is in Appendix H.
Outcomes and Questionnaires
●
IBDQ – Inflammatory Bowel disease Questionnaire (IBDQ) will be completed 
at the time points indicated in Table 3 (Appendix E).
●
WPAI – Work Productivity and impairment Questionnaire will be completed 
at the time points indicated in Table 3.  The data in the subject-completed 
questionnaire will be transferred to the appropriate eCRF (Electronic Case 
Report Form) 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).
●
Bristol Stool Form Scale (Appendix L).
●
SES-CD Scoring – Simplified endoscopic score for Crohn's 
disease – Investigator should complete all components of the SES-CD scoring 
sheet at the time points indicated in Table 3 (Appendix M).
Corticosteroid Taper
At Week 4, subjects who are on prednisone (or equivalent) or budesonide will taper their 
dose according to the following regimen or a regimen at the investigator's discretion.  If 
the Investigator feels that the steroid taper is not advisable for a particular subject at 
Week 4, the SDP should be consulted for evaluation and approval.
Dose
Rate
Prednisone (or equivalent)
> 10 mg/day
5 mg/day/week
≤ 10 mg/day
2.5 mg/day/week
Budesonide
≤ 9 mg/day
3 mg/day/week
If the subject should experience a loss of satisfactory clinical response in the opinion of 
the Investigator, the subject may have his/her corticosteroid dose increased per the 
investigator's discretion up to and beyond the dose used at Baseline.  Subjects may not be 
on both oral budesonide and oral prednisone (or equivalent) simultaneously.


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Subject Diary
Subjects will be dispensed an electronic diary at Screening and will be trained on how to 
complete the diary by site staff during the Screening visit.  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.  All relevant dosing 
information will be retained by the study coordinator and transcribed into the eCRF.  
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.
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.  The subject or a designated family member or friend will be trained to administer 
the SC injections of adalimumab.  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.
Study drug kits are assigned by the IVRS/IWRS following the subjects randomized 
treatment schedule.


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The Induction Study begins with the first four doses of study drug being administered on 
site the same day at the Baseline Visit.  At the Baseline and Week 2 visits, the IVR will 
have to be called twice.  The first call to the IVR will determine the first two kits to be 
administered to the subject during the visit.  Site staff will need to contact the IVR system 
a second time to obtain the additional two kits which will be provided to the subject to 
take home.  For Induction and Maintenance Studies, the site staff will remind the subject 
to take the syringes in the correct order per kit before opening a new kit, when applicable.  
The IVR will be contacted once at all remaining on-site visits to receive the correct study 
drug kit(s).  The first syringe will be administered at the site and the remaining kits 
containing syringes will be sent home with the subject.  Subjects must be reminded to take 
the syringes in the assigned kits in the order dispensed by the IVR system.
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 that 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 appropriate therapy initiated.  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.
Subjects will be instructed to return all used and unused syringes, sharp containers and 
empty boxes at each visit for accountability.


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Bristol Stool Assessment
Subjects will rate their stool consistency on a daily basis.  The subject should report the 
type which is most representative for that day according to the Bristol Stool Chart 
(Appendix L).  The Bristol Stool Chart defines 7 types of stool which may be seen in 
normal and abnormal bowel movements.
Endoscopy
An endoscopy will be performed on the following visits:
●
During Screening*
●
Week 12
●
Week 56/Premature Discontinuation if PD occurs after Week 26
It is expected all subjects will have a Week 12 and 56/PD Endoscopy.  Site staff should 
schedule the Week 12 Endoscopy during the Baseline visit, if possible.  For subjects that 
PD, the site should attempt to reschedule the Endoscopy prior to the discontinuation visit.
*An endoscopy performed before the Screening visit, may be used as the Screening 
endoscopy, with the approval of the AbbVie Study Designated Physician, if the following 
conditions are met:
1.
biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below.
2.
the endoscopy took place within 45 days before Baseline Visit.
3.
the endoscopy was performed and recorded in a video format as the endoscopic 
eligibility will be determined by the central reviewers.  The same endoscopist, 
where possible, should perform all endoscopies.
All ileocolonoscopies should be performed and recorded in a video format during the 
Screening Period or endoscopy performed within 45 days before Baseline and the 


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Week 56/PD visit.  Sites should also perform an SES-CD assessment and record findings 
on the provided SES-CD score sheet, refer to Appendix M.  The findings should be 
entered in the appropriate eCRF.  Videos from Screening endoscopies from subjects the 
Investigator believes are eligible for the trial (i.e., subjects with an SES-CD ≥ 6, excluding 
the presence of narrowing component, (or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum), and all Week 12 and 
Week 56/PD endoscopies conducted will undergo central review.  Two primary central 
reviewers will evaluate the data and provide their score.  If the SES-CD scores are 
discrepant between the two readers, a third central reviewer will review the video and 
choose between the first and second reviewers' scores.  The third reviewer's choice 
between the reviewers' scores will be considered final.  This process will apply to all 
video endoscopies where the first and second reviewers do not agree.  The adjudicator's 
assessment will be considered final.  If, in the opinion of the Investigator, the Screening 
endoscopy does not indicate the SES-CD criteria confirming study eligibility, the subject 
should be screen-failed and the video should not be sent for central review.  Endoscopic 
eligibility will be determined by the central reviewers.  The same endoscopist, where 
possible, should perform all endoscopies.
The endoscopy during the Screening Period or endoscopy performed within 45 days 
before Baseline and Week 56/PD will be used to provide the endoscopy subscores for 
calculating the Simplified Endoscopic Score (SES-CD) at Screening, Week 12, and 
Week 56/PD, refer to Appendix M.  The SES-CD values provided by the central reader 
will be used for all endpoint analyses.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available, a diagnostic biopsy from 
the most affected area of the ileum/colon must be performed during Screening and read by 
a qualified local pathologist and the results reviewed by the Investigator.  Biopsies to 
evaluate suspicious lesions or to rule out malignancy may be taken per the Investigator's 


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discretion and evaluated by the local pathologist.  If the biopsy sample(s) are obtained 
during the endoscopy used to determine subject eligibility, it should also be recorded.  
The biopsy should not interfere with the recording the central reviewers will use for their 
evaluation.
The signed pathology reports confirming diagnosis and when appropriate, ruling out 
current dysplasia/malignancy 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 Screening endoscopy or 
endoscopy performed within 45 days before Baseline.  If a diagnosis of colon dysplasia or 
malignancy is discovered during any subsequent endoscopic evaluation during the course 
of the study, the findings should be recorded as an adverse event and the subject should be 
discontinued from the study.
5.3.1.2
Blood Sample for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected per Table 3 from each 
subject who consents for pharmacogenetic analyses.  If the sample is not drawn at the 
Baseline visit, preferably it should be drawn at the next study visit.  The procedure for 
obtaining and documenting informed consent is discussed in Section 9.3.  Please refer to
the laboratory manual for instructions.
Samples will be shipped frozen to the central laboratory and then to AbbVie for long-term 
storage.  Samples should not be allowed to thaw prior to arrival at AbbVie or the 
designated laboratory.  Arrangements will be made with the central laboratory for the 
shipment of PG samples to AbbVie or specified lab for testing.
Samples will be stored 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.
See Section 5.3.6.1 for the variables of this analysis.


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5.3.1.3
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 3.  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 
serologic samples to AbbVie or specified lab for testing.
See Section 5.3.6.2 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 3.  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.
5.3.1.4
Collection and Handling of Optional Intestinal Biopsy 
Samples for Exploratory Research
Subjects will have the option to provide intestinal biopsy samples for exploratory 
research, where allowed by local requirements.  Subjects may participate in the main 
study even if they decide not to participate in this optional exploratory research.


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Exploratory research can improve our understanding of how individuals respond to drugs 
and our ability to predict which patients would benefit from receiving specific therapies.  
In addition, exploratory research may help to improve our understanding of how to 
diagnose and assess/monitor IBD by assessing associations between disease 
characteristics, outcomes data and biomarkers of interests.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on adalimumab (or drugs of 
this class) or Inflammatory Bowel Disease and related conditions continues, but for no 
longer than 20 years after study completion (where allowed by local requirements).
Collection of Optional Intestinal Biopsy Samples for Exploratory Research
During the Screening endoscopy, intestinal biopsy samples are desired from the 
recto-sigmoid, transverse and left colon.  If there is inflammation in any of these 3 colonic 
segments, use standard biopsy forceps to collect one biopsy from the most inflamed area 
or the edge of an ulcer if ulcers are present, and one biopsy from a normal area in that 
segment at least 15 mm away from any inflamed area.  If possible collect biopsies from 
several places in each inflamed segment up to a total of 24 biopsies per subject.
At Week 12 and Week 56 or Premature Discontinuation biopsies from the most inflamed 
areas are again requested.  A biopsy of the edge of an ulcer, if ulceration is present and 
one biopsy from a normal mucosa in each segment at least 15 mm from any inflamed area 
and one biopsy in a healed area, if an area showed active disease at baseline can be easily 
identified.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage.  
Instructions for the preparation and shipment of the biomarker exploratory research 
samples will be provided in a laboratory manual.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for adalimumab, AAA, infliximab, and HACA assays will be obtained at 
the time points as indicated in Table 3.
Testing of the adalimumab and AAA concentrations must not be performed locally.  All 
pharmacokinetic results will remain blinded to the investigator, study site personnel and 
the subject throughout 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.
A maximum of 15 samples (not including unscheduled visit sample collections) are 
planned to be collected per subject for adalimumab (9 samples) and AAA (6 samples) 
assays.  The total number of samples planned will not exceed 2,700 (9 samples 
× 300 subjects) for the adalimumab assay and 1,800 (6 samples × 300 subjects) for the 
AAA assay for the entire study.
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.


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Collection of Samples for Infliximab and HACA Assays
Blood samples for infliximab and HACA assay will be collected at Baseline by 
venipuncture into appropriately labeled 4-mL evacuated serum collection tubes without 
gel separator at Baseline.  The sample will be obtained immediately prior to dosing.  
Sufficient blood will be collected to provide approximately two 1 mL serum specimens 
(one tube for infliximab and one tube for HACA).  Please refer to the laboratory manual 
for instructions.
The total number of samples planned will not exceed 500 (2 samples × 300 subjects) for 
the entire study.
5.3.2.2
Handling/Processing of Samples
The blood samples for adalimumab, AAA, infliximab, and HACA assay 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 
(pharmacokinetic [PK]-Adalimumab or AAA; PK-Infliximab or HACA).  
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 3 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
5.3.3.1
Co-Primary Variables for Induction Study
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 4.
●
Proportion of subjects with endoscopic response (decrease > 50% SES-CD 
from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) at Week 12.
5.3.3.2
Secondary Variables for Induction Study
Ranked Secondary endpoints:
1.
Proportion of subjects with sustained clinical remission (CDAI < 150) at both 
Weeks 4 and 12.
2.
Proportion of subjects with CDAI < 150 at Week 4 and endoscopic response 
(decrease > 50% SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 
2 point reduction from Baseline]) at Week 12.
3.
Proportion of subjects with clinical remission (CDAI < 150) at Week 12.
4.
Proportion of subjects who discontinued corticosteroid use and achieved clinical 
remission (CDAI < 150) at Week 12 among subjects taking corticosteroids at 
Baseline.
5.
Proportion of subjects with endoscopic remission (SES-CD ≤ 4 and at least a 
2 point reduction versus baseline and no subscore greater than 1 in any individual 
variable) at Week 12.
6.
Change from Baseline in fecal calprotectin level at Week 4.
7.
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g at 
Week 4.


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8.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal calprotectin 
< 250 μg/g at Week 4.
9.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable, and fecal calprotectin < 250 μg/g at Week 12.
10.
Proportion of subjects who achieve an SES-CED ≤ 2 at Week 12.
11.
Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from 
Baseline) at Week 4.
12.
Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from 
Baseline) at Week 12.
13.
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at Week 4.
14.
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at Week 12.
15.
Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ 
fatigue item score ≥ 1) at Week 12.
All additional efficacy endpoints will be non-ranked.
●
Proportion of subjects with clinical response (decrease CDAI ≥70 points from 
Baseline) at each scheduled visit in Induction Study.
●
Proportion of subjects with enhanced clinical response (decrease CDAI 
≥100 points from Baseline) at each scheduled visit in Induction Study.
●
Proportion of subjects who discontinue corticosteroid use at each scheduled 
visit in Induction Study among subject taking corticosteroids at Baseline.
●
Proportion of subjects who achieve a composite subtotal score of SFPS < 50 at 
Week 12 who had an SFPS ≥ 100 at Baseline.
●
Proportion of subjects who achieve a composite subtotal score of SFPS < 50 at 
Week 4 who had an SFPS ≥ 100 at Baseline.


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●
Proportion of subjects who achieve SES-CD ≤ 3 and at least a 2 point 
reduction versus baseline and no subscore greater than 1 in any individual 
variable at Week 12.
●
Proportion of subjects with SES-CD = 0 at Week 12.
●
Change from Baseline in fecal calprotectin level at each scheduled visit in 
Induction Study.
●
Change from Baseline in hs-CRP at each scheduled visit in Induction Study.
●
Change in IBDQ total score and individual IBDQ domain scores (bowel, 
emotional, social, systemic) from Baseline at each scheduled visit in Induction 
Study.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (decrease ≥ 16 points from Baseline) at each scheduled visit 
in Induction Study.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) at each 
scheduled visit in Induction Study.
●
Proportion of subjects achieving response in IBDQ fatigue item (increase of 
IBDQ fatigue item score ≥ 1) at Week 4.
●
Change in WPAI from Baseline at each scheduled visit in Induction Study.
●
Change in EQ-5D from Baseline at each scheduled visit in Induction Study.
●
Change in CDAI from Baseline at each scheduled visit in Induction Study.
●
Change in SFPS from Baseline at each scheduled visit in Induction Study.
●
Change in Abdominal Pain Rating Scale score from Baseline at each scheduled 
visit in Induction Study.
●
Change in Bristol Stool Chart score from Baseline at each scheduled visit in 
Induction Study.
●
Proportion of subjects who achieve Bristol Stool Chart response at each 
scheduled visit in Induction Study.
●
Proportion of subjects who achieve CDAI remission (CDAI < 150) at each 
visit in Induction Study.
●
Proportion of subjects who achieve SFPS remission (SFPS < 50) at each 
scheduled visit in Induction Study.


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●
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 at 
each scheduled visit in Induction Study.
●
Time to clinical remission (CDAI < 150) in Induction Study.
●
Time to clinical response (CR –70) in Induction Study.
●
Time to all cause Hospitalization in Induction Study.
●
Time to CD-related Hospitalization in Induction Study.
●
Proportion of subjects with no draining fistulas at Week 12 among subjects 
with draining fistula at Baseline.
●
Proportion of subjects in each treatment group with > 50% reduction from 
Baseline in the number of draining fistulas at Week 12 among subjects with 
draining fistula at Baseline.
●
Resolution of extra-intestinal manifestations over time at each scheduled visit 
in Induction Study.
●
Proportion of subjects with an SES-CD decrease of ≥ 3 points compared to 
Baseline at Week 12.
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Induction Study among subjects with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Induction Study among subjects with 
Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
5.3.3.3
Endpoints for Exploratory Maintenance Study
●
Proportion of subjects who achieve endoscopic response (SES-CD > 50% from 
Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) at Week 56 among subjects with endoscopic response at Week 12


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●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable) at Week 56 among subjects with endoscopic  remission at 
Week 12.
●
Proportion of subjects who achieve CDAI < 150 at Week 56 among subjects 
with CDAI < 150 at Week 12.
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 56.
●
Proportion of subjects who achieve SES-CD ≤ 4 and at least 2 point reduction 
versus baseline and no subscore greater than 1 in any individual variable at 
Week 56.
●
Proportion of subjects who achieve SES-CD ≤ 2 at Week 56.
●
Proportion of subjects with CDAI < 150 at Week 4 and SES-CD ≤ 4 and at 
least 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable at Week 56.
●
Proportion of subjects who discontinued corticosteroid use and achieved 
clinical remission (CDAI < 150) at Week 56 among subjects taking 
corticosteroid at Baseline.
●
Proportion of subjects with endoscopic response (decrease > 50% SES-CD 
from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) at Week 56.
●
Change from Baseline in fecal calprotectin level at Week 56.
●
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g 
at Week 56.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal 
calprotectin < 250 μg/g at Week 56.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and 
at least 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable, and fecal calprotectin < 250 μg/g at Week 56.
●
Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points 
from Baseline) at Week 56.


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●
Proportion of subjects with clinical response (decrease CDAI ≥70 points from 
Baseline) at each scheduled visit in Maintenance Study.
●
Proportion of subjects with enhanced clinical response (decrease CDAI 
≥100 points from Baseline) at each scheduled visit in Maintenance Study.
●
Proportion of subjects who discontinue corticosteroid use at each scheduled 
visit in Maintenance Study among subjects taking corticosteroid at Baseline.
●
Proportion of subjects who achieve a composite subtotal score of SFPS < 50 at 
Week 56 who had an SFPS ≥ 100 at Baseline.
●
Proportion of subjects who achieve SES-CD ≤ 3 and at least a 2 point 
reduction versus baseline and no subscore greater than 1 in any individual 
variable at Week 56.
●
Proportion of subjects with SES-CD = 0 at Week 56.
●
Change from Baseline in fecal calprotectin level at each scheduled visit in 
Maintenance Study.
●
Change from Baseline in hs-CRP at each scheduled visit in Maintenance 
Study.
●
Change in IBDQ total score and individual IBDQ domain scores (bowel, 
emotional, social, systemic) from Baseline at each scheduled visit in 
Maintenance Study.
●
Change in WPAI from Baseline at each scheduled visit in Maintenance Study.
●
Change in EQ-5D from Baseline at each scheduled visit in Maintenance Study.
●
Change in CDAI from Baseline at each scheduled visit in Maintenance Study.
●
Change in SFPS from Baseline at each scheduled visit in Maintenance Study.
●
Change in Abdominal Pain Rating Scale score from Baseline at each scheduled 
visit in Maintenance Study.
●
Change in Bristol Stool Chart score from Baseline at each scheduled visit in 
Maintenance Study.
●
Proportion of subjects who achieve CDAI remission (CDAI < 150) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects who achieve SFPS remission (SFPS < 50) at each 
scheduled visit in Maintenance Study.


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●
Proportion of subjects with major CD related event (e.g., hospitalization, 
bowel surgery, abscess drainage) in Maintenance Study.
●
Proportion of subjects with no draining fistulas at Week 56 among subjects 
with draining fistula at Baseline.
●
Proportion of subjects in each treatment group with > 50% reduction from 
Baseline in the number of draining fistulas at Week 56 among subjects with 
draining fistula at Baseline.
●
Resolution of extra-intestinal manifestations at each scheduled visit in 
Maintenance Study.
●
Proportion of subjects with an SES-CD decrease of ≥ 3 points compared to 
Baseline at Week 56.
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Maintenance Study among subjects with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Maintenance Study among subjects 
with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Time to dose escalation in Maintenance Study.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (decrease ≥ 16 points from Baseline) at each scheduled visit 
in Maintenance Study.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at each scheduled visit 
in Maintenance Study.
●
Proportion of subjects achieving response in IBDQ fatigue item (increase of 
IBDQ fatigue item score ≥ 1) at each scheduled visit in Maintenance Study.


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●
Proportion of subjects requiring dose escalation to weekly dosing during 
Maintenance Study.
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 56 among subjects requiring dose escalation to weekly dosing during 
Maintenance Study.
●
Proportion of subjects who achieve endoscopic response (decrease > 50% 
SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point 
reduction from Baseline]) at Week 56 among subjects requiring dose 
escalation to weekly dosing during Maintenance Study.
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable) at Week 56 among subjects requiring dose escalation to 
weekly dosing during Maintenance Study.
5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.  Incidence of adverse events, 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 at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, 
Week 40, and Week 56/Premature discontinuation and anti adalimumab antibody (AAA) 
just prior to dosing at Baseline, Week 4, Week 12, Week 26, Week 40, and 
Week 56/Premature Discontinuation.
Blood samples will also be collected for measurement of infliximab serum levels and 
Human Anti-Chimeric Antibodies (HACA) just prior to dosing at Baseline.
Adalimumab trough serum concentrations will be summarized by treatment group at each 
time point using descriptive statistics.  In addition, pharmacokinetic model based analyses 


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will be performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F) of adalimumab.
5.3.6
Pharmacogenetic and Serologic Variables
5.3.6.1
Pharmacogenetic Variables
Samples may be sequenced and data analyzed for DNA sequences contributing to the 
disease or to subject's response to adalimumab, in terms of pharmacokinetics, efficacy, 
tolerability and safety.  Such DNA sequences may include those related to drug 
metabolizing enzymes, drug transport proteins, the target pathway, or others related to the 
disease or to drug response.  Some DNA sequences that are currently insufficiently 
characterized or unknown may be understood to be important at the time of analysis.  The 
samples may also be used for the development of diagnostic tests.  The results of 
pharmacogenetic analyses may not be reported with the study summary.
5.3.6.2
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 requirements 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 adverse events.  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.  As 
allowed by local requirements, the samples will be retained for up to 20 years after 
completion of the study research.


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5.3.7
Exploratory Research Variables
Optional intestinal biopsy samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to:  nucleic acids, proteins, lipids or metabolites. 
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of Inflammatory Bowel Disease or related conditions and/or 
adalimumab or drugs of similar class.  The results from these analyses are exploratory in 
nature and may not be included with the study report.
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be banked for future use.  
Samples may then be used to validate putative biomarker signatures obtained from a 
prospective study, leading to the development of diagnostic tests.
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 adverse event, 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 adverse event(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.


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●
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 (see Section 5.2 and Section 7.0).
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie SDP.
●
Subject is non-compliant with TB prophylaxis.
●
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.
●
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 that 
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.


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For subjects that 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 
notify the investigator by telephone and subsequently provide written instructions for
study termination.
5.5
Treatments
5.5.1
Treatments Administered
During the randomized double-blind Induction Study, subjects assigned to the higher 
induction regimen will receive blinded adalimumab 160 mg (4 syringes) at Baseline, 
Week 1, Week 2, and Week 3.  At Week 4, subjects will receive 40 mg (1 syringe) eow 
through Week 12.
Subjects assigned to the standard induction regimen will receive blinded adalimumab 
160 mg (4 syringes) at Baseline and matching placebo (4 syringes) at Week 1.  Subjects 
will receive 80 mg (2 syringes) and placebo (2 syringes) at Week 2 and matching placebo 
(4 syringes) at Week 3.  At Week 4, subjects will receive 40 mg (1 syringe) eow through 
Week 12.
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-
blinded exploratory treatment regimens (adalimumab clinically adjusted [CA] regimen 
and adalimumab therapeutic drug monitoring [TDM] regimen).  The re-randomization at 
Week 12 will be stratified by induction treatment regimen, clinical response (CR-70) 


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status at Week 12 and decrease in SES-CD > 50% from Baseline per the site investigator 
reading at Week 12.  Among subjects achieving SES-CD > 50% from Baseline at
Week 12, the randomization will be further stratified by achievement of an SES-CD ≤ 4 
and at least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable using the Week 12 SES-CD value provided by the site.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab 
every other week beginning at Week 12.  The adalimumab dose will be escalated to every 
week starting as early as Week 14 if the subject's CDAI is ≥ 220 or hs-CRP ≥ 10 mg/L 
(using results from the prior or current visit).  These subjects will also be allowed to 
escalate at unscheduled visits that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 
44, 46, 50, 52 and 54.  Once subjects in the CA regimen are escalated, they will remain on 
40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will 
be determined by the dose adjustment criteria table (Table 2).  Doses will be determined 
using blinded serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) 
as well as the CDAI or hs-CRP values from the current or prior visit.  For subjects who 
meet criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 40 mg 
weekly.
The duration of the study could be up to 60 weeks which includes a Screening Period of 
1 to 4 weeks, ± 3 days which is granted around all study visits, a 12-week double-blind 
period Induction Study, and a 44-week Maintenance Study.  The Screening period may be 
extended as necessary after consultation and approval with the AbbVie Study Designated 
Physician (SDP) for subjects who require initiation of prophylactic anti-tuberculosis (TB) 
therapy, or in case of external, not subject-related circumstances (e.g., due to delay of 


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availability of screening test results).  There will also be a 70-day follow-up phone call for 
subjects who complete Week 56 or discontinue from the study prematurely.
No dose will be given at the final visit.
5.5.2
Identity of Investigational Products
The individual study drug information is presented in Table 5.
Table 5.
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
Placebo
Parenteral
Pre-filled 
syringe
0.8 mL
0.8 mL solution for injection 
mannitol, Citric Acid 
monohydrate, Sodium citrate, 
Disodium phosphate dehydrate, 
Sodium dihydrogen phosphate 
dehydrate, 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 packaged separately in 0.8 mL syringe containing either 
adalimumab 40 mg/0.8 mL or matching placebo for adalimumab.  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/placebo 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 refrigerator temperature 
must be recorded on a temperature log to record proper function.
Malfunctions or any temperature excursion lasting longer than 30 minutes 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), or alternate system, deems the medication 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 assigned a unique identification number by the IRT at the screening 
study visit.  Subjects who meet the entry criteria in Section 5.2.1 and Section 5.2.2 will 
proceed to be enrolled into the study.  Subjects who enter the study will be randomized at 
Baseline in a 3:2 ratio to receive a higher induction regimen or standard induction 
regimen.


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At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-
blinded exploratory treatment regimens (adalimumab clinically adjusted [CA] regimen 
and adalimumab therapeutic drug monitoring [TDM] regimen).
The sites will be provided with appropriate kit number(s) for drug-dispensing purpose for 
each subject by the IRT.  Before the study is initiated, the directions for the IVRS will be 
provided to each site.  Study drug will be administered at the study visits summarized in 
Table 3.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
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 should 
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
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personally with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie's Drug Supply Management Team) the Investigator, study 
site personnel and the subject will remain blinded to each subject's treatment throughout 


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the blinded period of the study.  The IVRS/IWRS will provide access to blinded subject 
treatment information in the case of medical emergency.
In the event of a medical emergency in which the Investigator believes that knowledge of 
study drug treatment is required, every effort must be made to contact the AbbVie SDP 
(see Section 7.0) prior to breaking the blind, as long as it does not compromise subject 
safety.  The date and reason that the blind was broken must be conveyed to AbbVie and 
recorded on the appropriate eCRF.
5.5.6
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 medication.  If the subject does not 
return the diary, IP boxes and sharp containers (when applicable), the site should question 
the subject and obtain as much information as possible as to the dosing of the study drug.
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.
5.5.7
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 


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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 and 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 or 
site policy/procedure) until the CRA is on site to confirm the returned medication.  CRAs 
and site staff will complete study drug accountability via study drug logs, source 
documents, subject dosing diary sheets, empty IP boxes and by visually inspecting the 
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 facility.  Unused medication 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 demonstrate the efficacy of a higher 
induction regimen of adalimumab compared to the standard induction regimen.  The 
efficacy time points of Week 4 and Week 12 are comparable to prior studies with 
adalimumab, specifically Study M02-403, Study M04-691, and Study M05-769.  The 


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study is double-blinded and subjects are randomized to receive a higher induction regimen 
of adalimumab or a standard induction regimen of adalimumab.  After the induction 
regimens are provided, subjects in both treatment groups will receive blinded adalimumab 
40 mg eow until Week 12.  Subjects will begin tapering of corticosteroids at Week 4.
No placebo arm is planned since there is well-documented efficacy of adalimumab in CD 
and because the purpose of this study is to achieve better efficacy than the standard 
induction regimen in terms of clinical remission and endoscopic improvement.  
Additionally, since subjects will be required to have failed or been intolerant of standard 
therapies and have evidence of endoscopic damage confirmed by a central reader, it 
would be not medically acceptable to deny those patients effective treatment or feasible to 
enroll patients in the trial when adalimumab is available to be prescribed for CD.
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 Crohn's disease.  All clinical and laboratory procedures in this 
study are standard and generally accepted.
5.6.3
Suitability of Subject Population
Subjects with active CD who meet all inclusion criteria and none of the exclusion criteria 
are eligible for this study.  The specific subject population chosen was based on the unmet 
medical need for subjects with evidence of mucosal ulceration.
5.6.4
Selection of Doses in the Study
The use of an induction dose higher than the approved dose of 160/80 mg (Week 0/2) is 
supported by exposure-efficacy modeling analyses from the pivotal registration 
Study M02-403 (anti-TNF naïve subjects) and Study M04-691 (anti-TNF experienced 
subjects).


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The goal of the TDM regimen is to attain and maintain serum adalimumab levels above 
reasonably high concentration levels in subjects for mucosal healing.  Since exposure and 
endoscopic relationships are not currently available for adalimumab, clinical remission 
was used for the selection of concentration thresholds to be used in the TDM regimen.  
Based on the PK analyses of adalimumab concentrations in the adult Crohn's disease 
studies, Studies M02-403, M04-691 and M02-433, no concentration level could be 
identified as a significant and reliable predictor of remission.  Therefore, the TDM 
regimen will be based on two concentration thresholds in conjunction with clinical 
response criteria as expected to occur in the clinical setting.  About 75% of the subjects, 
who were in remission at Week 56 in Study M02-433, had serum concentration levels 
above 5 μg/mL.  The lower concentration threshold for the TDM regimen was selected as 
5 μg/mL; thus, any subject below 5 μg/mL concentration will be escalated to ew dosing 
regardless of their CDAI or hs-CRP level.  The second threshold was selected as 
10 μg/mL, which is similar to the median concentrations (9.4 μg/mL at Week 56) 
observed in subjects who were in remission.  The subjects with concentration above 5 and 
below 10 μg/mL may be dose escalated based on clinical response as outlined in the table 
below.  The subjects with serum concentration above 10 μg/mL will not be dose 
escalated.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this trial contains both: 
●
Biologic compound(s) and
●
Device component(s) (pre-filled syringe, pen).


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Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
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.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
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 adverse event 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 adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 


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event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention (see Section 6.2 regarding toxicity management) and/or if the 
investigator considers them to be adverse events.
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.  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 adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event 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 serious adverse event.
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.
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
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.


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6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event 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.
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, another cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All adverse events 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, serious adverse 
events 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 that 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 Adverse Events should be reported 


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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 Adverse Events 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 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
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
70 Days  
After Study 
Drug Stopped
6.1.5
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 investigator will notify the AbbVie Clinical Pharmacovigilance within 24 hours of the 
site being made aware of the event by entering the serious adverse event or nonserious 
event of malignancy in patients 30 years of age and younger data into the RAVE®
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® system or if RAVE® is not operable, should be documented on the 
SAE Non-case report forms (CRF) and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.




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In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
SDP:
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.
6.1.6
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 5.4.1).  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 adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
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 6.0 for definitions).  Study drug may be restarted 


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once the physician determines that the infection has been successfully treated.  Otherwise 
prohibited concomitant medications may be given if medically necessary.  Prior to use, 
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 
2 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 2 weeks after surgery once the physician has examined the surgical 
site and determined that it has healed and there is no sign of infection.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.


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6.2.2
Reporting
Product Complaints concerning the investigational product and/or device must be reported 
to the Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  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):




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efficacy analysis for the Induction Study.  If there is > 10% difference in number of 
subjects with actual treatment received and the treatment randomized, a sensitivity 
analysis for the co-primary endpoints based on the actual treatment received will be 
performed.
Modified Intent-to-Treat (mITT) set includes all ITT subjects who achieve clinical 
response (CR-70) at Week 12.  The mITT set is the primary population for the efficacy 
analysis for the Maintenance Study.
The safety set consists of all subjects who received at least one injection of study drug.  
The safety set will be analyzed as treated, according to treatment the subject actually 
received.  The safety set will be used only for safety analysis.
8.1.2
Planned Methods of Statistical Analysis
All statistical tests will be two-tailed with the significance level 0.05.  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.  The p-value will be provided to assess the comparability of the 
treatment groups assigned by randomization.  The continuous variables will be analyzed 
using the analysis of variance (ANOVA), and discrete variables will be analyzed using the 
chi-square test or Fisher's exact test.


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8.1.4
Statistical Analyses of Efficacy
8.1.4.1
Primary Efficacy Variable for Induction Study
The co-primary efficacy variables for Induction Study are proportion of subjects with 
moderately to severely active CD that have achieved clinical remission, defined as CDAI 
< 150, at Week 4 and proportion of subjects that have achieved endoscopic response, 
defined as a decrease > 50% SES-CD from Baseline (or for a Baseline SES-CD of 4, at 
least a 2 point reduction from Baseline) at Week 12.
The comparisons between treatment group difference on the two co-primary efficacy 
variables for Induction Study will be performed using the Cochran-Mantel-Haenszel 
(CMH) test and will be stratified by hs-CRP at Baseline (< 10 and ≥ 10 mg/L), prior 
infliximab use, and Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline.  A CMH 
based two-sided 95% confidence interval for the difference between treatment groups will 
be calculated.  The ITT set includes all subjects who were randomized at Baseline.  
Missing CDAI at Week 4 or SES-CD at Week 12 will be imputed using the non-
responder imputation (NRI) approach.
For Week 4 clinical remission, LOCF, OC and multiple imputation methods will be used 
as sensitivity analyses.  For Week 12 endoscopic response, OC will be used as sensitivity 
analysis.
In addition, as sensitivity analyses, the logistic regression including treatment, the 
randomization stratification factors and additional clinically important factors such as 
corticosteroid use at Baseline, IMM use at Baseline, Baseline fecal calprotectin, Baseline 
SES-CD, and Region (US versus ex-US), will also be performed for the co-primary 
endpoints.
8.1.4.2
Secondary Efficacy Variables for Induction Study
Secondary efficacy variables are divided into two groups.  The first group includes ranked 
secondary endpoints, which are ranked by clinical importance.  Statistical significance is 
assessed at 0.050 (2-sided) in ranked endpoint order until the significant level exceeds 


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0.05.  No additional statistically significant treatment differences could be declared after 
the first ranked endpoint fails to achieve 0.05.  The second group includes all other 
additional secondary variables.
For categorical ranked and non-ranked secondary endpoints, the difference in proportions 
of subjects between treatment groups will be analyzed using the CMH test adjusted for
stratification variables.  Additionally, the two-sided 95% confidence interval for the 
difference in proportions will be provided.  The non-responder imputation will be used for 
subjects with missing data at the endpoint evaluated.  The last observation carried forward 
(LOCF) method will also be used as the sensitivity analyses for the primary and ranked 
secondary endpoints.
Change from Baseline in continuous ranked and non-ranked secondary endpoints will be 
analyzed using an ANCOVA model including factors of treatment and adjusting for the 
baseline values and the stratification variables.  For analyses of changes from Baseline 
variables, both LOCF and OC analyses will be performed.  The LOCF analysis is 
considered primary for inferential purposes.  In addition, Mixed-Effect Model Repeated 
Measure (MMRM) will be applied, wherever appropriate, as a sensitivity analysis for the 
longitudinal continuous endpoints.
8.1.4.3
Efficacy Variables for Maintenance Study
For categorical endpoints, the difference in proportions of subjects between treatment 
groups will be analyzed using the CMH test adjusted for stratification variables.  
Additionally, the two-sided 95% confidence interval for the difference in proportions will 
be provided.  The non-responder imputation will be used for subjects with missing data at 
the endpoint evaluated.  The last observation carried forward (LOCF) method will also be 
used as the sensitivity analyses for the primary and ranked secondary endpoints.
Change from Baseline in continuous ranked and non-ranked secondary endpoints will be 
analyzed using an ANCOVA model including factors of treatment and adjusting for the 
baseline values and the stratification variables.  For analyses of changes from Baseline 


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variables, both LOCF and OC analyses will be performed.  The LOCF analysis is 
considered primary for inferential purposes.  In addition, Mixed-Effect Model Repeated 
Measure (MMRM) will be applied, wherever appropriate, as a sensitivity analysis for the 
longitudinal continuous endpoints.
8.1.5
Statistical Analyses of Safety
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in 
this study.  All safety comparisons will be performed for both induction and maintenance 
periods between treatment groups using the safety analysis set.
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 for 
subjects who do not participate in the OLE or until first dose of study drug in the OLE 
study if the subject is a completer and is enrolled in the OLE.
Treatment-emergent AEs will be summarized separately for:  a) Baseline to Week 12; 
b) Week 12 to Week 56; c) Baseline to Week 56 (overall study duration).  An overview of 
treatment-emergent AEs, including AEs of special interest such as adverse events leading 
to death and adverse events leading to premature discontinuation (see details in the SAP), 
AEs by Medical Dictionary for Drug Regulatory Activities (MedDRA version 20.1 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 and compared 
between treatment groups will be performed using a one-way Analysis of Variance 
(ANOVA).  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.


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●
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)
●
Baseline immunosuppressants use (YES, NO)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L) 
●
hs-CRP at Baseline (≤ median, > median)
●
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 (≤ 3 years, > 3 years)
●
Disease duration (≤ median, > median)
●
Region (US, ex-US)
8.1.7
Interim Analysis
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
the Induction Study only as well as safety data collected from Baseline through double-
blind Week 12 may be performed after the last subject in ITT population completes the 
12-week double-blind Induction Study.  A database cut will be performed and any 
discrepant data will be clarified before the lock.  Since this interim analysis is the only and 
final analysis of the co-primary efficacy endpoints of the Induction Study, multiplicity 
adjustment is deemed not necessary.


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8.1.8
Pharmacokinetic Analyses
Adalimumab trough serum concentrations will be summarized by dose 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 adverse events may be evaluated.  HACA will be 
evaluated for each subject and each dose, and rates of HACA positive will be calculated.
8.2
Determination of Sample Size
The calculated Week 4 remission rate for higher dose regimen are based on the average of 
the PK-PD Linear model and Emax model and is 56% [(70% [Linear] + 42% [Emax]) / 2] 
for infliximab naïve subjects and 45% [(60% [Linear] + 30% [Emax]) / 2] for infliximab 
experienced subjects.  Assuming the ratio in the proposed study of infliximab naïve 
subjects versus infliximab experienced is 75% versus 25%, respectively, the weighted 
Week 4 remission rate will be approximately 50% for higher induction dose regimen.  For 
the standard dose regimen, the Week 4 clinical remission rate will be approximately 30%.  
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the study and randomized in a 3:2 ratio at Baseline to receive a higher 
induction adalimumab regimen or standard induction adalimumab regimen during the 
double-blind period.  A sample size of 500 (300 higher dose and 200 standard dose) will 
be adequate to detect at least a 20% treatment difference in clinical remission rates at 
Week 4 between the dosing regimens using Fisher's exact test with 99% power at a 
0.05 two-sided significant level.
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts a ~50% increase in 
the proportion of subjects with endoscopic response is expected.  The observed rate of


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endoscopic response in Study M05-769 was 44% at Week 12 with the currently approved 
dosing regimen.  Thus, by extrapolation, the expected rate endoscopic response at 
Week 12 using the higher induction regimen is 66%.  A sample size of 500 subjects 
(300 higher induction regimen and 200 standard induction regimen) will be adequate to 
detect at least an 22% treatment difference in endoscopic response rates at Week 12 
between the dosing regimens using Fisher's exact test with approximately 99% power at a 
0.05 two-sided significance level.
Since the clinical remission at Week 4 endpoint and the endoscopic response at Week 12 
endpoint are likely not independent of each other, the power for the co-primary endpoints 
for the study is expected to be > 98%.
8.3
Randomization Methods
At Baseline, subjects will be randomized 3:2 to one of two double-blinded adalimumab 
Induction Study regimens (higher induction regimen or standard induction regimen).  The 
randomization will be stratified by hs-CRP at Baseline (< 10 and ≥ 10 mg/L), using 
Screening hs-CRP values, prior infliximab use, Crohn's disease severity (CDAI ≤ 300, 
> 300) at Baseline.  
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of two double-blinded 
exploratory treatment regimens (clinically adjusted [CA] regimen and adalimumab 
therapeutic drug monitoring [TDM] regimen).  The re-randomization at Week 12 will be 
stratified by induction treatment regimen, clinical response (CR-70) status at Week 12, 
and decrease in SES-CD > 50% from Baseline per the site investigator reading at Week 
12.  Among subjects achieving SES-CD > 50% from Baseline at Week 12, the 
randomization will be further stratified by achievement of an SES-CD ≤ 4 and at least a 
2 point reduction versus baseline and no subscore greater than 1 in any individual variable 
using the Week 12 SES-CD value provided by the site.
The randomization schedule will be prepared by the Statistics Department of AbbVie.


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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 serious adverse events 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.
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.


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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.
Any optional testing will only be performed if the subject has voluntarily signed and dated 
a separate informed consent, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
informed consent must be signed before the optional testing is performed.  If the subject 
does not consent to the optional testing, it will not impact the subject's participation in the 
study.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and optional samples will continue to be used for research and analysis.  In the event that 
a subject would like to withdraw consent for research using these samples, the subject 
may request that their samples not be analyzed.  Once AbbVie receives the request, 
remaining biomarker and/or optional samples will be destroyed.  However, if the subject 
changes his/her consent, and the samples have already been tested, those results will 
remain as part of the overall research data.


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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 
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.
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 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 


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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 
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
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.  


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10.3
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) tool called Trialmax, provided by the technology vendor CRF Health of Plymouth 
Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR Part 11.  The 
documentation related to the system validation of the ePRO tool is available through the 
vendor, CRF Health, while the user acceptance testing of the study-specific ePRO design 
will be conducted and maintained at AbbVie.
The subject will be entering the data into an electronic device, these data will be uploaded 
to a server.  The data on the server will be considered source documentation, and 
maintained and managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the investigational sites, 
as well as delegated personnel.  Such access will be removed from investigational sites 
following the receipt of the study archive.  Data from the ePRO tool will be archived on 
appropriate data media (CD-ROM, etc.) and provided to the investigational site at that 
time as a durable record of the site's ePRO data.  It will be possible for the investigational 
site to create paper print-outs from that media. 
The ePRO data (Bristol Stool Form scale, number of liquid or very soft stools, use of 
medications used for endoscopy preparation, dosing information, and general well-being) 
will be collected electronically via a handheld device into which the patient will record 
the required pieces of information on a daily basis.  The electronic device will be 
programmed to allow for data entry once per day.  All data entered on the device will be 
immediately stored to the device itself and manually/automatically uploaded to a central 
server administrated by CRF Health.  The investigational site staff will be able to access 
all uploaded subject entered data via a password protected website, until the generation, 
receipt and confirmation of the study archive.


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10.4
Data Collection Process
AbbVie is using an Electronic Patient Reported Outcome (ePRO) tool to capture portions 
of the clinical data defined in this protocol.  The use of ePRO requires certain process 
changes compared to the use of traditional paper PROs.  Trial-Specific Guidelines 
(T-SGs) have been developed to document the changes from the traditional paper PRO 
process.  These T-SGs govern the ePRO processes in this trial.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
Investigators and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, eCRF, Subject 
Questionnaires and Subject Dosing Diary completion, and specimen collection methods.
Sites will be monitored throughout the study and 100% source document verification will 
be performed.
All data entered in the database will be verified at AbbVie.  Any discrepancies will be 
reviewed and necessary corrections will be made to the eCRF by the site.  The data will 
be reviewed and computer electronic logic checks will be run to identify items such as 
inconsistent study dates.  A manual review of selected line listings will also be performed 
throughout and at the end of the study.
The data from the central laboratory analyses will be electronically transferred from the 
central laboratory to the study database.  A review of all laboratory results will be 
conducted by the AbbVie monitors (or their representatives), the Study Investigator and 
other appropriate personnel from AbbVie.  A final review of all laboratory results will be 
conducted by a physician and clinical review team at AbbVie.
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.
If this protocol or the information gained from the conduct of this study will be made 
public (disclosed/published), AbbVie will determine the information that is not yet in the 
public domain and if the disclosure of such information may undermine AbbVie's 
interests, will remain confidential at the time of disclosure/publication.
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.
Any research that may be done using pharmacogenetic or exploratory research samples 
from this study will be experimental in nature and the results will not be suitable for 
clinical decision making or patient management.  Hence, neither the investigator, the 
subject, nor the subject's physician (if different from the investigator) will be informed of 
individual subject results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, researchers will have no access to subject 


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identifiers.  Individual results will not be reported to anyone not directly involved in this 
research other than for regulatory purposes.  Aggregate pharmacogenetic or exploratory 
research information from this study may be used in scientific publications or presented at 
medical conventions.  Information will be published or presented only in a way that does 
not identify any individual subject.
13.0
Completion of the Study
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.
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.
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.


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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, Randomized, Double-Blind Study to 
Evaluate Higher Versus Standard Adalimumab Dosing 
Regimens for Induction and Maintenance Therapy in 
Subjects with Moderately to Severely Active Crohn's 
Disease and Evidence of Mucosal Ulceration
Protocol Date:
27 November 2018
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.
Rutgeerts P, Van Assche G, Sandborn WJ, et al.  Adalimumab induces and 
maintains mucosal healing in patients with Crohn's disease:  data from the 
EXTEND trial.  Gastroenterology.  2012;142(5):1102-11.e2.
8.
Daperno M, D'Haens G, Van Assche G, et al.  Development and validation of a 
new, simplified endoscopic activity score for Crohn's disease:  the SES-CD.  
Gastrointest Endosc.  2004;60(4):505-12.
9.
Vuitton L, Marteau P, Sandborn WJ, et al.  IOIBD technical review on endoscopic 
indices for Crohn's Disease clinical trials.  Gut.  2015;0:1-9.


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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
Clinical
Statistics
Bioanalysis
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)
Work Productivity and Activity Impairment Questionnaire:
Crohn's Disease (WPAI-CD)
The following questions ask about the effect of your Crohn's disease on your ability to 
work and perform regular activities such as physical or emotional problems or symptoms.  
Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? ____  NO ____  YES
If NO, check "NO" and skip to Question 6.
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of 
problems associated with your Crohn's disease?  Include hours you missed on sick 
days, times you went in late, left early, etc., because of your Crohn's disease.  Do 
not include time you missed to participate in this study.
_____HOURS
3.
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4.
During the past seven days, how many hours did you actually work?
_____HOURS (If "0," skip to question 6.)
5.
During the past seven days, how much did your Crohn's disease affect your 
productivity while you were working?
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 


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usual.  If Crohn's disease affected your work only a little, choose a low number.  Choose a 
high number if Crohn's disease affected your work a great deal.
Consider only how much Crohn's disease affected productivity while you were working.
Crohn's disease 
had no effect on 
my work
Crohn's disease 
completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past seven days, how much did your Crohn's disease affect your ability 
to do your regular daily activities, other than work at a job?
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If Crohn's disease affected your activities only a little, 
choose a low number.  Choose a high number if Crohn's disease affected your 
activities a great deal.
Consider only how much Crohn's disease affected your ability to do your regular daily 
activities, other than work at a job.
Crohn's disease had 
no effect on my 
daily activities
Crohn's disease 
completely prevented 
me from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER


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Appendix D.
Sample EQ-5D Questionnaires
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking
I have slight problems walking 
I have moderate problems walking
I have severe problems walking
I am unable to walk
SELF-CARE
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES
(e.g., work, study, housework, family or leisure activities)
I have no problems doing my usual activities 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
PAIN/DISCOMFORT
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY/DEPRESSION
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
USA (English) © 2009 EuroQol Group.  EQ-5D™is a trade mark of the EuroQol Group


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USA (English) © 2009 EuroQol Group.  EQ-5D™is a trade mark of the EuroQol Group
Copyright
Please note that without the prior written consent of the EuroQol Executive Office, you are not permitted to i.e., use, 
reproduce, alter, amend, convert, translate, publish or make available in whatever way (digital, hard-copy etc.) the 
EQ-5D and related proprietary materials.
The EuroQol Group stresses that any and all copyrights in the EQ-5D, its (digital) representations, and its translations 
exclusively vest in the EuroQol Group.  EQ-5D™ is a trade mark of the EuroQol Group.


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Appendix E.
Sample Quality of Life in Inflammatory Bowel Disease 
Questionnaire (IBDQ)


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Appendix F.
Abdominal Pain Rating Scale
Please rate your abdominal pain intensity by indicating the number that best describes 
your abdominal pain on average in the last 24 hours.
None
Worst Pain 
Imaginable
0 None – No symptoms.
1 – 3 Mild – The pain is transient and easily tolerated, not requiring any treatment.
4 – 6 Moderate – The pain caused discomfort and interrupted usual activities.  Some 
form of treatment was required.
7 – 9 Severe – The pain caused considerable interference with usual activities and may 
have been incapacitating, requiring treatment.
10 Worst Imaginable – The pain causes extensive interference with usual activities and 
is incapacitating, requiring strong analgesics and/or hospitalization.


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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 M14-115
Tables 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.
You will receive the following number of injections during the study:
●
Baseline Visit (the first visit to receive study medication for this study), you 
will receive 4 injections (2 kits) at the clinic.
●
Week 1 you will administer 4 injections (2 kits) at home.
●
Week 2 you will receive 4 injections (2 kits) at the clinic.
●
Week 3 you will administer 4 injections (2 kits) at home.
●
At Weeks 4, 6, 8, 12, 14, 20, 26, 28, 34, 40, 42 and 48 you will receive 
1 injection at the clinic.
●
At Weeks 10, 13, 15 – 19, 21 – 25, 27, 29 – 33, 35 – 39, 41, 43 – 47, 49 – 55 
you will administer 1 injection at home.
For all doses, kits must be used in the order dispensed.  All doses of study medication 
must be taken in order, starting with the syringe labeled with a "1," then at the next dose, 
using the syringe labeled with a "2."
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" versus Placebo.
●
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.


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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)
●
alcohol prep(s)
●
cotton ball or gauze pad(s)


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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
●
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.


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●
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.


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4. Injecting Adalimumab
●
With your other hand, gently squeeze an area of the cleaned area of skin and 
hold it firmly.
●
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)
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
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
Standard 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
Standard 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)
76.4 (168.4)
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)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard 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)
*Standard height is calculated 
using actual height obtained at 
screening (without shoes) plus 
one inch
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 that 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 or moved 
into the OLE study (M14-347).
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.
Guidelines to Evaluate Loss of Response and Intolerance to 
Infliximab
To enroll in this study, subjects who have previously been exposed to infliximab must 
meet one of the two conditions defined below.
Loss of Response
The Investigator judges the subject to have responded to infliximab in the past and 
demonstrated a loss of response after a full and adequate course of infliximab based on the 
Investigator's assessment.
Intolerance to Infliximab
A subject is defined as intolerant when, in the opinion of the Investigator, therapy was 
discontinued as a result of a significant acute or delayed infusion/administration reaction 
to the medication.


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Appendix L.
Bristol Stool Form Scale


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Appendix M.
SES-CD Scoring
SES-CD Scoring8
Rectum
Sigmoid 
and Left 
Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL =




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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-115
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  20 March 2017
Protocol Title:  A Multicenter, Randomized, Double-Blind Study to Evaluate Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Crohn's Disease and Evidence of Mucosal Ulceration
Objectives:
The objective of Study M14-115 is to evaluate efficacy and safety of higher induction and maintenance 
dosing regimens in subjects with moderately to severely active Crohn's disease.
Investigators:  Multicenter
Study Sites:  Approximately 150 sites worldwide.
Study Population:  Males and females ≥ 18 and ≤ 75 years of age with a diagnosis of moderately to 
severely active Crohn's disease, CDAI ≥ 220 and ≤ 450, and evidence of mucosal ulceration by Simple 
Endoscopic Score (SES-CD) ≥ 6, excluding the presence of narrowing component, or SES-CD ≥ 4, 
excluding the presence of narrowing component, for patients with disease limited to the ileum, on 
screening endoscopy (or endoscopy performed within 45 days before Baseline), confirmed by a central 
reader.
Number of Subjects to be Enrolled:  Approximately 600 (360 in higher induction regimen group and 
240 in standard induction regimen group) subjects with moderately to severely active Crohn's Disease, 
CDAI of ≥ 220 and ≤ 450 and evidence of mucosal ulceration, confirmed by centrally read endoscopy.
Methodology:
This Phase 3 study design includes the Screening Period followed by a 12-Week double-blind Induction 
Study and 44-Week double-blind Maintenance Study.  The Induction Study will assess the efficacy and 
safety of two adalimumab induction regimens in achieving clinical remission, defined as Crohn's Disease 
Activity Index (CDAI) < 150 at Week 4, and endoscopic improvement, defined as Simplified Endoscopic 
Score for Crohn's Disease (SES-CD) ≤ 4 and at least a 2 point reduction versus baseline and no subscore 
greater than 1 in any individual variable at Week 12, in subjects with moderately to severely active 
Crohn's disease and evidence of mucosal ulceration at Baseline.
The Maintenance Study will assess the efficacy and safety of two adalimumab maintenance regimens in 
maintaining clinical and endoscopic improvements at Week 56.  Analyses of the outcomes from the 
maintenance regimens are considered exploratory.
During both the Induction Study and the Maintenance Study, visit week designations will represent 
weeks since first dose in the Induction Study.  Week 0 (Baseline) will reflect the date of first adalimumab 
dosing in the Induction Study.  Week 12 will represent the final assessment in the Induction Study. 
Week 56 will represent the final assessment in the Maintenance Study (representing 44 weeks of 
maintenance treatment in the Maintenance Study).  


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Methodology (Continued):
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
study and randomized in a 3:2 ratio at Baseline to receive a higher induction adalimumab regimen or 
standard induction adalimumab regimen during the double-blind Induction Study.  Up to 25% of subjects 
with previous infliximab exposure may be enrolled.  All subjects who complete the Induction Study 
(regardless of achievement of response at Week 12) will continue into the Maintenance Study.  Assuming 
the Week 4 clinical remission rate will be approximately 50% for the higher induction dose regimen and 
approximately 30% for the standard dose regimen, a sample size of 600 (360 higher dose and 
240 standard dose) will be adequate to detect at least a 20% treatment difference in clinical remission 
rates at Week 4 between the dosing regimens using Fisher's exact test with 99% power at a 
0.05 two-sided significant level.
Since exposure/endoscopic relationships are not currently available for adalimumab, clinical remission 
will be based on PK/PD modeling which predicts an expected ~50% increase in the proportion of 
subjects with endoscopic improvement compared to the standard adalimumab induction regimen.  The 
observed rate of SES-CD ≤ 4 in Study M05-769 was 37% at Week 12 with the currently approved dosing 
regimen.  Thus, by extrapolation, the expected rate for SES-CD ≤ 4 at Week 12 using the higher 
induction regimen is 55%.  A sample size of 600 subjects (360 higher induction regimen and 
240 standard induction regimen) will be adequate to detect at least an 18% treatment difference in 
endoscopic improvement rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 98% power at a 0.05 two-sided significance level.
Since clinical remission at the Week 4 endpoint and the endoscopic improvement at the Week 12 
endpoint are not likely to be independent of each other, the power for the co-primary endpoints for the 
Induction Study is expected to be > 97% (see protocol for detailed assumptions of the sample size 
calculation).
The randomization of subjects for the Induction Study will be stratified by high-sensitivity C-Reactive 
Protein (hs-CRP) at Baseline (< 10 and ≥ 10 mg/L), using the Screening hs-CRP value, prior infliximab 
use, and Crohn's disease activity (CDAI ≤ 300, > 300) at Baseline.  Subjects with prior infliximab 
experience will be limited to 25% of the study population.  Subjects assigned to the higher induction 
regimen will receive blinded adalimumab 160 mg at Baseline, Week 1, Week 2, and Week 3.  At Week 4, 
subjects will receive adalimumab 40 mg every other week (eow) through Week 12.  Subjects assigned to 
the standard induction regimen will receive blinded adalimumab 160 mg at Baseline and matching 
placebo at Week 1, adalimumab 80 mg at Week 2 and matching placebo at Week 3.  At Week 4, subjects 
will receive adalimumab 40 mg every other week through Week 12.
Maintenance Study:
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-blinded exploratory 
treatment regimens (adalimumab clinically adjusted [CA] regimen and adalimumab therapeutic drug 
monitoring [TDM] regimen).  The re-randomization at Week 12 will be stratified by induction treatment 
regimen, clinical response (CR-70) status at Week 12 and endoscopic response status (decrease in 
SES-CD > 50% from Baseline) per the site investigator reading at Week 12.  Among Week 12 
endoscopic responders, the randomization will be further stratified by endoscopic improvement, defined 
as achievement of an SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no subscore greater 
than 1 in any individual variable using the Week 12 SES-CD value provided by the site.


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Methodology (Continued):
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab every other week 
beginning at Week 12.  The adalimumab dose will be escalated to every week (ew) as early as Week 14 if 
the subject's CDAI ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or current visit) as shown by 
the dose adjustment criteria below.  These subjects will also be allowed to escalate at unscheduled visits 
that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 54.  Once subjects in the 
clinically adjusted regimen are escalated, they will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will be determined 
by the dose adjustment criteria referenced in the table below.  Doses will be determined using blinded 
serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI or hs-
CRP values from the current or prior visit.  For subjects who meet criteria for dose escalation at Weeks 
14, 28 or 42, subjects will receive 40 mg weekly.
The goal of the TDM regimen is to attain and maintain serum adalimumab levels above a reasonably high 
concentration levels in subjects for mucosal healing.  Since exposure-endoscopic relationships are not 
currently available for adalimumab, clinical remission was used for selection of concentration threshold 
to be used in TDM arm.  Based on the PK analyses of concentrations in Studies M02-403, M04-691 and 
M02-433, no concentration level could be identified as significant and reliable predictor of remission in 
adult CD.  Therefore, the TDM regimen will be based on two concentration thresholds in conjunction 
with clinical response criteria as expected to occur in clinical setting.  About 75% of the subjects who 
were in remission at Week 56 in Study M02-433 had serum concentration above 5 μg/mL.  Therefore, the 
lower concentration threshold for the TDM regimen was selected as 5 μg/mL and any subject below 
5 μg/mL concentration will be escalated to ew dosing.  The second threshold was selected as 10 μg/mL, 
which is similar to the median concentrations (9.4 μg/mL at Week 56) observed in subjects who were in 
remission.  The subjects with concentration above 5 and below 10 μg/mL may be dose escalated based on 
clinical response as outlined in the table below.  The subjects with serum concentration above 10 μg/mL 
will not be dose escalated.


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Methodology (Continued):
Adalimumab Dose Adjustment Criteriaa
ADA Serum Concentrationb (ug/mL)
CDAIc
hs-CRPd (mg/L)
Dose Change?
Clinically Adjusted Regimen
any
< 220
< 10
no
any
any
≥ 10
yes; dose escalate to ew
any
≥ 220
any
yes; dose escalate to ew
Therapeutic Drug Monitoring Regimen
< 5
any
any
yes; dose escalate to ew
5 – 10
< 220
< 10
no
5 – 10
any
≥ 10
yes; dose escalate to ew
5 – 10
≥ 220
any
yes; dose escalate to ew
> 10
any
any
no
a.
For subjects experiencing an active infection or those for whom the investigator feels dose escalation is not 
advisable, the investigator should contact the Study Designated Physician.
b.
Measured from the serum concentration taken at the prior study visit.
c.
Measured using hematocrit taken from prior study visit for CDAI calculation.
d.
Measured using hs-CRP from the prior or current study visit.
The duration of the study could be up to 60 weeks which includes a Screening Period (1 – 4 weeks), a 
12-week double-blind Induction Study and a 44-week Maintenance Study.  The Screening Period may be 
extended as necessary after consultation with and approval by the AbbVie Study Designated Physician 
(SDP) for subjects who require initiation of prophylactic anti-tuberculosis (TB) therapy, or in case of 
external, not subject-related circumstances (e.g., due to delay of availability of screening test results).  
There will also be a 70-day follow-up phone call for subjects who complete Week 56 or discontinue from 
the study prematurely.
Clinical evaluation will occur at Baseline, Weeks 2, 4, 6, 8, 12, 14, 20, 26, 28, 34, 40, 42, 48, and 
56/Premature Discontinuation (PD) visits.  An electronic diary will be dispensed at the Screening visit.  
In addition to routine physical examination, CDAI calculation, diary review, laboratory, adverse event, 
concomitant medication and vital sign assessments, the following will be collected:
!
Results of study questionnaires (IBDQ, EQ-5D, WPAI) at Baseline, Week 4, Week 8, Week 12, 
Week 26, Week 40 and Week 56/PD.
!
Calculation of the SFPS at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 14, 
Week 20, Week 26, Week 28, Week 34, Week 40, Week 42, Week 48 and Week 56/PD.  The 
Screening visit results will serve as the Baseline value.
!
Results of daily Bristol Stool Form Scale beginning at Baseline through Week 56/PD.
!
Results of 11-point Abdominal Pain Rating Scale beginning at Baseline, Week 2, Week 4, 
Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of adalimumab concentrations just prior to dosing at Baseline, Week 2, 
Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.


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Methodology (Continued):
!
Serum for measurement of Anti-Adalimumab Antibodies (AAA) just prior to dosing at Baseline, 
Week 4, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of infliximab serum levels and Human Anti-Chimeric Antibodies 
(HACA) just prior to dosing at Baseline.
!
Serum biomarkers/mRNA at Baseline, Week 2, Week 4, Week 8, Week 12, Week 26, Week 40, 
and Week 56/PD.
!
Stool samples for analysis of fecal calprotectin during Screening, at Week 4, Week 12, Week 26, 
and Week 56/PD.
!
Stool samples for microbiota metagenomic analyses during Screening, at Week 4, Week 12, 
Week 26, and Week 56/PD.
!
Endoscopic evaluations, confirmed by central reader, will be done at Screening, Week 12, and 
Week 56/PD.
!
An optional pharmacogenetic sample should be drawn at Baseline and Week 12.
Throughout the study, subjects will only be allowed to change the dosage of CD-specific concomitant 
medications as specified below:
!
At Week 4, subjects who are taking corticosteroid therapy at Baseline will have their 
corticosteroid therapy tapered according to a tapering schedule specified in the clinical study 
protocol.  If the Investigator feels that the steroid taper is not advisable for a particular subject at 
Week 4, the Study Designated Physician (SDP) should be consulted for evaluation and approval.
!
Subjects taking corticosteroids at Baseline who have a loss of satisfactory clinical response per 
the Investigator's judgment after the steroid taper has been initiated may have their 
corticosteroid dose increased per the Investigator's discretion during the study.  Subjects in 
whom the maximum equivalent steroid dose exceeds the dose used at Baseline will be censored 
for efficacy assessments (i.e., they will be considered non-responders for categorical endpoints 
and will have Baseline values carried forward for non-categorical assessments) from that point 
forward.  These subjects will continue to be evaluated in the safety population.
!
Immunosuppressant doses may be decreased or terminated in the event of moderate-to-severe 
treatment-related toxicities.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion
1.
Males and females ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of colonic, ileocolonic, or ileal Crohn's disease for ≥ 3 months prior to Baseline and 
confirmed by endoscopy during the Screening period or endoscopy performed within 45 days before 
Baseline, with exclusion of current infection, dysplasia, and/or malignancy.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the 
Investigator, must be available.
3.
Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6, excluding the presence of 
narrowing component, or SES-CD ≥ 4, excluding the presence of narrowing component, for patients 
with disease limited to the ileum, on a screening endoscopy or endoscopy performed within 45 days 
before Baseline, confirmed by a central reader.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued)
4.
Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450 at Baseline despite concurrent or prior 
treatment with a full and adequate course, in the opinion of the Investigator, of at least one of the 
following (oral corticosteroids and/or immunosuppressants or both as defined below):
!
Subject taking oral corticosteroids, excluding budesonide:
o
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
!
For subjects with a dose > 10 and ≤ 40 mg/day, dose has been stable for at least 7 days 
prior to Baseline and the duration of the current steroid course has been at least 14 days 
prior to Baseline.
!
For subjects with a dose ≤ 10 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior to 
Baseline.
!
Subject taking oral budesonide:
o
Dose must not exceed 9 mg/day;
!
For subjects with a dose ≥ 6 mg/day, dose has been stable for at least 7 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
!
For subjects with a dose < 6 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
or,
!
At least a consecutive 42-day course of azathioprine, 6-MP or injectable MTX prior to Baseline, 
with a stable dose for at least 28 days prior to Baseline of azathioprine ≥1.5 mg/kg/day or 6-MP 
≥ 1 mg/kg/day (rounded to the nearest available tablet or half tablet formulation) or a 
documented 6-TGN level of at least 230 pmol/8 × 108 RBC to clarify a therapeutic level was 
achieved on the current dosing regimen or MTX ≥15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the subject (e.g., due to 
leukopenia, elevated liver enzymes, nausea) during that time.
Note:  If a subject is taking both an oral corticosteroid and an immunosuppressant listed above, 
BOTH of the drugs need to meet the above criteria.  Oral MTX use is allowed during the study 
(at a stable dose for 28 days prior to Baseline) however current or prior use of oral MTX is not 
sufficient for inclusion into the study.
or,
!
Concurrent therapy with oral corticosteroids or immunosuppressants (azathioprine, 6-MP or 
SC/IM MTX) is not required for subjects not currently taking these medications who were 
previously treated during the past 1 year and have confirmed documentation of failure to 
respond, or were previously treated during the past 5 years and have confirmed documentation 
indicating lack of tolerability, see Section 10.1.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Subject may be included if they have previously experienced a benefit from infliximab and 
discontinued its use due to a subsequent loss of response (judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of CD-related symptoms) or intolerance (in the opinion of the Investigator therapy was 
discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication) to the agent. Confirmed documentation indicating loss of response or lack of tolerability 
will be required.
6.
Subject has a negative TB Screening Assessment (including a PPD test or QuantiFERON TB Gold 
test [or equivalent]) and negative chest x-ray (CXR – PA and lateral view) at Screening.  If the 
subject has evidence of a latent TB infection; the subject must initiate and complete a minimum of 
2 weeks of an ongoing TB prophylaxis or have documented completion of a full course of anti-TB 
prophylaxis, prior to Baseline.
7.
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.
8.
Subject must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.
9.
Subject is judged to be in otherwise good health as determined by the Principal Investigator based 
upon the results of medical history, laboratory profile, physical examination, CXR, and a 12-lead 
electrocardiogram (ECG) performed during Screening.
10. Subject must be able and willing to self-administer subcutaneous (SC) injections or have a qualified 
person available to administer SC injections.
Main Exclusion:
1.
Subject with a current diagnosis of ulcerative colitis (UC) or indeterminate colitis.
2.
Subject on azathioprine, 6-mercaptopurine (6-MP), methotrexate (MTX), or another 
immunosuppressant (e.g., thalidomide) who:
!
Has not been on these medications for at least 42 days prior to Baseline; or
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or 
!
Has discontinued these medications within 14 days of Baseline.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
3.
Subject on oral aminosalicylates who:
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or
!
Has discontinued use of aminosalicylates within 14 days of Baseline.
4.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subjects on budesonide 
> 9 mg/day; or
!
Subject taking an oral corticosteroid (excluding budesonide):
o
dose > 10 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose > 10 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose ≤ 10 mg/day or equivalent, but has not been on a stable dose for at least 10 days prior 
to Baseline; or
o
dose ≤ 10 mg/day or equivalent but has not been on a current steroid course of at least 
14 days in duration prior to Baseline, or
!
Subject taking budesonide:
o
dose ≥ 6 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose ≥ 6 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose < 6 mg/day dose but has not been on a stable dose of at least 10 days prior to Baseline; 
or
o
dose < 6 mg/day but the current course has not been at least 14 days in duration prior to 
Baseline; or
Has been taking both oral budesonide and prednisone (or equivalent) simultaneously, with the 
exception of inhalers.
5.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
6.
Subject who has had surgical bowel resections within the past 6 months or is planning any resection 
at any time point while enrolled in the study.
7.
Subject with a symptomatic bowel stricture.
8.
Subject with an abdominal or peri-anal abscess.
9.
Subject with an ostomy or ileoanal pouch.
10. Subject who has short bowel syndrome.
11. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 
14 days prior to Screening and/or during the Screening period.
12. Subject with prior exposure to medications that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML) including participation in a clinical trial of 
investigational agents targeting white cell trafficking (e.g., natalizumab [Tysabri®], rituximab 
[Rituxan®], efalizumab [Raptiva®]).  Prior exposure to any anti-tumor necrosis factor (TNF) agent 
other than infliximab (including etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
13. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to 
Baseline, whichever is longer.
14. Subject who previously received treatment with adalimumab or previously participated in an 
adalimumab clinical study.
15. Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 60 days prior to 
Baseline.
16. Subject who previously received stem cell transplantation.
17. Subject who previously received fecal microbial transplantation.
18. Subject that received non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to 
Screening and during the Screening Visit, except low-dose aspirin for prevention of heart attacks, 
unstable angina or transient ischemic attacks or topical NSAIDs.
19. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives for non-Crohn's disease related infections within 14 days prior 
to the Baseline Visit.
20. Subjects on Crohn's disease related antibiotics that have not been on stable doses for at least 28 days 
prior to Baseline.  Subjects on Crohn's disease related antibiotics that have discontinued these 
medications within 28 days of Baseline are excluded.
21. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during 
the course of the study.
22. Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the Screening period.
23. Screening laboratory and other analyses show any of the following abnormal results:
!
AST, ALT > 1.75 × upper limit of the reference range;
!
WBC count < 3.0 × 109/L;
!
Electrocardiogram (ECG) – with clinically significant abnormalities;
!
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert syndrome;
!
Serum creatinine > 1.6 mg/dL.
24. Known hypersensitivity to adalimumab or its excipients.
25. Subject who has previously used infliximab:
!
and had not clinically responded at any time ("primary non-responder") unless subject 
experienced a treatment limiting reaction;
or
!
who used infliximab within 56 days of Baseline.
26. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
27. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency 
syndrome (HIV).
28. 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
29. Subjects with a positive result for the Hepatitis B surface antigen (HBs Ag) will be excluded.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core 
antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab Total (+) require 
PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection 
sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require HBV DNA 
PCR qualitative testing:
!
HBc Ab Total (–) and HBs Ab* (–)  
!
HBc Ab Total (–) and HBs Ab* (+) 
!
HBc Ab Total (+) and HBs Ab* (+)
*
For HBs Ab test results, a (–) result is equivalent to nonreactive and a (+) result is 
equivalent to reactive.
30. Chronic recurring infections.
31. Subject with active TB.
32. Subject with latent TB infection unless there is evidence the subject initiated and completed a 
minimum of 2 weeks of an ongoing TB prophylaxis or have documented completion of a full course 
of anti-TB prophylaxis, prior to Baseline.
33. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular 
accident and any other condition which, in the opinion of the Investigator, would put the subject at 
risk by participation in the study.
34. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in 
any biopsy performed during the Screening endoscopy or endoscopy performed within 45 days 
before Baseline.
35. Positive pregnancy test at Screening (serum) or Baseline (urine).
36. Female subjects who are breastfeeding or considering becoming pregnant during the study.
37. History of clinically significant drug or alcohol abuse in the last 12 months.
38. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
39. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other 
than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or 
localized carcinoma in situ of the cervix.
40. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.


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Investigational Products:
Adalimumab (40 mg/0.8 mL)
Double-Blind Induction
Subjects will be randomized to receive one of 2 double-blind 
adalimumab Induction Study regimens.
Doses:
(Higher Induction Regimen)
160 mg at Baseline, Weeks 1, 2, and 3, and 40 mg at Week 4, continuing 
at 40 mg every other week through Week 12.
(Standard Induction Regimen)
160 mg at Baseline and matching placebo at Week 1, 80 mg at Week 2 
and matching placebo at Week 3 and 40 mg every other week beginning 
at Week 4 through Week 12.
Double-Blind Maintenance
Subjects will receive one of two double-blind adalimumab Maintenance 
Study regimens.
Doses:
NOTE:  In order to retain 
blinding across regimens, all 
subjects who do not meet the 
criteria for dose escalation in 
either maintenance regimen 
will receive matching placebo 
injections in addition to the 
adalimumab injection.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 
40 mg adalimumab every other week beginning at Week 12.  The 
adalimumab dose will be escalated to every week starting at Week 14 if 
CDAI is ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or 
current visit) as shown by the dose adjustment criteria table.  These 
subjects will also be allowed to escalate at unscheduled visits that may 
occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 
54.  Once subjects in the clinically adjusted regimen are escalated, they 
will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized 
to the TDM regimen will be determined by the dose adjustment criteria 
table.  Doses will be determined using blinded serum concentrations at 
the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI 
or hs-CRP values from the current or prior visit.  For subjects who meet 
criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 
40 mg weekly.
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:
The study will include a Screening Period of 1 – 4 weeks, a double-blind Induction Study of 12 weeks,
and a double-blind Maintenance Study of 44 weeks.  There will also be a 70-day follow-up phone call for 
subjects who complete the study or discontinue from the study prematurely.


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Criteria for Evaluation:
Efficacy Endpoints:
Subjects participating in the Induction Study randomized to the higher adalimumab induction dose 
regimen will be compared to those subjects randomized to the standard adalimumab induction regimen.  
Subject data from the Maintenance Study will be used for exploratory analyses.
Co-Primary Induction Study Efficacy Endpoints:
!
Proportion of subjects who achieve a CDAI < 150 at Week 4.
!
Proportion of subjects who achieve an SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable at Week 12.
Ranked Secondary Endpoints:
1.
Proportion of subjects with sustained clinical remission (CDAI < 150) at both Weeks 4 and 12.
2.
Proportion of subjects with CDAI < 150 at Week 4 and SES-CD ≤ 4 and at least a 2 point reduction 
versus baseline and no subscore greater than 1 in any individual variable at Week 12.
3.
Proportion of subjects with clinical remission (CDAI < 150) at Week 12.
4.
Proportion of subjects who discontinued corticosteroid use and achieved clinical remission (CDAI 
< 150) at Week 12 among subjects taking corticosteroids at Baseline.
5.
Proportion of subjects with endoscopic response (decrease > 50% SES-CD from baseline) at 
Week 12.
6.
Change from Baseline in fecal calprotectin level at Week 4.
7.
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g at Week 4.
8.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal calprotectin < 250 μg/g at 
Week 4.
9.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore > 1 in any individual variable, and fecal calprotectin 
< 250 μg/g at Week 12.
10. Proportion of subjects who achieve an SES-CD ≤ 2 at Week 12.
11. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 4.
12. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 12.
13. Change in IBDQ from baseline at Week 4.
14. Change in IBDQ from baseline at Week 12.
Endpoints for Exploratory Maintenance Study:
!
Proportion of subjects who achieve endoscopic improvement (SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore greater than 1 in any individual variable) at Week 56 
among subjects with endoscopic improvement at Week 12. 
!
Proportion of subjects who achieve a CDAI < 150 at Week 56 among subjects who achieve 
CDAI < 150 at Week 12.
All other efficacy and exploratory endpoints will be non-ranked.
Additional analyses are outlined in the protocol.


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Criteria for Evaluation (Continued):
Pharmacokinetic:
Blood samples will be collected for measurement of serum adalimumab concentration just prior to dosing 
at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/Premature 
Discontinuation and anti-adalimumab antibody (AAA) just prior to dosing at Baseline, Week 4, Week 12, 
Week 26, Week 40, and Week 56PD.
Blood samples will also be collected for measurement of infliximab serum levels and Human 
Anti-Chimeric Antibodies (HACA) just prior to dosing at Baseline.
Exploratory Research Using Intestinal Mucosal Biopsy Samples (Optional):
Optional intestinal biopsies will be collected with consent at Screening, Week 12, and Week 56 or at 
premature discontinuation.  The purpose of these samples is to test potential biomarker signatures and 
new drug targets for IBD.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of study drug.  Incidence 
of adverse events, changes in vital signs, physical examination results, and clinical laboratory data will be 
assessed.
Statistical Methods:
Efficacy:
The co-primary efficacy variables for the Induction Study are proportion of subjects with moderately to 
severely active CD that have achieved clinical remission, defined as CDAI < 150, at Week 4 and 
proportion of subjects with moderately to severely active CD that have achieved endoscopic 
improvement defined as an SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no subscore 
greater than 1 in any individual variable at Week 12. The comparison between treatment groups for the 
two co-primary efficacy variables will be performed using the Cochran-Mantel-Haenszel (CMH) test and 
will be stratified by hs-CRP at Baseline (< 10 and ≥ 10 mg/L) (the Screening hs-CRP will serve as the 
Baseline value), prior infliximab use, and Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline.  A 
CMH based two-sided 95% confidence interval for the difference between treatment groups will be 
calculated.  The ITT set includes all subjects who were randomized at baseline.  Missing CDAI at 
Week 4 or missing SES-CD at Week 12 will be imputed using the non-responder imputation (NRI) 
approach.  For Week 4 clinical remission, LOCF, OC and multiple imputation methods will be used as 
sensitivity analyses.  For Week 12 endoscopic improvement, LOCF and OC will be used as sensitivity 
analyses.
Secondary efficacy variables for the Induction Study are divided into two groups.  The first group 
includes ranked secondary endpoints, which are ranked by clinical importance.  Statistical significance is 
assessed at 0.050 (2-sided) in ranked endpoint order until the significance level exceeds 0.05.  No 
additional statistically significant treatment differences may be declared after the first ranked endpoint 
fails to achieve 0.05.  The second group includes all other additional secondary variables.


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Statistical Methods (Continued):
Efficacy (Continued):
In general, continuous secondary efficacy variables, including all efficacy variables for Maintenance 
Study, will be analyzed using Analysis of Covariance (ANCOVA) model including factor for treatment 
group, stratification factors and Baseline values, whereas CMH test stratified by stratification factors 
used for discrete data.  NRI for missing data will be used for categorical endpoints.  Both last observation 
carried forward (LOCF) and observed case (OC) analyses will be performed for continuous endpoint.  
The LOCF analysis is considered primary for inferential purposes.  In addition, Mixed-Effect Model 
Repeated Measure (MMRM) will be applied, wherever appropriate, as a sensitivity analysis for the 
longitudinal continuous endpoints.
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 regimen, and rates of AAA positive will be calculated.  
As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment 
emergent adverse events may be evaluated.
Safety:
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  
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 for subjects who do not participate in 
the OLE or until first dose of study drug in the OLE study if the subject is a study completer and is 
enrolled in the OLE.  Treatment-emergent AEs will be summarized separately for:  a) Baseline to 
Week 12; b) Week 12 to Week 56; c) Baseline to Week 56 (overall study duration).  An overview of 
treatment-emergent AEs, including AEs of special interest such as adverse events leading to death and 
adverse events 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.  Treatment group differences in the overall incidence of treatment-emergent AEs 
will be assessed with Fisher's exact test for each preferred term.
Changes in laboratory data will be described using statistical characteristics and compared 
between-treatment groups will be performed using a one-way Analysis of Variance (ANOVA).  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.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-115
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  27 November 2018
Protocol Title:  A Multicenter, Randomized, Double-Blind Study to Evaluate Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Crohn's Disease and Evidence of Mucosal Ulceration
Objectives:
The objective of Study M14-115 is to evaluate efficacy and safety of higher induction and maintenance 
dosing regimens in subjects with moderately to severely active Crohn's disease.
Investigators:  Multicenter
Study Sites:  Approximately 150 sites worldwide.
Study Population:  Males and females ≥ 18 and ≤ 75 years of age with a diagnosis of moderately to 
severely active Crohn's disease, CDAI ≥ 220 and ≤ 450, and evidence of mucosal ulceration by Simple 
Endoscopic Score (SES-CD) ≥ 6, excluding the presence of narrowing component, or SES-CD ≥ 4, 
excluding the presence of narrowing component, for patients with disease limited to the ileum, on 
screening endoscopy (or endoscopy performed within 45 days before Baseline), confirmed by a central 
reader.
Number of Subjects to be Enrolled:  Approximately 500 (300 in higher induction regimen group and 
200 in standard induction regimen group) subjects with moderately to severely active Crohn's Disease, 
CDAI of ≥ 220 and ≤ 450 and evidence of mucosal ulceration, confirmed by centrally read endoscopy.
Methodology:
This Phase 3 study design includes the Screening Period followed by a 12-Week double-blind Induction 
Study and 44-Week double-blind Maintenance Study.  The Induction Study will assess the efficacy and 
safety of two adalimumab induction regimens in achieving clinical remission, defined as Crohn's Disease 
Activity Index (CDAI) < 150 at Week 4, and endoscopic response, defined as a decrease in Simplified 
Endoscopic Score for Crohn's Disease (SES-CD) > 50% from Baseline (or for a Baseline SES-CD of 4, 
at least a 2 point reduction from Baseline), as scored by central reviewer, at Week 12; in subjects with 
moderately to severely active Crohn's disease and evidence of mucosal ulceration at Baseline.
The Maintenance Study will assess the efficacy and safety of two adalimumab maintenance regimens in 
maintaining clinical and endoscopic improvements at Week 56.  Analyses of the outcomes from the 
maintenance regimens are considered exploratory.
During both the Induction Study and the Maintenance Study, visit week designations will represent 
weeks since first dose in the Induction Study.  Week 0 (Baseline) will reflect the date of first adalimumab 
dosing in the Induction Study.  Week 12 will represent the final assessment in the Induction Study.  
Week 56 will represent the final assessment in the Maintenance Study (representing 44 weeks of 
maintenance treatment in the Maintenance Study).  


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Methodology (Continued):
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
study and randomized in a 3:2 ratio at Baseline to receive a higher induction adalimumab regimen or 
standard induction adalimumab regimen during the double-blind Induction Study.  Up to 25% of subjects 
with previous infliximab exposure may be enrolled.  All subjects who complete the Induction Study 
(regardless of achievement of response at Week 12) will continue into the Maintenance Study.  Assuming 
the Week 4 clinical remission rate will be approximately 50% for the higher induction dose regimen and 
approximately 30% for the standard dose regimen, a sample size of 500 (300 higher dose and 
200 standard dose) will be adequate to detect at least a 20% treatment difference in clinical remission 
rates at Week 4 between the dosing regimens using Fisher's exact test with 99% power at a 
0.05 two-sided significant level.
Since exposure/endoscopic relationships are not currently available for adalimumab, clinical remission 
will be based on PK/PD modeling which predicts an expected ~50% increase in the proportion of 
subjects with endoscopic response compared to the standard adalimumab induction regimen.  The 
observed rate of endoscopic response in Study M05-769 was 44% at Week 12 with the currently 
approved dosing regimen.  Thus, by extrapolation, the expected rate for endoscopic response at Week 12 
using the higher induction regimen is 66%.  A sample size of 500 subjects (300 higher induction regimen 
and 200 standard induction regimen) will be adequate to detect at least a 22% treatment difference in 
endoscopic response rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 99% power at a 0.05 two-sided significance level.
Since clinical remission at the Week 4 endpoint and the endoscopic response at the Week 12 endpoint are 
not likely to be independent of each other, the power for the co-primary endpoints for the Induction Study 
is expected to be > 98% (see protocol for detailed assumptions of the sample size calculation).
The randomization of subjects for the Induction Study will be stratified by high-sensitivity C-Reactive 
Protein (hs-CRP) at Baseline (< 10 and ≥ 10 mg/L), using the Screening hs-CRP value, prior infliximab 
use, and Crohn's disease activity (CDAI ≤ 300, > 300) at Baseline.  Subjects with prior infliximab 
experience will be limited to 25% of the study population.  Subjects assigned to the higher induction 
regimen will receive blinded adalimumab 160 mg at Baseline, Week 1, Week 2, and Week 3.  At Week 4, 
subjects will receive adalimumab 40 mg every other week (eow) through Week 12.  Subjects assigned to 
the standard induction regimen will receive blinded adalimumab 160 mg at Baseline and matching 
placebo at Week 1, adalimumab 80 mg at Week 2 and matching placebo at Week 3.  At Week 4, subjects 
will receive adalimumab 40 mg every other week through Week 12.
Maintenance Study:
At Week 12, subjects will be re-randomized in a 1:1 ratio to one of the two double-blinded exploratory 
treatment regimens (adalimumab clinically adjusted [CA] regimen and adalimumab therapeutic drug 
monitoring [TDM] regimen).  The re-randomization at Week 12 will be stratified by induction treatment 
regimen, clinical response (CR-70) status at Week 12 and decrease in SES-CD > 50% from Baseline per 
the site investigator reading at Week 12.  Among subjects achieving SES-CD > 50% from Baseline at 
Week 12, the randomization will be further stratified by SES-CD ≤ 4 and at least a 2 point reduction 
versus baseline and no subscore greater than 1 in any individual variable using the Week 12 SES-CD 
value provided by the site.


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Methodology (Continued):
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab every other week 
beginning at Week 12.  The adalimumab dose will be escalated to every week (ew) as early as Week 14 if 
the subject's CDAI ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or current visit) as shown by 
the dose adjustment criteria below.  These subjects will also be allowed to escalate at unscheduled visits 
that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 54.  Once subjects in the 
clinically adjusted regimen are escalated, they will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will be determined 
by the dose adjustment criteria referenced in the table below.  Doses will be determined using blinded 
serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI or hs-
CRP values from the current or prior visit.  For subjects who meet criteria for dose escalation at Weeks 
14, 28 or 42, subjects will receive 40 mg weekly.
The goal of the TDM regimen is to attain and maintain serum adalimumab levels above a reasonably high 
concentration levels in subjects for mucosal healing.  Since exposure-endoscopic relationships are not 
currently available for adalimumab, clinical remission was used for selection of concentration threshold 
to be used in TDM arm.  Based on the PK analyses of concentrations in Studies M02-403, M04-691 and 
M02-433, no concentration level could be identified as significant and reliable predictor of remission in 
adult CD.  Therefore, the TDM regimen will be based on two concentration thresholds in conjunction 
with clinical response criteria as expected to occur in clinical setting.  About 75% of the subjects who 
were in remission at Week 56 in Study M02-433 had serum concentration above 5 μg/mL.  Therefore, the 
lower concentration threshold for the TDM regimen was selected as 5 μg/mL and any subject below 
5 μg/mL concentration will be escalated to ew dosing.  The second threshold was selected as 10 μg/mL, 
which is similar to the median concentrations (9.4 μg/mL at Week 56) observed in subjects who were in 
remission.  The subjects with concentration above 5 and below 10 μg/mL may be dose escalated based on 
clinical response as outlined in the table below.  The subjects with serum concentration above 10 μg/mL 
will not be dose escalated.


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Methodology (Continued):
Adalimumab Dose Adjustment Criteriaa
ADA Serum Concentrationb (ug/mL)
CDAIc
hs-CRPd (mg/L)
Dose Change?
Clinically Adjusted Regimen
any
< 220
< 10
no
any
any
≥ 10
yes; dose escalate to ew
any
≥ 220
any
yes; dose escalate to ew
Therapeutic Drug Monitoring Regimen
< 5
any
any
yes; dose escalate to ew
5 – 10
< 220
< 10
no
5 – 10
any
≥ 10
yes; dose escalate to ew
5 – 10
≥ 220
any
yes; dose escalate to ew
> 10
any
any
no
a.
For subjects experiencing an active infection or those for whom the investigator feels dose escalation is not 
advisable, the investigator should contact the Study Designated Physician.
b.
Measured from the serum concentration taken at the prior study visit.
c.
Measured using hematocrit taken from prior study visit for CDAI calculation.
d.
Measured using hs-CRP from the prior or current study visit.
   
The duration of the study could be up to 60 weeks which includes a Screening Period (1 – 4 weeks), a 
12-week double-blind Induction Study and a 44-week Maintenance Study.  The Screening Period may be 
extended as necessary after consultation with and approval by the AbbVie Study Designated Physician 
(SDP) for subjects who require initiation of prophylactic anti-tuberculosis (TB) therapy, or in case of 
external, not subject-related circumstances (e.g., due to delay of availability of screening test results).  
There will also be a 70-day follow-up phone call for subjects who complete Week 56 or discontinue from 
the study prematurely.
Clinical evaluation will occur at Baseline, Weeks 2, 4, 6, 8, 12, 14, 20, 26, 28, 34, 40, 42, 48, and 
56/Premature Discontinuation (PD) visits.  An electronic diary will be dispensed at the Screening visit.  
In addition to routine physical examination, CDAI calculation, diary review, laboratory, adverse event, 
concomitant medication and vital sign assessments, the following will be collected:
!
Results of study questionnaires (IBDQ, EQ-5D, WPAI) at Baseline, Week 4, Week 8, Week 12, 
Week 26, Week 40 and Week 56/PD.
!
Calculation of the SFPS at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 14, 
Week 20, Week 26, Week 28, Week 34, Week 40, Week 42, Week 48 and Week 56/PD.  The 
Screening visit results will serve as the Baseline value.
!
Results of daily Bristol Stool Form Scale beginning at Baseline through Week 56/PD.
!
Results of 11-point Abdominal Pain Rating Scale beginning at Baseline, Week 2, Week 4, 
Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of adalimumab concentrations just prior to dosing at Baseline, Week 2, 
Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/PD.


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Methodology (Continued):
!
Serum for measurement of Anti-Adalimumab Antibodies (AAA) just prior to dosing at Baseline, 
Week 4, Week 12, Week 26, Week 40, and Week 56/PD.
!
Serum for measurement of infliximab serum levels and Human Anti-Chimeric Antibodies 
(HACA) just prior to dosing at Baseline.
!
Serum biomarkers/mRNA at Baseline, Week 2, Week 4, Week 8, Week 12, Week 26, Week 40, 
and Week 56/PD.
!
Stool samples for analysis of fecal calprotectin during Screening, at Week 4, Week 12, Week 26, 
and Week 56/PD.
!
Stool samples for microbiota metagenomic analyses during Screening, at Week 4, Week 12, 
Week 26, and Week 56/PD.
!
Endoscopic evaluations, confirmed by central reader, will be done at Screening, Week 12, and 
Week 56/PD.
!
An optional pharmacogenetic sample should be drawn at Baseline and Week 12.
Throughout the study, subjects will only be allowed to change the dosage of CD-specific concomitant 
medications as specified below:
!
At Week 4, subjects who are taking corticosteroid therapy at Baseline will have their 
corticosteroid therapy tapered according to a tapering schedule specified in the clinical study 
protocol.  If the Investigator feels that the steroid taper is not advisable for a particular subject at 
Week 4, the Study Designated Physician (SDP) should be consulted for evaluation and approval.
!
Subjects taking corticosteroids at Baseline who have a loss of satisfactory clinical response per 
the Investigator's judgment after the steroid taper has been initiated may have their 
corticosteroid dose increased per the Investigator's discretion during the study.  Subjects in 
whom the maximum equivalent steroid dose exceeds the dose used at Baseline will be censored 
for efficacy assessments (i.e., they will be considered non-responders for categorical endpoints 
and will have the last non-missing values carried forward for non-categorical assessments) from 
that point forward.  These subjects will continue to be evaluated in the safety population.
!
Immunosuppressant doses may be decreased or terminated in the event of moderate-to-severe 
treatment-related toxicities.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion
1.
Males and females ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of colonic, ileocolonic, or ileal Crohn's disease for ≥ 3 months prior to Baseline and 
confirmed by endoscopy during the Screening period or endoscopy performed within 45 days before 
Baseline, with exclusion of current infection, dysplasia, and/or malignancy.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the 
Investigator, must be available.
3.
Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6, excluding the presence of 
narrowing component, or SES-CD ≥ 4, excluding the presence of narrowing component, for patients 
with disease limited to the ileum, on a screening endoscopy or endoscopy performed within 45 days 
before Baseline, confirmed by a central reader.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued)
4.
Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450 at Baseline despite concurrent or prior 
treatment with a full and adequate course, in the opinion of the Investigator, of at least one of the 
following (oral corticosteroids and/or immunosuppressants or both as defined below):
!
Subject taking oral corticosteroids, excluding budesonide:
o
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
!
For subjects with a dose > 10 and ≤ 40 mg/day, dose has been stable for at least 7 days 
prior to Baseline and the duration of the current steroid course has been at least 14 days 
prior to Baseline.
!
For subjects with a dose ≤ 10 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior to 
Baseline.
!
Subject taking oral budesonide:
o
Dose must not exceed 9 mg/day;
!
For subjects with a dose ≥ 6 mg/day, dose has been stable for at least 7 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
!
For subjects with a dose < 6 mg/day, dose has been stable for at least 10 days prior to 
Baseline and the duration of the current steroid course has been at least 14 days prior 
to Baseline;
or,
!
At least a consecutive 42-day course of azathioprine, 6-MP or injectable MTX prior to Baseline, 
with a stable dose for at least 28 days prior to Baseline of azathioprine ≥1.5 mg/kg/day or 6-MP 
≥ 1 mg/kg/day (rounded to the nearest available tablet or half tablet formulation) or a 
documented 6-TGN level of at least 230 pmol/8 × 108 RBC to clarify a therapeutic level was 
achieved on the current dosing regimen or MTX ≥15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the subject (e.g., due to 
leukopenia, elevated liver enzymes, nausea) during that time.
Note:  If a subject is taking both an oral corticosteroid and an immunosuppressant listed above, 
BOTH of the drugs need to meet the above criteria.  Oral MTX use is allowed during the study 
(at a stable dose for 28 days prior to Baseline) however current or prior use of oral MTX is not 
sufficient for inclusion into the study.
or,
!
Concurrent therapy with oral corticosteroids or immunosuppressants (azathioprine, 6-MP or 
SC/IM MTX) is not required for subjects not currently taking these medications who were 
previously treated during the past 1 year and have confirmed documentation of failure to 
respond, or were previously treated during the past 5 years and have confirmed documentation 
indicating lack of tolerability, see Section 10.1.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Subject may be included if they have previously experienced a benefit from infliximab and 
discontinued its use due to a subsequent loss of response (judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of CD-related symptoms) or intolerance (in the opinion of the Investigator therapy was 
discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication) to the agent.  Confirmed documentation indicating loss of response or lack of tolerability 
will be required.
6.
Subject has a negative TB Screening Assessment (including a PPD test or QuantiFERON TB Gold 
test [or equivalent]) and negative chest x-ray (CXR – PA and lateral view) at Screening.  If the 
subject has evidence of a latent TB infection; the subject must initiate and complete a minimum of 
2 weeks of an ongoing TB prophylaxis or have documented completion of a full course of anti-TB 
prophylaxis, prior to Baseline.
7.
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.
8.
Subject must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.
9.
Subject is judged to be in otherwise good health as determined by the Principal Investigator based 
upon the results of medical history, laboratory profile, physical examination, CXR, and a 12-lead 
electrocardiogram (ECG) performed during Screening.
10. Subject must be able and willing to self-administer subcutaneous (SC) injections or have a qualified 
person available to administer SC injections.
Main Exclusion:
1.
Subject with a current diagnosis of ulcerative colitis (UC) or indeterminate colitis.
2.
Subject on azathioprine, 6-mercaptopurine (6-MP), methotrexate (MTX), or another 
immunosuppressant (e.g., thalidomide) who:
!
Has not been on these medications for at least 42 days prior to Baseline; or
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or 
!
Has discontinued these medications within 14 days of Baseline.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
3.
Subject on oral aminosalicylates who:
!
Has not been on stable doses of these medications for at least 28 days prior to Baseline; or
!
Has discontinued use of aminosalicylates within 14 days of Baseline.
4.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subjects on budesonide 
> 9 mg/day; or
!
Subject taking an oral corticosteroid (excluding budesonide):
o
dose > 10 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose > 10 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose ≤ 10 mg/day or equivalent, but has not been on a stable dose for at least 10 days prior 
to Baseline; or
o
dose ≤ 10 mg/day or equivalent but has not been on a current steroid course of at least 
14 days in duration prior to Baseline, or
!
Subject taking budesonide:
o
dose ≥ 6 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
o
dose ≥ 6 mg/day, but has not been on a current steroid course for at least 14 days prior to 
Baseline; or
o
dose < 6 mg/day dose but has not been on a stable dose of at least 10 days prior to Baseline; 
or
o
dose < 6 mg/day but the current course has not been at least 14 days in duration prior to 
Baseline; or
Has been taking both oral budesonide and prednisone (or equivalent) simultaneously, with the 
exception of inhalers.
5.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
6.
Subject who has had surgical bowel resections within the past 6 months or is planning any resection 
at any time point while enrolled in the study.
7.
Subject with a symptomatic bowel stricture.
8.
Subject with an abdominal or peri-anal abscess.
9.
Subject with an ostomy or ileoanal pouch.
10. Subject who has short bowel syndrome.
11. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 
14 days prior to Screening and/or during the Screening period.
12. Subject with prior exposure to medications that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML) including participation in a clinical trial of 
investigational agents targeting white cell trafficking (e.g., natalizumab [Tysabri®], rituximab 
[Rituxan®], efalizumab [Raptiva®]).  Prior exposure to any anti-tumor necrosis factor (TNF) agent 
other than infliximab (including etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
13. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to 
Baseline, whichever is longer.
14. Subject who previously received treatment with adalimumab or previously participated in an 
adalimumab clinical study.
15. Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 60 days prior to 
Baseline.
16. Subject who previously received stem cell transplantation.
17. Subject who previously received fecal microbial transplantation.
18. Subject that received non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to 
Screening and during the Screening Visit, except low-dose aspirin for prevention of heart attacks, 
unstable angina or transient ischemic attacks or topical NSAIDs.
19. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives for non-Crohn's disease related infections within 14 days prior 
to the Baseline Visit.
20. Subjects on Crohn's disease related antibiotics that have not been on stable doses for at least 28 days 
prior to Baseline.  Subjects on Crohn's disease related antibiotics that have discontinued these 
medications within 28 days of Baseline are excluded.
21. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during 
the course of the study.
22. Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the Screening period.
23. Screening laboratory and other analyses show any of the following abnormal results:
!
AST, ALT > 1.75 × upper limit of the reference range;
!
WBC count < 3.0 × 109/L;
!
Electrocardiogram (ECG) – with clinically significant abnormalities;
!
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert syndrome;
!
Serum creatinine > 1.6 mg/dL.
24. Known hypersensitivity to adalimumab or its excipients.
25. Subject who has previously used infliximab:
!
and had not clinically responded at any time ("primary non-responder") unless subject 
experienced a treatment limiting reaction;
or
!
who used infliximab within 56 days of Baseline.
26. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
27. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency 
syndrome (HIV).
28. 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
29. Subjects with a positive result for the Hepatitis B surface antigen (HBs Ag) will be excluded.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core 
antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab Total (+) require 
PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection 
sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require HBV DNA 
PCR qualitative testing:
!
HBc Ab Total (–) and HBs Ab* (–)  
!
HBc Ab Total (–) and HBs Ab* (+) 
!
HBc Ab Total (+) and HBs Ab* (+)
*
For HBs Ab test results, a (–) result is equivalent to nonreactive and a (+) result is 
equivalent to reactive.
30. Chronic recurring infections.
31. Subject with active TB.
32. Subject with latent TB infection unless there is evidence the subject initiated and completed a 
minimum of 2 weeks of an ongoing TB prophylaxis or have documented completion of a full course 
of anti-TB prophylaxis, prior to Baseline.
33. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular 
accident and any other condition which, in the opinion of the Investigator, would put the subject at 
risk by participation in the study.
34. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in 
any biopsy performed during the Screening endoscopy or endoscopy performed within 45 days 
before Baseline.
35. Positive pregnancy test at Screening (serum) or Baseline (urine).
36. Female subjects who are breastfeeding or considering becoming pregnant during the study.
37. History of clinically significant drug or alcohol abuse in the last 12 months.
38. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
39. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other 
than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or 
localized carcinoma in situ of the cervix.
40. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.


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Investigational Products:
Adalimumab (40 mg/0.8 mL)
Double-Blind Induction
Subjects will be randomized to receive one of 2 double-blind 
adalimumab Induction Study regimens.
Doses:
(Higher Induction Regimen)
160 mg at Baseline, Weeks 1, 2, and 3, and 40 mg at Week 4, continuing 
at 40 mg every other week through Week 12.
(Standard Induction Regimen)
160 mg at Baseline and matching placebo at Week 1, 80 mg at Week 2 
and matching placebo at Week 3 and 40 mg every other week beginning 
at Week 4 through Week 12.
Double-Blind Maintenance
Subjects will receive one of two double-blind adalimumab Maintenance 
Study regimens.
Doses:
NOTE:  In order to retain 
blinding across regimens, all 
subjects who do not meet the 
criteria for dose escalation in 
either maintenance regimen 
will receive matching placebo 
injections in addition to the 
adalimumab injection.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 
40 mg adalimumab every other week beginning at Week 12.  The 
adalimumab dose will be escalated to every week starting at Week 14 if 
CDAI is ≥ 220 or hs-CRP ≥ 10 mg/L (using results from the prior or 
current visit) as shown by the dose adjustment criteria table.  These 
subjects will also be allowed to escalate at unscheduled visits that may 
occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 44, 46, 50, 52 and 
54.  Once subjects in the clinically adjusted regimen are escalated, they 
will remain on 40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized 
to the TDM regimen will be determined by the dose adjustment criteria 
table.  Doses will be determined using blinded serum concentrations at 
the prior visit (Weeks 12, 26 and 40, respectively) as well as the CDAI 
or hs-CRP values from the current or prior visit.  For subjects who meet 
criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 
40 mg weekly.
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:
The study will include a Screening Period of 1 – 4 weeks, a double-blind Induction Study of 12 weeks,
and a double-blind Maintenance Study of 44 weeks.  There will also be a 70-day follow-up phone call for 
subjects who complete the study or discontinue from the study prematurely.


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Criteria for Evaluation:
Efficacy Endpoints:
Subjects participating in the Induction Study randomized to the higher adalimumab induction dose 
regimen will be compared to those subjects randomized to the standard adalimumab induction regimen.  
Subject data from the Maintenance Study will be used for exploratory analyses.
Induction Study Co-Primary Efficacy Endpoints:
!
Proportion of subjects who achieve a CDAI < 150 at Week 4.
!
Proportion of subjects with decrease in SES-CD > 50% from Baseline (or for a Baseline SES-
CD of 4, at least a 2 point reduction from Baseline) at Week 12.
Induction Study Ranked Secondary Endpoints:
1.
Proportion of subjects with sustained clinical remission (CDAI < 150) at both Weeks 4 and 12.
2.
Proportion of subjects with CDAI < 150 at Week 4 and decrease in SES-CD > 50% from Baseline 
(or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline) at Week 12.
3.
Proportion of subjects with clinical remission (CDAI < 150) at Week 12.
4.
Proportion of subjects who discontinued corticosteroid use and achieved clinical remission (CDAI 
< 150) at Week 12 among subjects taking corticosteroids at Baseline.
5.
Proportion of subjects with endoscopic remission (SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable) at Week 12.
6.
Change from Baseline in fecal calprotectin level at Week 4.
7.
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g at Week 4.
8.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal calprotectin < 250 μg/g at 
Week 4.
9.
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore > 1 in any individual variable, and fecal calprotectin 
< 250 μg/g at Week 12.
10. Proportion of subjects who achieve an SES-CD ≤ 2 at Week 12.
11. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 4.
12. Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points from baseline) at 
Week 12.
13. Proportion of subjects achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 8) at Week 4.
14. Proportion of subjects achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 8) at Week 12.
15. Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ fatigue item score 
≥ 1) at Week 12.
All other efficacy and exploratory endpoints will be non-ranked.


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Criteria for Evaluation (Continued):
All endpoints for the Exploratory Maintenance Study will be non-ranked.
Pharmacokinetic:
Blood samples will be collected for measurement of serum adalimumab concentration just prior to dosing 
at Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and Week 56/Premature 
Discontinuation and anti-adalimumab antibody (AAA) just prior to dosing at Baseline, Week 4, Week 12, 
Week 26, Week 40, and Week 56PD.
Blood samples will also be collected for measurement of infliximab serum levels and Human 
Anti-Chimeric Antibodies (HACA) just prior to dosing at Baseline.
Exploratory Research Using Intestinal Mucosal Biopsy Samples (Optional):
Optional intestinal biopsies will be collected with consent at Screening, Week 12, and Week 56 or at 
premature discontinuation.  The purpose of these samples is to test potential biomarker signatures and 
new drug targets for IBD.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of study drug.  Incidence 
of adverse events, changes in vital signs, physical examination results, and clinical laboratory data will be 
assessed.
Statistical Methods:
Efficacy:
The co-primary efficacy variables for the Induction Study are proportion of subjects with moderately to 
severely active CD that have achieved clinical remission, defined as CDAI < 150, at Week 4 and 
proportion of subjects with moderately to severely active CD that have achieved a decrease in SES-CD 
> 50% from Baseline (or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), at 
Week 12. The comparison between treatment groups for the two co-primary efficacy variables will be 
performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by hs-CRP at Baseline 
(< 10 and ≥ 10 mg/L) (the Screening hs-CRP will serve as the Baseline value), prior infliximab use, and 
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline.  A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated.  The ITT set includes all subjects 
who were randomized at baseline.  For the evaluation of co-primary endpoints, missing data of CDAI at 
Week 4 or missing SES-CD at Week 12 will be imputed using the non-responder imputation (NRI) 
approach.  For Week 4 clinical remission, LOCF, OC and multiple imputation methods will be used as 
sensitivity analyses.  For Week 12 endoscopic response (decrease in SES-CD > 50% from Baseline [or 
for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline]), OC will be used as sensitivity 
analysis.


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Statistical Methods (Continued):
Efficacy (Continued):
Secondary efficacy variables for the Induction Study are divided into two groups.  The first group 
includes ranked secondary endpoints, which are ranked by clinical importance.  Statistical significance is 
assessed at significance level of 0.050 (2-sided) in ranked endpoint order until the significance level 
exceeds 0.05.  No additional statistically significant treatment differences may be declared after the first 
ranked endpoint fails to achieve statistical significance at a two-sided significance level of 0.05.  The 
second group includes all other secondary variables.
In general, continuous secondary efficacy variables, including all efficacy variables for Maintenance 
Study, will be analyzed using Analysis of Covariance (ANCOVA) model including factor for treatment 
group, stratification factors and Baseline values, whereas CMH test stratified by stratification factors is 
used for categorical endpoints.  NRI for missing data will be used for categorical endpoints.  Both last 
observation carried forward (LOCF) and observed case (OC) analyses will be performed for continuous 
endpoints.  The LOCF analysis is considered primary for inferential purposes.  In addition, Mixed-Effect 
Model Repeated Measure (MMRM) will be applied, wherever appropriate, as a sensitivity analysis for 
the longitudinal continuous endpoints.
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 regimen, and rates of AAA positive will be calculated.  
As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment 
emergent adverse events may be evaluated.
Safety:
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  
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 for subjects who do not participate in 
the OLE or until first dose of study drug in the OLE study if the subject is a study completer and is 
enrolled in the OLE.  Treatment-emergent AEs will be summarized separately for:  a) Baseline to 
Week 12; b) Week 12 to Week 56; c) Baseline to Week 56 (overall study duration).  An overview of 
treatment-emergent AEs, including AEs of special interest, adverse events leading to death and adverse 
events leading to premature discontinuation (see details in the SAP), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version 20.1 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 and compared 
between-treatment groups will be performed using a one-way Analysis of Variance (ANOVA).  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.


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Section 4.0  Study Objective
First paragraph previously said:
The primary objective of this study is to assess the efficacy and safety of two adalimumab 
induction regimens in achieving clinical remission (CDAI < 150) at Week 4 and 
endoscopic improvement defined as Simplified Endoscopic Score for Crohn's Disease 
(SES-CD) ≤ 4 and at least a 2 point reduction versus baseline and no subscore greater than 
1 in any individual variable at Week 12 in subjects with moderately to severely active 
Crohn's disease and evidence of mucosal ulceration at Baseline.
Has been changed to read:
The primary objective of this study is to assess the efficacy and safety of two adalimumab 
induction regimens in achieving clinical remission (CDAI < 150) at Week 4 and 
endoscopic response defined as decrease in SES-CD > 50% from Baseline (or for a 
Baseline SES-CD of 4, at least a 2 point reduction from Baseline) at Week 12, in subjects 
with moderately to severely active Crohn's disease and evidence of mucosal ulceration at 
Baseline.
Section 5.1  Overall Study Design and Plan:  Description
First paragraph, second sentence previously read:
No placebo arm is planned since there is well-documented efficacy of adalimumab in CD 
and because the purpose of this study is to achieve better efficacy than the standard 
induction and maintenance regimens in terms of clinical remission and endoscopic 
improvement.
Has been changed to read:
No placebo arm is planned since there is well-documented efficacy of adalimumab in CD 
and because the purpose of this study is to achieve better efficacy than the standard 
induction and maintenance regimens in terms of clinical remission and endoscopic 
response.


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Section 5.1  Overall Study Design and Plan:  Description
Second paragraph previously read:
Approximately 600 adult subjects with active Crohn's disease, defined as having a CDAI 
of ≥ 220 and ≤ 450 and evidence of mucosal ulceration defined as SES-CD ≥ 6, excluding 
the presence of narrowing component, or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
centrally read endoscopy, will be enrolled at approximately 150 sites worldwide.
Has been changed to read:
Approximately 500 adult subjects with active Crohn's disease, defined as having a CDAI 
of ≥ 220 and ≤ 450 and evidence of mucosal ulceration defined as SES-CD ≥ 6, excluding 
the presence of narrowing component, or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
centrally read endoscopy, will be enrolled at approximately 150 sites worldwide.
Section 5.1  Overall Study Design and Plan:  Description
Third paragraph, last sentence previously read:
Assuming the Week 4 clinical remission rate will be approximately 50% for the higher 
induction dose regimen and approximately 30% for the standard dose regimen, a sample 
size of 600 (360 higher dose and 240 standard dose) will be adequate to detect at least a 
20% treatment difference in clinical remission rates at Week 4 between the dosing 
regimens using Fisher's exact test with 99% power at a 0.05 two-sided significant level.
Has been changed to read:
Assuming the Week 4 clinical remission rate will be approximately 50% for the higher 
induction dose regimen and approximately 30% for the standard dose regimen, a sample 
size of 500 (300 higher dose and 200 standard dose) will be adequate to detect at least a 


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20% treatment difference in clinical remission rates at Week 4 between the dosing 
regimens using Fisher's exact test with 99% power at a 0.05 two-sided significant level.
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph previously read:
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts an expected ~50% 
increase in the proportion of subjects with endoscopic improvement compared to the 
standard adalimumab induction regimen.  The observed rate of SES-CD ≤ 4 in 
Study M05-769 was 37% at Week 12 with the currently approved dosing regimen.  Thus, 
by extrapolation, the expected rate for SES-CD ≤ 4 using the higher induction regimen is 
55%.  A sample size of 600 subjects (360 higher induction regimen and 240 standard 
induction regimen) will be adequate to detect at least a 18% treatment difference in 
endoscopic improvement rates at Week 12 between the dosing regimens using Fisher's 
exact test with approximately 98% power at a 0.05 two-sided significance level.
Has been changed to read:
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts an expected ~50% 
increase in the proportion of subjects with endoscopic response compared to the standard 
adalimumab induction regimen.  The observed rate of endoscopic response (decrease 
> 50% SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction 
from Baseline]) in Study M05-769 was 44% at Week 12 with the currently approved 
dosing regimen.  Thus, by extrapolation, the expected rate for endoscopic response at 
Week 12 using the higher induction regimen is 66%.  A sample size of 500 subjects 
(300 higher induction regimen and 200 standard induction regimen) will be adequate to 
detect at least a 22% treatment difference in endoscopic response (decrease >50% SES-
CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 99% power at a 0.05 two-sided significance level.


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Section 5.1  Overall Study Design and Plan:  Description
Fifth paragraph previously read:
Since the clinical remission at Week 4 endpoint and the endoscopic improvement at 
Week 12 endpoint are likely not independent of each other, the power for the co-primary 
endpoints for the study is expected to be > 97% (see Section 8.2 for detailed assumptions 
of the sample size calculation).
Has been changed to read:
Since the clinical remission at Week 4 endpoint and the endoscopic response at Week 12 
endpoint are likely not independent of each other, the power for the co-primary endpoints 
for the study is expected to be > 98% (see Section 8.2 for detailed assumptions of the 
sample size calculation).
Section 5.1  Overall Study Design and Plan:  Description
Eighth paragraph, second and third sentence previously read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12 and endoscopic response status (decrease in 
SES-CD > 50% from Baseline) per the site investigator reading at Week 12.  Among 
Week 12 endoscopic responders, the randomization will be further stratified by 
endoscopic improvement, defined as achievement of an SES-CD ≤ 4 and at least a 2 point 
reduction versus Baseline and no subscore greater than 1 in any individual variable using 
the Week 12 SES-CD value provided by the site.
Has been changed to read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12 and decrease in SES-CD > 50% from 
Baseline per the site investigator reading at Week 12.  Among subjects achieving SES-CD 
> 50% from Baseline at Week 12, the randomization will be further stratified by 
achievement of an SES-CD ≤ 4 and at least a 2 point reduction versus Baseline and no 


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subscore greater than 1 in any individual variable using the Week 12 SES-CD value 
provided by the site.
Section 5.1  Overall Study Design and Plan:  Description
Fourteenth paragraph, second bullet
Second sentence previously read:
Subjects in whom the maximum steroid dose equivalent exceeds the dose used at Baseline 
will be censored for efficacy assessments (i.e., will be considered non-responders for 
categorical endpoints and will have Baseline values carried forward for non-categorical 
assessments) from that point forward.
Has been changed to read:
Subjects in whom the maximum steroid dose equivalent exceeds the dose used at Baseline 
will be censored for efficacy assessments (i.e., will be considered non-responders for 
categorical endpoints and will have the last non-missing values carried forward for non-
categorical assessments) from that point forward.
Section 5.1  Overall Study Design and Plan:  Description
Last paragraph, first sentence previously read:
The study was designed to enroll 600 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.
Has been changed to read:
The study was designed to enroll 500 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.
Section 5.2.3.2  Concomitant Therapy
Sixth paragraph, second sentence previously read:
Subjects in whom the maximum equivalent steroid dose exceeds the dose used at Baseline 
will be censored for efficacy assessments (i.e., they will be considered non-responders for 


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categorical endpoints and will have Baseline values carried forward for non-categorical 
assessments) from that point forward.
Has been changed to read:
Subjects in whom the maximum equivalent steroid dose exceeds the dose used at Baseline 
will be censored for efficacy assessments (i.e., they will be considered non-responders for 
categorical endpoints and will have the last non-missing values carried forward for non-
categorical assessments) from that point forward.
Section 5.2.3.2  Concomitant Therapy
Sixth paragraph
Add:  new last sentence
In addition, subjects in whom the CD-related corticosteroids that were not being taken at 
Baseline and are initiated during the study will be censored for efficacy assessments 
(i.e., they will be considered non-responders for categorical endpoints and will have the 
last non-missing values carried forward for non-categorical assessments) from that point 
forward.  These subjects will continue to be evaluated in the safety population.
Section 5.2.3.2  Concomitant Therapy
Ninth paragraph previously read:
Subjects in whom the following CD-related medications (oral or rectal aminosalicylates, 
systemic or rectal corticosteroids thiopurines and MTX) that were not being taken at 
Baseline and are initiated during the study or who have dosages of these medications 
increased to greater than the dose taken at Baseline will be censored for efficacy 
assessments (i.e., will be considered non-responders for categorical endpoints and will 
have Baseline values carried forward for non-categorical assessments) from that point 
forward.  These subjects will continue to be evaluated in the safety population.
Has been changed to read:
Subjects in whom the following CD-related medications (oral or rectal aminosalicylates, 
thiopurines and MTX) that were not being taken at Baseline and are initiated during the 


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study or who have dosages of these medications increased to greater than the dose taken at 
Baseline is prohibited during the study, except in the event of moderate-to-severe 
treatment related toxicities and after discussion with the AbbVie TA MD.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Collection of Samples for Infliximab and HACA Assays
Last paragraph previously read:
The total number of samples planned will not exceed 600 (2 samples × 300 subjects) for 
the entire study.
Has been changed to read:
The total number of samples planned will not exceed 500 (2 samples × 300 subjects) for 
the entire study.
Section 5.3.3.1  Co-Primary Variables for Induction Study
Second bullet previously read:
Proportion of subjects who achieve SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable at Week 12.
Has been changed to read:
Proportion of subjects with endoscopic response (decrease > 50% SES-CD from Baseline 
[or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline]) at Week 12.
Section 5.3.3.2  Secondary Variables for Induction Study
Item 2, 5, 13, and 14 previously read:
2.
Proportion of subjects with CDAI < 150 at Week 4 and SES-CD ≤ 4 and at least a 2 
point reduction versus baseline and no subscore greater than 1 in any individual 
variable at Week 12.
5.
Proportion of subjects with endoscopic response (decrease > 50% SES-CD from 
Baseline) at Week 12.


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13.
Change in IBDQ from Baseline at Week 4.
14.
Change in IBDQ from Baseline at Week 12.
Has been changed to read:
2.
Proportion of subjects with CDAI < 150 at Week 4 and endoscopic response 
(decrease > 50% SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 
2 point reduction from Baseline]) at Week 12.
5.
Proportion of subjects with endoscopic remission (SES-CD ≤ 4 and at least a 2 
point reduction versus baseline and no subscore greater than 1 in any individual 
variable) at Week 12.
13.
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at Week 4.
14.
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at Week 12.
15.
Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ 
fatigue item score ≥ 1) at Week 12.
Section 5.3.3.2  Secondary Variables for Induction Study
Tenth bullet previously read:
Change in IBDQ from Baseline at Week 8.
Has been changed to read:
Change in IBDQ total score and individual IBDQ domain scores (bowel, emotional, 
social, systemic) from Baseline at each scheduled visit in Induction Study.


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Section 5.3.3.2  Secondary Variables for Induction Study
Add:  new thirteenth bullet
Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ fatigue 
item score ≥ 1) at Week 4.
Section 5.3.3.2  Secondary Variables for Induction Study
Eighteenth bullet previously read:
●
Change in Bristol Stool Scale score from Baseline at each scheduled visit in 
Induction Study.
Has been changed to read:
●
Change in Bristol Stool Chart score from Baseline at each scheduled visit in 
Induction Study.
●
Proportion of subjects who achieve Bristol Stool Chart response at each 
scheduled visit in Induction Study.
Section 5.3.3.2  Secondary Variables for Induction Study
Thirtieth and Thirty-first bullet previously read:
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 1.5 (and not worse than baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Induction Study.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Induction Study.
Has been changed to read:
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than baseline) and average daily 


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abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Induction Study among subjects with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Induction Study among subjects with 
Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
First bullet previously read:
Proportion of subjects who achieve endoscopic improvement (SES-CD ≤ 4 and at least a 
2 point reduction versus baseline and no subscore greater than 1 in any individual 
variable) at Week 56 among subjects with endoscopic improvement at Week 12.
Has been changed to read:
●
Proportion of subjects who achieve endoscopic response (SES-CD > 50% from 
Baseline [or for a Baseline SES-CD of 4, at least a 2 point reduction from 
Baseline]) at Week 56 among subjects with endoscopic response at Week 12
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable) at Week 56 among subjects with endoscopic  remission at 
Week 12.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Eighth bullet previously read:
Proportion of subjects with endoscopic response (decrease > 50% SES-CD from Baseline) 
at Week 56.


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Has been changed to read:
Proportion of subjects with endoscopic response (decrease > 50% SES-CD from Baseline 
[or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline]) at Week 56.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Delete:  fourteenth bullet
Change in IBDQ from Baseline at Week 56.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Twenty-third bullet previously read:
Change in IBDQ from Baseline at each scheduled visit in Maintenance Study.
Has been changed to read:
Change in IBDQ total score and individual IBDQ domain scores (bowel, emotional, 
social, systemic) from Baseline at each scheduled visit in Maintenance Study.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Twenty-eighth bullet previously read:
Change in Bristol Stool Scale score from Baseline at each scheduled visit in Maintenance 
Study.
Has been changed to read:
Change in Bristol Stool Chart score from Baseline at each scheduled visit in Maintenance 
Study.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Thirty-seventh and thirty-eighth bullet previously read:
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 1.5 (and not worse than baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Maintenance Study.


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●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Maintenance Study.
Has been changed to read:
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than baseline) and average daily 
abdominal pain ≤ 1.0 (and not worse than baseline), at each scheduled visit in 
Maintenance Study among subjects with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from baseline and average daily 
abdominal pain not worse than baseline or average daily abdominal pain at 
least 30% reduction from baseline and average daily stool frequency not worse 
than baseline, at each scheduled visit in Maintenance Study among subjects 
with Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Add:  new forty-second and forty-third bullet
●
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at each scheduled visit 
in Maintenance Study.
●
Proportion of subjects achieving response in IBDQ fatigue item (increase of 
IBDQ fatigue item score ≥ 1) at each scheduled visit in Maintenance Study.
Section 5.3.3.3  Endpoints for Exploratory Maintenance Study
Add:  new forty-fifth, forty-sixth, and forty-seventh bullet
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 56 among subjects requiring dose escalation to weekly dosing during 
Maintenance Study.


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●
Proportion of subjects who achieve endoscopic response (decrease > 50% 
SES-CD from Baseline [or for a Baseline SES-CD of 4, at least a 2 point 
reduction from Baseline]) at Week 56 among subjects requiring dose 
escalation to weekly dosing during Maintenance Study.
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any 
individual variable) at Week 56 among subjects requiring dose escalation to 
weekly dosing during Maintenance Study.
Section 5.5.1  Treatments Administered
Third paragraph, second and third sentence previously read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12 and endoscopic response status (decrease in 
SES-CD > 50% from Baseline) per the site investigator reading at Week 12.  Among 
Week 12 endoscopic responders, the randomization will be further stratified by 
endoscopic improvement, defined as achievement of an SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore greater than 1 in any individual variable using 
the Week 12 SES-CD value provided by the site.
Has been changed to read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12 and decrease in SES-CD > 50% from 
Baseline per the site investigator reading at Week 12.  Among subjects achieving SES-CD 
> 50% from Baseline at Week 12, the randomization will be further stratified by 
achievement of an SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable using the Week 12 SES-CD value 
provided by the site.
Section 5.5.2.2  Storage and Disposition of Study Drugs
Second paragraph, first sentence previously read:
Malfunctions or any temperature excursion must be reported to the Sponsor immediately.






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Has been changed to read:
For Week 12 endoscopic response, OC will be used as sensitivity analysis.
Section 8.1.5  Statistical Analyses of Safety
Third paragraph, second sentence previously read:
An overview of treatment-emergent AEs, including AEs of special interest such as 
adverse events leading to death and adverse events 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.
Has been changed to read:
An overview of treatment-emergent AEs, including AEs of special interest such as 
adverse events leading to death and adverse events leading to premature discontinuation 
(see details in the SAP), AEs by Medical Dictionary for Drug Regulatory Activities 
(MedDRA version 20.1 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.
Section 8.1.5  Statistical Analyses of Safety
Third paragraph
Delete:  last sentence
Treatment group differences in the overall incidence of treatment-emergent AEs will be 
assessed with Fisher's exact test for each preferred term.
Section 8.1.7  Interim Analysis
Previously read:
No interim analyses are planned.


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Has been changed to read:
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
the Induction Study only as well as safety data collected from Baseline through double-
blind Week 12 may be performed after the last subject in ITT population completes the 
12-week double-blind Induction Study.  A database cut will be performed and any 
discrepant data will be clarified before the lock.  Since this interim analysis is the only and 
final analysis of the co-primary efficacy endpoints of the Induction Study, multiplicity 
adjustment is deemed not necessary.
Section 8.2  Determination of Sample Size
First paragraph, last sentence previously read:
A sample size of 600 (360 higher dose and 240 standard dose) will be adequate to detect 
at least a 20% treatment difference in clinical remission rates at Week 4 between the 
dosing regimens using Fisher's exact test with 99% power at a 0.05 two-sided significant 
level.
Has been changed to read:
A sample size of 500 (300 higher dose and 200 standard dose) will be adequate to detect 
at least a 20% treatment difference in clinical remission rates at Week 4 between the 
dosing regimens using Fisher's exact test with 99% power at a 0.05 two-sided significant 
level.
Section 8.2  Determination of Sample Size
Second and third paragraph previously read:
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts a ~50% increase in 
the proportion of subjects with endoscopic improvement is expected.  The observed rate 
of SES-CD ≤ 4 in Study M05-769 in subjects with Baseline SES-CD > 6 was 37% at 
Week 12 with the currently approved dosing regimen.  Thus, by extrapolation, the 
expected rate for SES-CD ≤ 4 using the higher induction regimen is 55%.  A sample size 


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of 600 subjects (360 higher induction regimen and 240 standard induction regimen) will 
be adequate to detect at least an 18% treatment difference in endoscopic improvement 
rates at Week 12 between the dosing regimens using Fisher's exact test with 
approximately 98% power at a 0.05 two-sided significance level.
Since the clinical remission at Week 4 endpoint and the endoscopic improvement at 
Week 12 endpoint are likely not independent of each other, the power for the co-primary 
endpoints for the study is expected to be > 97%.
Has been changed to read:
Since exposure/endoscopic relationships are not currently available for adalimumab, 
clinical remission will be based on PK/PD modeling which predicts a ~50% increase in 
the proportion of subjects with endoscopic response is expected.  The observed rate of 
endoscopic response in Study M05-769 was 44% at Week 12 with the currently approved 
dosing regimen.  Thus, by extrapolation, the expected rate endoscopic response at 
Week 12 using the higher induction regimen is 66%.  A sample size of 500 subjects 
(300 higher induction regimen and 200 standard induction regimen) will be adequate to 
detect at least an 22% treatment difference in endoscopic response rates at Week 12 
between the dosing regimens using Fisher's exact test with approximately 99% power at a 
0.05 two-sided significance level.
Since the clinical remission at Week 4 endpoint and the endoscopic response at Week 12 
endpoint are likely not independent of each other, the power for the co-primary endpoints 
for the study is expected to be > 98%.
Section 8.3  Randomization Methods
Second paragraph, second and third sentence previously read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12, and endoscopic response status (decrease in 
SES-CD > 50% from Baseline) per the site investigator reading at Week 12.  Among 
Week 12 endoscopic responders, the randomization will be further stratified by 


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endoscopic improvement, defined as achievement of an SES-CD ≤ 4 and at least a 2 point 
reduction versus baseline and no subscore greater than 1 in any individual variable using 
the Week 12 SES-CD value provided by the site.
Has been changed to read:
The re-randomization at Week 12 will be stratified by induction treatment regimen, 
clinical response (CR-70) status at Week 12, and decrease in SES-CD > 50% from 
Baseline per the site investigator reading at Week 12.  Among subjects achieving SES-CD 
> 50% from Baseline at Week 12, the randomization will be further stratified by 
achievement of an SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable using the Week 12 SES-CD value 
provided by the site.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Statistics
Bioanalysis
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical


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Has been changed to read:
Name
Title
Functional Area
Clinical
Statistics
Bioanalysis
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical

SAP_001.pdf: 
Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
1
1.0
Title Page
Statistical Analysis Plan for the Double-Blind 
Maintenance Study
Study M14-115
A Multicenter, Randomized, Double-Blind Study to 
Evaluate Higher Versus Standard Adalimumab 
Dosing Regimens for Induction and Maintenance 
Therapy in Subjects with Moderately to Severely 
Active Crohn's Disease and Evidence of Mucosal 
Ulceration
Date:  15 November 2019
Version 1.0
NCT02065570


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Objectives, Design and Procedures.............................4
4.1
Objectives ..................................................................................................4
4.2
Study Design and Design Diagram............................................................4
4.3
Sample Size..............................................................................................18
4.4
Interim Analysis.......................................................................................18
5.0
Analysis Populations .............................................................18
5.1
Definition for Analysis Populations.........................................................18
5.2
Variables Used for Stratification of Re-Randomization..........................18
6.0
Analysis Conventions ............................................................19
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............31
7.1
Demographic and Induction Baseline Characteristics .............................31
7.2
Medical History .......................................................................................33
7.3
Previous Treatment and Concomitant Medications.................................34
8.0
Patient Disposition.................................................................34
9.0
Study Drug Exposure and Compliance...............................35
10.0
Efficacy Analysis....................................................................35
10.1
General Considerations............................................................................35
10.2
Efficacy Analyses ....................................................................................36
10.3
Handling of Multiplicity ..........................................................................41
11.0
Safety Analysis.......................................................................41
11.1
General Considerations............................................................................41
11.2
Analysis of Adverse Events.....................................................................41
11.2.1
Treatment-Emergent Adverse Events ......................................................41
11.2.2
Adverse Events of Special Interest ..........................................................43
11.3
Analysis of Laboratory Data....................................................................45
11.3.1
Assessment of Shifts from Induction Baseline in Liver-Specific 
Laboratory Variables................................................................................46


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11.3.2
Hy's Law Cases........................................................................................47
11.4
Analysis of Vital Signs and Weight.........................................................48
12.0
Summary of Changes ............................................................49
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP .......................................................................................49
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .....................................................................50
13.0
Appendix.................................................................................50
14.0
References...............................................................................50
List of Tables
Table 1.
Adalimumab Dose Adjustment Criteria.....................................................8
Table 2.
Study Activities........................................................................................12
Table 3.
Visit Windows for Analysis of CDAI and Vital Signs for 
Maintenance Study...................................................................................21
Table 4.
Visit Windows for Analysis of Chemistry, Hematology, 
Urinalysis, hs-CRP, Fecal Calprotectin, Abdominal Pain Rating 
Scale, IBDQ, EQ-5D, and WPAI for Maintenance Study.......................21
Table 5.
Visit Windows for Analysis of SES-CD for Maintenance Study............22
Table 6.
Visit Windows for Analysis of Fistulas and EIM for Maintenance 
Study ........................................................................................................22
Table 7.
An EQ-5D-5L Value Set for England......................................................30
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Findings..........49
List of Figures
Figure 1.
Therapeutic Drug Monitoring (TDM) Regimen Schematic ......................7
Figure 2.
Study Schematic.........................................................................................8


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Global Statistics Department for study Protocol M14-115 Amendment 6.  It 
provides details to further elaborate statistical methods as outlined in the protocol and 
describes analysis conventions to guide the statistical programming work.
This is the first version of the SAP for the 44-week Double-Blind Maintenance Study of 
Protocol M14-115.
This analysis plan describes the efficacy analysis as well as the safety analysis for the 
double-blind maintenance study.
This document describes the analysis of data except pharmacokinetic, microbiota 
metagenomic, pharmacogenetic and serologic data 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 9.4 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objective of this Maintenance study is to assess the efficacy and safety of 
two adalimumab maintenance regimens in reducing signs and symptoms of Crohn's 
disease at Week 56 as well as to assess pharmacokinetics (PK) and immunogenicity of 
two adalimumab induction regimens following subcutaneous (SC) administration.
4.2
Study Design and Design Diagram
This is a randomized, double-blind multicenter study of two adalimumab induction and 
maintenance regimens in subjects with moderately to severely active CD with evidence of 
mucosal ulceration confirmed by central reading.  No placebo arm is planned since there 
is well-documented efficacy of adalimumab in CD and because the purpose of this study 


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is to achieve better efficacy than the standard induction and maintenance regimens in 
terms of clinical remission and endoscopic response.  Additionally, since subjects are 
required to have failed or been intolerant of standard therapies and have evidence of 
endoscopic damage confirmed by a central reader, it would be not medically acceptable to 
deny those subjects effective treatment or feasible to enroll subjects in the trial when 
adalimumab is available to be prescribed for CD.
Approximately 500 adult subjects with active Crohn's disease, defined as having a CDAI 
of ≥ 220 and ≤ 450 and evidence of mucosal ulceration defined as SES-CD ≥ 6, excluding 
the presence of narrowing component, or SES-CD ≥ 4, excluding the presence of 
narrowing component, for patients with disease limited to the ileum on screening 
endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a 
centrally read endoscopy, are enrolled at approximately 150 sites worldwide.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria are 
enrolled into the study and randomized in a 3:2 ratio at Baseline to receive a higher 
induction adalimumab regimen or standard induction adalimumab regimen during the 
double-blind Induction Study.
The randomization of subjects for the Induction Study is stratified by hs-CRP at Baseline 
(< 10 and ≥ 10 mg/L), using the Screening hs-CRP value, prior infliximab use, and 
Crohn's disease activity (CDAI ≤ 300, > 300), at Baseline.  Enrollment of subjects with 
prior infliximab use is limited to 25% of the total study population.
Subjects assigned to the higher induction regimen receive blinded adalimumab 160 mg at 
Baseline, Week 1, Week 2, and Week 3.  At Week 4, subjects receive 40 mg every other 
week (eow) through Week 12.  Subjects assigned to the standard adalimumab induction 
regimen receive blinded adalimumab 160 mg at Baseline and matching placebo at 
Week 1.  Subjects receive 80 mg and matching placebo at Week 2, and then matching 
placebo at Week 3.  At Week 4, subjects receive 40 mg every other week through 
Week 12.


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At Week 12, subjects are re-randomized in a 1:1 ratio to one of the two double-blinded 
exploratory treatment regimens (adalimumab clinically adjusted [CA] regimen and 
adalimumab therapeutic drug monitoring [TDM] regimen).  The re-randomization at 
Week 12 is stratified by induction treatment regimen, clinical response (CR-70) status at 
Week 12, and decrease in SES-CD > 50% from Baseline per the site investigator reading 
at Week 12.  Among subjects achieving decrease in SES-CD > 50% from Baseline at 
Week 12, the randomization is further stratified by achievement of an SES-CD ≤ 4 and at 
least a 2 point reduction versus Baseline and no subscore greater than 1 in any individual 
variable using the Week 12 SES-CD value provided by the site.  No study drug is 
administered or injected at the final visit.
Clinically Adjusted (CA) Regimen:
Subjects randomized to the clinically adjusted regimen will receive 40 mg adalimumab 
every other week beginning at Week 12.  The adalimumab dose will be escalated to every 
week starting as early as Week 14 if the subject's CDAI is ≥ 220 or hs-CRP ≥ 10 mg/L 
(using results from the prior or current visit).  These subjects will also be allowed to 
escalate at unscheduled visits that may occur only on Weeks 16, 18, 22, 24, 30, 32, 36, 38, 
44, 46, 50, 52 and 54.  Once subjects in the CA regimen are escalated, they will remain on 
40 mg ew dosing.
Therapeutic Drug Monitoring (TDM) Regimen:
At Weeks 14, 28 and 42, the adalimumab dose for subjects randomized to the TDM will 
be determined by the dose adjustment criteria table (Table 1).  Doses will be determined 
using blinded serum concentrations at the prior visit (Weeks 12, 26 and 40, respectively) 
as well as the CDAI or hs-CRP values from the current or prior visit.  For subjects who 
meet criteria for dose escalation at Weeks 14, 28 or 42, subjects will receive 40 mg 
weekly.


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Figure 1.
Therapeutic Drug Monitoring (TDM) Regimen Schematic


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Table 1.
Adalimumab Dose Adjustment Criteria
Adalimumab Dose Adjustment Criteriaa
ADA Serum Concentrationb (ug/mL)
CDAIc
hs-CRPd (mg/L)
Dose Change?
Clinically Adjusted Regimen
any
< 220
< 10
no
any
any
≥ 10
yes; dose escalate to ew
any
≥220
any
yes; dose escalate to ew
Therapeutic Drug Monitoring Regimen
< 5 
any
any
yes; dose escalate to ew
5 – 10
< 220
< 10
no
5 – 10
any
≥ 10
yes; dose escalate to ew
5 – 10
≥ 220
any
yes; dose escalate to ew
> 10
any
any
no
a.
For subjects experiencing an active infection or those for whom the investigator feels dose escalation is not 
advisable, the investigator should contact the Study Designated Physician.
b.
Measured from the serum concentration taken at the prior study visit.
c.
Measured using hematocrit taken from prior study visit for CDAI calculation.
d.
Measure using hs-CRP from the prior or current study visit.
A schematic of the study design is presented in Figure 2.
Figure 2.
Study Schematic


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Clinical evaluation is included at the following visits: Baseline, Weeks 2, 4, 6, 8, 12, 14, 
20, 26, 28, 34, 40, 42, 48, and 56/PD.  An electronic diary is dispensed at the Screening 
visit.  In addition to routine physical examination, CDAI calculation, diary review, 
laboratory, adverse event, concomitant medication and vital sign assessments, the 
following are collected:
●
Results of study questionnaires (inflammatory bowel disease questionnaire 
[IBDQ], European Quality of Life 5 dimensions [EQ-5D], work productivity 
and impairment [WPAI]) at Baseline, Week 4, Week 8, Week 12, Week 26, 
Week 40 and Week 56/PD.
●
Calculation of the SFPS at Baseline, Week 2, Week 4, Week 6, Week 8, 
Week 12, Week 14, Week 20, Week 26, Week 28, Week 34, Week 40, 
Week 42, Week 48 and Week 56/PD.  The Screening results serve as the 
Baseline value.
●
Results of daily Bristol Stool Form Scale beginning at Baseline through 
Week 56/PD.
●
Results of 11-point Abdominal Pain Rating Scale beginning at Baseline, 
Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, and 
Week 56/PD.
●
Serum for measurement of adalimumab concentrations just prior to dosing at 
Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 26, Week 40, 
and Week 56/PD.
●
Serum for measurement of Anti-Adalimumab Antibodies (AAA) just prior to 
dosing at Baseline, Week 4, Week 12, Week 26, Week 40, and Week 56/PD.
●
Serum for measurement of infliximab serum levels and Human Anti-Chimeric 
Antibodies (HACA) just prior to dosing at Baseline.
●
Serological biomarkers/mRNA at Baseline, Week 2, Week 4, Week 8, 
Week 12, Week 26, Week 40, and Week 56/PD.
●
Stool samples for analysis of fecal calprotectin during Screening, at Week 4, 
Week 12, Week 26, and Week 56/PD.


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●
Stool samples for microbiota metagenomic analyses during Screening, at 
Week 4, Week 12, Week 26, and Week 56/PD.  The stool samples should be 
taken before starting bowel preparations for endoscopy.
●
Endoscopic evaluations, eligibility confirmed by central reader, are done at 
Screening, Week 12, and Week 56/PD.
●
An optional pharmacogenetic sample should be drawn at Baseline and 
Week 12.
Throughout the study, subjects are only allowed to change the dosage of CD-specific 
concomitant medications as specified below:
●
At Week 4, subjects who are taking corticosteroid therapy at Baseline have 
their corticosteroid therapy tapered according to a tapering schedule specified 
in the clinical study protocol.  If the Investigator feels that the steroid taper is 
not advisable for a particular subject at Week 4, the Study Designated 
Physician (SDP) should be consulted for evaluation and approval.
●
Subjects taking corticosteroids at Baseline who have a loss of satisfactory 
clinical response per the Investigator's judgment after the steroid taper has 
been initiated may have their corticosteroid dose increased per the 
Investigator's discretion during the study.  Subjects in whom the maximum 
steroid dose equivalent exceeds the dose used at Baseline will be censored for 
efficacy assessments (i.e., will be considered non-responders for categorical 
endpoints and will have last non-missing values carried forward for non-
categorical assessments) from that point forward.  These subjects will continue 
to be evaluated in the safety population.
●
Immunosuppressant doses may be decreased or terminated in the event of 
moderate-to-severe treatment-related toxicities.
The study was designed to enroll 500 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target number of subjects has been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.


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Re-Screening
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  All screening procedures with the possible exceptions noted below will be 
repeated.  The subject must meet all inclusion and none of the exclusion criteria at the 
time of re-screening in order to qualify for the study.  There is no minimum period of time 
a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon Gamma Release Assay (IGRA; QuantiFERON-TB Gold 
In-Tube test or T SPOT TB test) chest x-ray (if applicable) and electrocardiogram (ECG), 
these tests will not be required to be repeated for re-screening provided the conditions 
noted in Protocol Section 5.3.1.1 are met and no more than 90 days have passed.  If an 
endoscopy was performed, this will not be required to be repeated for re-screening 
provided the conditions noted in protocol Section 5.3.1 are met and no more than 45 days 
have passed between the endoscopy date and the Baseline date.  As appropriate, sites are 
encouraged to contact the AbbVie Study Designated Physician (SDP) to confirm if 
subjects should or should not be re-screened.
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have a Premature Discontinuation Visit.  
All subjects who discontinue from the study prematurely will 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 will not be 
required for any subject that initiates commercial adalimumab.
The study activities are presented in Table 2.


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Table 2.
Study Activities
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/Premature 
Discontinuation
Informed Consent
X
Inclusion/Exclusionb
X
X
Medical/Surgery Historyb
X
X
Previous and Concomitant Medicationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopyd
X
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB Screeningf
X
Chest X-Rayg
X
ECGh
X
Chemistry and Hematologyi
X
X
X
X
X
X
X
X
X
X
Urinalysisi,j
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testsk
Xk
X
X
X
Hepatitis B Screen and HIVl
X


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Table 2.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/Premature 
Discontinuation
hs-CRP
X
X
X
X
X
X
X
X
X
X
C.-difficile toxin
X
Antinuclear antibody (ANA)/Anti-double-
stranded DNA (anti dsDNA)m
X
Stool Sample (microbiota metagenomic 
analyses and fecal calprotectin)n
X
X
X
X
X
X
Human Antichimeric Antibodies 
(HACA)/Infliximab Concentrations
X
Adalimumab Concentrationo
X
X
X
X
X
X
X
X
X
X
AAA Concentrationo
X
X
X
X
X
X
X
Pharmacogenetic Markerp
X
X
Serological Biomarkers/mRNA
X
X
X
X
X
X
X
X


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Table 2.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/Premature 
Discontinuation
Crohn's Disease Activity Index (CDAI) 
CDAI components "Number of liquid or 
very soft stools" and "Abdominal pain" 
(Stool [liquid/soft] Frequency + 
Abdominal Pain Score; SFPS)
X
Xu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SES-CD Score
X
X
X
Inflammatory Bowel disease 
Questionnaire (IBDQ)
X
X
X
X
X
X
X
European Quality of Life 5 dimensions 
(EQ‑5D)
X
X
X
X
X
X
X
Work Productivity and Impairment 
Questionnaire (WPAI)
X
X
X
X
X
X
X
Abdominal Pain Rating Scale
X
X
X
X
X
X
X
X
X
Corticosteroid Taperq
X
X
X
X
X
Monitor Adverse Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing/Administrations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 2.
Study Activities (Continued)
Screening 
Period 
(30 Days)a
12-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Unscheduled Visitv
70-Day Follow-Upt
Activity
Screening
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12 
(Re-Randomization)
Week 14 
Week 20
Week 26
Week 28
Week 34
Week 40
Week 42
Week 48
Week 56/Premature 
Discontinuation
Dispense Subject Diary
X
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intestinal Biopsiesp
X
X
X
a.
The Screening period will be a minimum of 7 days for CDAI calculation.  The CDAI calculated at Screening will serve as the Baseline CDAI.  Baseline visit date will serve 
as the reference for all subsequent visits.  A ± 3-day window is permitted around all study visits.
b.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
c.
Height will be measured at Screening only (with shoes off, and then adding 1 inch or 2.5 cm).
d.
An ileocolonoscopy will be performed during Screening or one performed within 45 days before Baseline, Week 12, and at Week 56/PD.  A biopsy will be performed at 
Screening, Week 12, and Week 56/PD if a suspicious lesion or suspected malignancy, in the assessment of the Investigator, is observed, and evaluated by the local 
pathologist.  Site staff should schedule the Week 12 Endoscopy during the Baseline visit, if possible.  Appropriate documentation of biopsy results consistent with the 
diagnosis of CD, in the assessment of the Investigator, must be available in order to confirm the subject's eligibility for the study.  If this documentation is not available, a 
diagnostic biopsy from the most affected observed area of the ileum/colon must be performed during the Screening endoscopy and evaluated by a qualified local pathologist 
and the results reviewed by the Investigator.  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.


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Table 2.
Study Activities (Continued)
e.
Physical examination performed at Screening, Week 12 and Week 56/Premature Discontinuation Visits are full physical examinations which must include an assessment of 
extra intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations at all other visits are symptom based and must include a count 
of the number of cutaneous fistulas.
f.
Subjects with negative PPD test and/or QuantiFERON-TB Gold test within 90 days of Screening will not require a repeat skin test, if documentation is available.  PPD skin 
test is to be read 48 to 72 hours after placement.
g.
Chest x-ray includes posterior-anterior (PA) and lateral views.  Subjects with normal chest x-ray within 3 months of Screening would not require a repeat chest x-ray, if 
documentation is available.
h.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.
i.
Lab assessments will only need to be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if the subject's health status has changed to 
warrant a repeat test.
j.
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.  Further explanations of these tests are provided in the laboratory manual.
k.
Serum pregnancy test will be performed on all women of childbearing potential at Screening.  Urine pregnancy test will be performed locally at Baseline Visit, and at the 
Week 12 and Week 56/PD for all women of child-bearing 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.
l.
Subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  A positive result for the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Please refer to hepatitis procedures for details on testing requirements.  If required by country regulatory authorities to confirm eligibility, subjects will be tested for HIV and 
documented that the test has been performed.  This testing is to be done at a local laboratory.  A subject will not be eligible for study participation if test results indicate a 
positive HIV infection.  AbbVie will not receive results from the testing and not be made aware of any positive result.
m.
Anti-dsDNA performed if ANA result is positive.
n.
If a sample cannot be obtained during the site visit, the site will give 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 chart by ePRO.  All stool samples for metagenomic analysis should be collected before 
any bowel preparation for endoscopy is started and should be returned to the site within 3 days of collection.
Note:
The Screening stool sample may be taken anytime during the Screening period but should be collected prior to any bowel prep.
o.
Blood samples for the measurement of adalimumab and AAA concentrations will be collected prior to dosing.  Testing of the adalimumab and AAA concentrations must not 
be performed locally.  All pharmacokinetic results will remain blinded to the investigator, study site personnel and the subject throughout the study.


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Table 2.
Study Activities (Continued)
p.
Pharmacogenetic Marker and intestinal biopsy samples are optional.  Separate consents must be signed prior to the sample draw.  If the pharmacogenetic sample is not 
collected at Baseline, preferably it should be collected at the next study visit.
q.
Subject will begin corticosteroid taper at Week 4.  If the Investigator feels that the steroid taper is not advisable for a particular subject at Week 4, the SDP should be 
consulted for evaluation and approval.
r.
Collection of SAEs begins the day the subject signs the informed consent.
s.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
t.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects that continue on adalimumab 
therapy after the end of study participation.
u.
The Screening results of the SFPS will serve as the Baseline value.
v.
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 according to this table are for purposes when the subject is coming in for a visit for evaluation, assessment and 
potential dose escalation.


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4.3
Sample Size
There is no sample size calculation for the Maintenance study.
4.4
Interim Analysis
No interim analysis is planned for the Maintenance study.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The following populations will be used for analyses in the study:
Modified Intent-to-Treat (mITT) set includes all ITT subjects who achieve clinical 
response (CR-70) at Week 12.  The mITT set is the primary population for the efficacy 
analysis for the Maintenance Study.
The safety set consists of all subjects who received at least one injection of study drug 
during maintenance study.  The safety set will be analyzed as treated, according to 
treatment the subject actually received.  The safety set will be used only for safety 
analysis.
5.2
Variables Used for Stratification of Re-Randomization
At Week 12, subjects are re-randomized in a 1:1 ratio to one of two double-blinded 
exploratory treatment regimens (clinically adjusted [CA] regimen and adalimumab 
therapeutic drug monitoring [TDM] regimen).  The re-randomization at Week 12 is 
stratified by induction treatment regimen, clinical response (CR-70) status at Week 12, 
and decrease in SES-CD > 50% from Baseline per the site investigator reading at 
Week 12.  Among subjects achieving decrease in SES-CD > 50% from Baseline at 
Week 12, the randomization is further stratified by achievement of an SES-CD ≤ 4 and at 
least a 2 point reduction versus baseline and no subscore greater than 1 in any individual 
variable using the Week 12 SES-CD value provided by the site.


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The randomization schedule was prepared by the Statistics Department of AbbVie.
6.0
Analysis Conventions
Definition of Induction Baseline
The Induction Baseline visit date is the date when the first dose of study drug is received 
and referred to as Day 1 or Week 0.  If a subject has not taken any study drug during 
Induction Study, the randomization date will be used as Day 1.  The Baseline value for a 
variable is defined as the last non-missing value on or before the date of the first dose of 
study drug.
Definition of Maintenance Baseline
The Maintenance Baseline visit date is the date when the first dose of study drug during 
Maintenance Study is received and referred to as Day 1 of Maintenance Study or Week 0 
of Maintenance Study.  If a subject has not taken any study drug during Maintenance 
Study, the re-randomization date will be used as Day 1.  The Maintenance Baseline value 
for a variable is defined as the last non-missing value on or before Day 1 of Maintenance 
Study, and after the Induction Baseline.
Definition of Maintenance Final Observation
Final Observation in the 56-week period (44-week double-blind Maintenance Study) is 
defined as the last non-missing observation collected within 70 days following the last 
dose of study drug who are re randomized.
Definition of Rx Days (Days Relative to the First Dose of Maintenance Study Drug)
Rx Days are calculated for each time point of interest and it provides a quantitative 
measure of days between the event and the first dose date.  That is, the Rx Day is 
calculated as the event date minus the date of first dose of study drug plus 1.  The Rx Day 
will be a negative value when the time point of interest is prior to the date of first dose of 
study drug, and the Rx Day will be a positive value when the time point of interest is after 


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the first dose date.  By this calculation algorithm the first dose day is Rx Day 1 of 
Maintenance Study, while the day prior to the date of first dose is defined as Rx Day –1 of 
Maintenance Study (there is no Rx Day 0).  Rx Days are used to map actual study visits to 
the protocol specified study visits.
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 one with later time will 
be used if collection time is also available, 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 
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 two or more actual 
visits in one visit window, the visit closest to the schedule visit will be used as the study 
visit for that window.  If two visits are equidistant from the target, then the later visit will 
be used for reporting.  If more than one assessment is collected on the same day, then the 
average of those assessments will be used in analyses.


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Table 3.
Visit Windows for Analysis of CDAI and Vital Signs for 
Maintenance Study
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 12 (Week 0 of Maintenance Study)
1a
≤1
Week 14 (Week 2 of Maintenance Study)
15
2 – 36
Week 20 (Week 8 of Maintenance Study)
57
37 – 78
Week 26 (Week 14 of Maintenance Study)
99
79 – 106
Week 28 (Week 16 of Maintenance Study)
113
107 – 134
Week 34 (Week 22 of Maintenance Study)
155
135 – 176
Week 40 (Week 28 of Maintenance Study)
197
177 – 204
Week 42 (Week 30 of Maintenance Study)
211
205 – 232
Week 48 (Week 36 of Maintenance Study)
253
233 – 281
Week 56 (Week 44 of Maintenance Study)
309
282 – 379
Rx Day = date of visit – date of first study drug injection in double-blind maintenance study + 1
a.
Day of first dose of study drug in double-blind maintenance study.  If a subject has not taken any study drug during 
Maintenance Study, the randomization date will be use as Day 1 of Maintenance Study.
Table 4.
Visit Windows for Analysis of Chemistry, Hematology, Urinalysis, 
hs-CRP, Fecal Calprotectin, Abdominal Pain Rating Scale, IBDQ, 
EQ-5D, and WPAI for Maintenance Study
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 12 (Week 0 of Maintenance Study)
1a
≤ 1
Week 26 (Week 14 of Maintenance Study)
99
2 – 148
Week 40 (Week 28 of Maintenance Study)
197
149 – 253
Week 56 (Week 44 of Maintenance Study)
309
254 – 379
Rx Day = date of visit – date of first study drug injection in double-blind maintenance study + 1
a.
Day of first dose of study drug in double-blind maintenance study.  If a subject has not taken any study drug during 
Maintenance Study, the randomization date will be use as Day 1 of Maintenance Study.


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Table 5.
Visit Windows for Analysis of SES-CD for Maintenance Study
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 12 (Week 0 of Maintenance Study)
1a
≤ 1
Week 56 (Week 44 of Maintenance Study)
309
2 – 379
Rx Day = date of visit – date of first study drug injection in double-blind maintenance study + 1
a.
Day of first dose of study drug in double-blind maintenance study.  If a subject has not taken any study drug during 
Maintenance Study, the randomization date will be use as Day 1 of Maintenance Study.
Table 6.
Visit Windows for Analysis of Fistulas and EIM for Maintenance 
Study
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 12 (Week 0 of Maintenance Study)
1a
≤ 1
Week 56 (Week 44 of Maintenance Study)
309
2 – 379
Rx Day = date of visit – date of first study drug injection in double-blind maintenance study + 1
a.
Day of first dose of study drug in double-blind maintenance study.  If a subject has not taken any study drug during 
Maintenance Study, the randomization date will be use as Day 1 of Maintenance Study.
CD-Related Concomitant Corticosteroid Therapy
Subjects in whom the CD-related corticosteroids (systemic or rectal corticosteroids) that 
were not being taken at Induction Baseline and are initiated during the study or who have 
equivalent dose of these medications increased to greater than the dose taken at Induction 
Baseline will be censored for efficacy assessments (i.e., will be considered non-
responders for categorical endpoints and will have last non-missing 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.
Subjects in whom systemic corticosteroids were used at Induction Baseline and initiated 
rectal corticosteroids during the study will be censored for efficacy assessment, regardless 
of rectal corticosteroid dose.
The equivalent steroid dose will be determined based on the table below:


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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
Definition of Missing Data Imputation
The following imputation methods will be used to impute missing values in the efficacy 
analyses.  In addition, an observed case analysis will be performed.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy variables.  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.'
Last Observation Carried Forward (LOCF)
For all variables (categorical variables and continuous variables), the following rules will 
be used for the LOCF approach:
1.
Maintenance Baseline and Pre-Maintenance Baseline values will not be used to 
impute the missing Post-Maintenance Baseline values.


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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 Maintenance Baseline, then the LOCF value will be missing.
Mixed-Effect Model Repeated Measure (MMRM)
The MMRM model will be used for continuous efficacy variables with longitudinal data 
as a sensitivity analysis.  The MMRM model includes the Induction baseline values as 
covariate; randomization strata, region (US versus non-US), treatment, time point and 
treatment-by-time point interaction as fixed effects; and subjects within treatment as 
random effect.  An unstructured (co)variance structure will be used to model the 
within-subject error.  The comparison at a time point will be the contrast between 
treatments at that time point.
Observed Case (OC)
Observed case analysis will be performed such that missing values will not be imputed.  
Subjects in whom the following CD-related systemic or rectal corticosteroids that were 
not being taken at Induction Baseline and are initiated during the study or who have 
dosages of these medications increased to greater than the dose taken at Induction 
Baseline will be censored for efficacy assessments (i.e., will be considered non-
responders for categorical endpoints and the observed non-categorical assessments will be 
replaced by last non-missing values prior to censoring) from that point through the end of 
the study.
Subjects in whom systemic corticosteroids were used at Induction Baseline and initiated 
rectal corticosteroids during the study will be censored for efficacy assessment, regardless 
of rectal corticosteroid dose.


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Imputation of Missing Dates
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
Rule for CDAI Calculation
Up to 14 days of diary entries will be evaluated from the ePRO tool 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 that are based on ePRO (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.
Sensitivity analyses will be performed to make use of all available data based on the 
above rule if more than 5% of subjects have less than 4 days of diary data.
Definition of Clinical Remission
CDAI < 150.


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Definition of Clinical Response
Decrease in CDAI ≥ 70 points from Induction Baseline.
Definition of Enhanced Clinical Response
Decrease in CDAI ≥ 100 points from Induction Baseline.
Definition of Endoscopic Remission
Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≤ 4 and at least 2 point 
reduction versus Induction baseline and no subscore greater than 1 in any individual 
variable, as scored by central reviewer.
Definition of Endoscopic Response
Decrease in SES-CD > 50% from Induction Baseline (or for a Induction Baseline SES-
CD of 4, at least a 2 point reduction from Induction Baseline), as scored by central 
reviewer.
Stool Frequency + Abdominal Pain Score (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.
Definition of Time to Dose Escalation
Time to Dose Escalation is defined as number of days from Study Day 1 in Maintenance 
Study to the date of Dose Escalation.  It is calculated as (date of dose escalation – Study 
Day 1 date in Maintenance Study).  Subjects who discontinue prior to dose escalation are 
censored at the time of discontinuation.  Subjects who are not experiencing dose 
escalation by Week 56 are censored at the Week 56 visit.


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Definition of Symptomatic Remission
Average daily stool frequency ≤ 2.8 (and not worse than induction baseline) and average 
daily abdominal pain ≤ 1.0 (and not worse than induction baseline).  The analysis will be 
only performed on subjects with induction baseline average daily stool frequency 
score ≥4.0 or average daily abdominal pain score ≥ 2.0.
Definition of Symptomatic Response
Average daily stool frequency at least 30% reduction from induction baseline and average 
daily abdominal pain not worse than induction baseline or average daily abdominal pain at 
least 30% reduction from induction baseline and average daily stool frequency not worse 
than induction baseline.  The analysis will be only performed on subjects with induction 
baseline average daily stool frequency score ≥ 4.0 or average daily abdominal pain 
score ≥ 2.0.
Discontinued Corticosteroid Use at Each Visit during Maintenance Study Among 
Subjects Who Used Corticosteroids at Induction Baseline
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 date of vital signs 
will be used.  If no vital signs date, then the steroid use on the nominal day for that visit 
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, 'discontinued 
steroid use' will be classified as No from that point through the end of the study.
SES-CD Scoring
All videotaped colonoscopies will undergo central review providing the investigator's 
SES-CD score meets the entry criteria.  Two primary central reviewers will evaluate the 


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videotaped colonoscopies separately and provide their SES-CD scores to Parexel.  A 
third central reviewer will adjudicate between the two initial reviewers' SES-CD scores if 
there is discrepancy in any SES-CD variable.  The adjudicator will select the final SES-
CD score that he/she most agrees with from those provided by the two primary reviewers, 
and this final SES-CD score 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 
score 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 Baseline will be imputed as 0.  The Week 12 
or Week 56 missing SES-CD individual variables 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.
Bristol Stool Chart Score
Up to 14 days of diary entries will be evaluated from the ePRO tool for the Bristol Stool 
Chart calculation.  These assessments on the day of endoscopy procedure, the day before 
endoscopy procedure (due to preparation medications), and 2 days after endoscopy 
procedure are excluded.  The 7 most recent non-missing assessments will be used for the 
analysis.  Bristol Stool Form Scale is not a continuous variable.  The new variable Bristol 
Stool Chart score is defined as the number of days the subjects with Type 6 or Type 7 
divided by the total number days with non-missing assessments, rounded to two decimals.
If a subject has less than 4 days of diary data, the Bristol Stool Chart score will not be 
calculated and will be considered missing.
If a subject achieved reduction from Baseline ≥ 50%, this subject will be classified as 
Bristol Stool Chart Responder.


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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 M14-115 approximately 423 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 
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 M14-115, 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.
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.  
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 


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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).
Table 7.
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.


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The minimum index value is –0.281 (health state 55555), and the maximum index value 
is 1 (health state 11111).1
If one of the 5 dimensions is missing, the EQ-5D index value will be missing.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Induction Baseline Characteristics
For the subjects in mITT and safety analysis set, demographic information and Induction 
Baseline values will be summarized by descriptive statistics.  Categorical data will be 
summarized by number and percent; and quantitative data will be presented by n, mean, 
standard deviation, minimum value, median, and maximum value.
In general, continuous variables will be analyzed using analysis of variance (using SAS 
procedure 'PROC GLM') with treatment group as factor.  Categorical variable will be 
analyzed using chi-square test or Fisher's exact test if ≥ 20% of the cells have expected 
cell count < 5.
The following demographic and Baseline values will be summarized.
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)
●
IBDQ score


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●
CDAI
●
SFPS
●
Total SES-CD score
●
Crohn's Disease Duration (years)
●
hs-CRP mg/L
●
WPAI and its components
●
EQ-5D
●
Abdominal Pain Rating Scale
●
Bristol Stool Chart score
●
Fecal calprotectin
Categorical Variables:
●
Sex (male, female)
●
Race
●
Ethnicity
●
Age (≤ median, > median)
●
Age (< 40, 40 to < 65, 65 to < 75, ≥ 75)
●
Baseline fecal calprotectin (≤ median, > median)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
hs-CRP at Baseline (≤ median, > median)
●
Baseline fecal calprotectin (≤ median, > median)
●
Baseline fecal calprotectin (≤ 250 μg/g, > 250 μg/g)
●
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline
●
Baseline CDAI (≤ median, > median)
●
Baseline SES-CD (≤ median, > median)
●
Prior infliximab use (or prior anti-TNF use for subjects randomized under 
original protocol) (yes, no)


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●
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)
7.2
Medical History
Medical and Surgical History:  A complete medical and surgical history (which includes 
CD-onset date), history of tobacco and alcohol use, will be obtained from each subject 
during the Screening period.  Medical history will be summarized using body system and 
preferred term by treatment group.  No statistical tests will be performed.
Chest X-Ray Results:  All subjects undergo a standard chest X-ray of chest (including a 
posteroanterior [PA] and lateral view) at Screening period.  Number and percent of 
subjects with presence or absence of finding for the previous TB infection, calcified 
granulomas, Pleural scarring/thickening, and other findings will be presented by treatment 
group.  No statistical tests will be performed.
TB Test Results:  Results of PPD skin test or QuantiFERON-TB Gold test at screening 
visit will be summarized.  Induration will be summarized descriptively using n, mean, 
standard deviation, minimum values, median, and maximum values.  The frequency 
distribution of induration ≥ 5 and < 5 will be provided.  No statistical tests will be 
performed.
ECG Results:  ECG results at screening will be presented as frequency distribution 
showing results as Normal, Abnormal (Not clinically significant), Abnormal (Clinically 
significant) and Unable to evaluate/missing.  No statistical tests will be performed.


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7.3
Previous Treatment and Concomitant Medications
Prior medications are those medications taken prior to the first dose of study drug.  This 
includes medications with a start date before the first study drug administration date, 
regardless of the end date of these medications.  Medications taken on the day of the 
first dose of study drug are not counted as prior medications.
Concomitant medications are those medications, other than study drug, taken after the 
first dose of study drug in Maintenance, which include medications with a start date prior 
to the Maintenance Baseline date which are continuing after Baseline and all medications 
with a start date between the Maintenance Baseline date and last study drug 
administration + 14 days.
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by number and percent for mITT and 
safety analysis sets for the treatment groups.  No statistical tests will be performed.
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, immunosuppressants, and antibiotics) at the Induction Baseline will be 
tabulated.  In addition, the number and percent of subjects using any Crohn's disease 
specific medications including infliximab prior to Induction Baseline will be tabulated.
8.0
Patient Disposition
Subject disposition will be presented for subjects in the mITT and safety analysis sets 
using the following information by treatment group:
●
Number and percent of subjects in various analysis sets by treatment group and 
by investigator and/or site number
●
Number and percent of subjects completing 44-week Maintenance study
●
Subject disposition including the number and percent of subjects who 
prematurely discontinued the Maintenance study by primary reason and by any 
reason


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Summary of protocol deviations will be provided.
9.0
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized using the mean, standard 
deviation, minimum, median, and maximum.  Exposure to study drug (total patient years) 
will be summarized by treatment group.
The number of injections received at each schedule time point will be summarized with 
number and percent for each treatment group.
Study Drug Exposure (in Days) during the Maintenance Study:
●
Date of last dose of Maintenance Study drug – Date of first dose of 
Maintenance Study drug + 14 days
Study Drug Compliance:
Treatment compliance will be summarized for each treatment group in the mITT 
population.  The treatment compliance is defined as the number of injections actually 
taken by the subject divided by the number of injections planned to be taken by the 
subject during the Maintenance Study. 
10.0
Efficacy Analysis
10.1
General Considerations
All statistical tests will be two-sided with the significance level of 0.05.  Descriptive 
statistics will be provided.  These include the number of observations, mean, standard 
deviation, minimum, median, and maximum for continuous variables; and number and 
percent for discrete variables.  The analysis will be performed using SAS® Version 9.4 or 
later (SAS Institute Inc., Cary, NC, USA).


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10.2
Efficacy Analyses
This section provides the details of the efficacy analysis for the Maintenance Study.
For these endpoints which are categorical variables, NRI method of imputation will be 
used for the missing values.  LOCF will be used as a sensitivity analysis wherever 
applicable.
Both LOCF and OC analyses will be performed for continuous endpoints.  The LOCF 
analysis is considered primary for inferential purposes.  In additional, Mixed-Effect 
Model Repeated Measure (MMRM) will be applied as a sensitivity analysis, wherever 
appropriate, for the longitudinal continuous endpoints.
For endoscopy related endpoints, there will be no LOCF imputation as there is only 
one post-baseline endoscopy during Maintenance. OC will be used as a sensitivity 
analysis.
The difference in proportions of subjects between treatment groups will be analyzed using 
the two-sided Cochran-Mantel-Haenszel (CMH) test adjusted for induction treatment 
regimen, and decrease in SES-CD > 50% from Induction Baseline per central reading at 
Week 12.  Additionally, the CMH-based two-sided 95% confidence interval (CI) for the 
difference in the proportions between the treatment groups will be calculated.
The difference in change from Induction Baseline between treatment groups will be 
analyzed using an ANCOVA model including factors of treatment, induction treatment 
regimen, decrease in SES-CD > 50% from Induction Baseline per central reading at 
Week 12 and Induction Baseline values.  Parameter estimates with 95% confidence 
interval and P-value will be provided.
All efficacy endpoints for Maintenance Study are non-ranked.
●
Proportion of subjects who achieve endoscopic response (SES-CD > 50% from 
Induction Baseline [or for a Induction Baseline SES-CD of 4, at least a 2 point 


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reduction from Induction Baseline]) at Week 56 among subjects with 
endoscopic response at Week 12
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus Induction Baseline and no subscore greater 
than 1 in any individual variable) at Week 56 among subjects with endoscopic 
remission at Week 12.
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus Induction Baseline and no subscore greater 
than 1 in any individual variable) at Week 56 among subjects with endoscopic 
response at Week 12.
●
Proportion of subjects who achieve sustained clinical remission, CDAI < 150 
at Week 56 among subjects with CDAI < 150 at Week 12.
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 56.
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least 2 point reduction versus Induction Baseline and no subscore greater than 
1 in any individual variable) at Week 56.
●
Proportion of subjects who achieve SES-CD ≤ 2 at Week 56.
●
Proportion of subjects with deep remission, CDAI < 150 at Week 56 and SES-
CD ≤ 4 and at least 2 point reduction versus Induction Baseline and no 
subscore greater than 1 in any individual variable at Week 56.
●
Proportion of subjects who discontinued corticosteroid use and achieved 
clinical remission (CDAI < 150) at Week 56 among subjects taking 
corticosteroid at Induction Baseline.
●
Proportion of subjects with endoscopic response (decrease > 50% SES-CD 
from Induction Baseline [or for a Induction Baseline SES-CD of 4, at least a 
2 point reduction from Induction Baseline]) at Week 56.
●
Change from Induction Baseline in fecal calprotectin level at Week 56.
●
Proportion of subjects with hs-CRP < 5 mg/L and fecal calprotectin < 250 μg/g 
at Week 56.
●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, and fecal 
calprotectin < 250 μg/g at Week 56.


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●
Proportion of subjects with CDAI < 150, hs-CRP < 5 mg/L, SES-CD ≤ 4 and 
at least 2 point reduction versus Induction Baseline and no subscore greater 
than 1 in any individual variable, and fecal calprotectin < 250 μg/g at 
Week 56.
●
Proportion of subjects with endoscopic response, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.
●
Proportion of subjects with endoscopic remission, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.
●
Proportion of subjects with clinical remission, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.
●
Proportion of subjects with clinical response (decrease in CDAI ≥ 70 points 
from Induction Baseline) at Week 56.
●
Proportion of subjects with clinical response (decrease CDAI ≥70 points from 
Induction Baseline) at each scheduled visit in Maintenance Study.
●
Proportion of subjects with enhanced clinical response (decrease 
CDAI ≥100 points from Induction Baseline) at each scheduled visit in 
Maintenance Study.
●
Proportion of subjects who discontinue corticosteroid use at each scheduled 
visit in Maintenance Study among subjects taking corticosteroid at Induction 
Baseline.
●
Proportion of subjects who achieve a composite subtotal score of SFPS < 50 at 
Week 56 who had an SFPS ≥ 100 at Induction Baseline.
●
Proportion of subjects who achieve SES-CD ≤ 3 and at least a 2 point 
reduction versus Induction Baseline and no subscore greater than 1 in any 
individual variable at Week 56.
●
Proportion of subjects with SES-CD = 0 at Week 56.
●
Change from Induction Baseline in fecal calprotectin level at each scheduled 
visit in Maintenance Study.
●
Change from Induction Baseline in hs-CRP at each scheduled visit in 
Maintenance Study.


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●
Change in IBDQ total score and individual IBDQ domain scores (bowel, 
emotional, social, systemic) from Induction Baseline at each scheduled visit in 
Maintenance Study.
●
Change in WPAI from Induction Baseline at each scheduled visit in 
Maintenance Study.
●
Change in EQ-5D from Induction Baseline at each scheduled visit in 
Maintenance Study.
●
Change in CDAI from Induction Baseline at each scheduled visit in 
Maintenance Study.
●
Change in SFPS from Induction Baseline at each scheduled visit in 
Maintenance Study.
●
Change in Abdominal Pain Rating Scale score from Induction Baseline at each 
scheduled visit in Maintenance Study.
●
Change in Bristol Stool Chart score from Induction Baseline at each scheduled 
visit in Maintenance Study.
●
Proportion of subjects who achieve CDAI remission (CDAI < 150) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects who achieve SFPS remission (SFPS < 50) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects with major CD related event (e.g., hospitalization, 
bowel surgery, abscess drainage) in Maintenance Study.
●
Proportion of subjects with no draining fistulas at Week 56 among subjects 
with draining fistula at Induction Baseline.
●
Proportion of subjects in each treatment group with > 50% reduction from 
Induction Baseline in the number of draining fistulas at Week 56 among 
subjects with draining fistula at Induction Baseline.
●
Resolution of extra-intestinal manifestations at each scheduled visit in 
Maintenance Study.
●
Proportion of subjects with an SES-CD decrease of ≥ 3 points compared to 
Induction Baseline at Week 56.
●
Proportion of subjects who achieve symptomatic remission, defined as average 
daily stool frequency ≤ 2.8 (and not worse than Induction Baseline) and 


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average daily abdominal pain ≤ 1.0 (and not worse than Induction Baseline), at 
each scheduled visit in Maintenance Study among subjects with Induction 
Baseline SF ≥ 4.0 and/or AP ≥ 2.0.
●
Proportion of subjects who achieve symptomatic response, defined as average 
daily stool frequency at least 30% reduction from Induction Baseline and 
average daily abdominal pain not worse than Induction Baseline or average 
daily abdominal pain at least 30% reduction from Induction Baseline and 
average daily stool frequency not worse than Induction Baseline, at each 
scheduled visit in Maintenance Study among subjects with Induction Baseline 
SF ≥ 4.0 and/or AP ≥ 2.0.
●
Time to dose escalation in Maintenance Study.
●
Proportion of subjects with Inflammatory Bowel Disease Questionnaire 
(IBDQ) response (increase ≥ 16 points from Induction Baseline) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects with IBDQ remission (IBDQ ≥ 170 points) at each 
scheduled visit in Maintenance Study.
●
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 8) at each scheduled visit 
in Maintenance Study.
●
Proportion of subjects achieving response in IBDQ fatigue item (increase of 
IBDQ fatigue item score ≥ 1) at each scheduled visit in Maintenance Study.
●
Proportion of subjects requiring dose escalation to weekly dosing during 
Maintenance Study.
●
Proportion of subjects who achieve clinical remission (CDAI < 150) at 
Week 56 among subjects requiring dose escalation to weekly dosing during 
Maintenance Study.
●
Proportion of subjects who achieve endoscopic response (decrease 
> 50% SES-CD from Induction Baseline [or for an Induction Baseline SES-
CD of 4, at least a 2 point reduction from Induction Baseline]) at Week 56 
among subjects requiring dose escalation to weekly dosing during 
Maintenance Study.
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus Induction Baseline and no subscore greater 


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than 1 in any individual variable) at Week 56 among subjects requiring dose 
escalation to weekly dosing during Maintenance Study.
Major CD related events will be identified by review of serious adverse events (SAEs) 
according to the hospitalization adjudication charter.  P values from both Log-rank test 
and Cox proportional hazards model will be provided.
10.3
Handling of Multiplicity
No adjustment for multiplicity will be done.
11.0
Safety Analysis
11.1
General Considerations
All safety analyses will be performed on the safety analysis set.  The safety variable will 
be summarized by treatment according to the treatment a subject actually received.
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs during Maintenance Study 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. 
The 70-day follow-up phone call will not be required for any subject that initiates 
commercial adalimumab.
An overview of treatment-emergent AEs, including AEs of special interest such as 
adverse events leading to death and adverse events leading to premature discontinuation, 
AEs by Medical Dictionary for Drug Regulatory Activities (MedDRA version 21.0 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 percent.


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The number and percent of subjects experiencing treatment-emergent adverse events will 
be summarized for the following adverse event categories.
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility).
●
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.
●
Any Deaths
Treatment-emergent adverse events will be summarized as follows:
●
Grouped by System Organ Class and Preferred Term.
●
A by-subject listing will be provided.
●
Grouped by System Organ Class, Preferred Term and Severity.
●
Grouped by System Organ Class, Preferred Term and Relationship to Study 
Drug.
●
Grouped by System Organ Class and Preferred Term with subject numbers.
In treatment-emergent AE tables, a subject who reports more than one treatment-emergent 
AE in different system organ classes will be counted only once in the overall total.  A 
subject who reports two or more different preferred terms which are in the same SOC will 
be counted only once in the SOC total.  A subject who reports more than one treatment 
AE with the same preferred term will be counted only once for that preferred term using 
the most extreme incident (i.e., most "severe" for the severity tables and most "related" for 
the relationship tables).


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
43
Adverse events will also be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 
category of "unknown," even if the subject has another occurrence of the same adverse 
event with a severity present.  The only exception is if the subject has another occurrence 
of the same adverse event with the most extreme severity – "Severe."  In this case, the 
subject will be counted under the "Severe" category.
Adverse events will also be summarized by maximum relationship to study, as assessed 
by the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same adverse event with a relationship present.  The only 
exception is if the subject has another occurrence of the same adverse event with a 
relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category, respectively.
Incidence rates per 100 patient years of exposure to study drug will be presented for AE 
overviews and for AEs by SOC and preferred term where the number of events will be 
used as the numerator.
All Adverse Events identified to AbbVie from the 70-day follow-up phone call will be 
collected as source data to be evaluated and reported.  Thus, all SAEs and nonserious AEs 
as defined by AbbVie, reported during the 70-day follow-up phone call must be captured 
in the clinical database.  The end of trial is the last subject contact, i.e., the 70-day 
follow-up call.
11.2.2
Adverse Events of Special Interest
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


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
44
●
Any Serious Infection AE
●
Any Legionella Infection AE
●
Any Diverticulitis AE
●
Any Opportunistic Infection AE (Excluding Oral Candidiasis and TB)
●
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


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
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●
Any Pulmonary Embolism Related AE
●
Any Interstitial Lung Disease AE
●
Any Intestinal Perforation AE
●
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
●
Any Humira Administration Related Medication Errors AE
●
Any Injection Site Reaction AE
●
Any Intestinal Stricture
●
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.
11.3
Analysis of Laboratory Data
All laboratory data collected after first dose of maintenance study drug will be included in 
this analysis.
Changes from Baseline in continuous laboratory parameters will be summarized by n, 
mean, standard deviation, minimum value, median, and maximum value for each 
treatment group.


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
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Cross (Shift) tables from Baseline to the minimum, maximum, and final value according 
to the normal range will be provided for each hematology, clinical chemistry parameter 
and urinalysis parameter except for the microscopic examination.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 3.0 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 laboratory data using Abbott platform will be used for this analysis.  If the data 
measured using Abbott platform are not available, the Abbott equivalent (the values 
measured using Roche platform that were converted to Abbott equivalent) will be used.
11.3.1
Assessment of Shifts from Induction Baseline in 
Liver-Specific Laboratory Variables
Induction Baseline and post-maintenance baseline livers-specific laboratory will be 
categorized as follows:
●
< 1.5 times the upper limit of the reference range
●
≥ 1.5 to < 3 the upper limit of the reference range
●
≥ 3 to < 5 the upper limit of the reference range
●
≥ 5 to < 8 the upper limit of the reference range
●
≥ 8 the upper limit of the reference range
For each variable, shift tables will be generated as deemed appropriate:
●
Category of the induction baseline value versus category of the final value,
●
Category of the induction baseline value versus post-maintenance baseline 
high/low category


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
47
Note that the maximum category is used, rather than the category of the maximum values.  
The two may be different due to variation in the reference range.
No statistical tests will be performed for this analysis.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing includes 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.
11.3.2
Hy's Law Cases
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
48
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
11.4
Analysis of Vital Signs and Weight
All vital signs and weight data collected after first dose of maintenance study drug will be 
included in this analysis.
The following vital signs are measured at every visit during the study.
●
Body Weight (kg)
●
Blood Pressure (Systolic/Diastolic) (mmHg)
●
Pulse (bpm)
●
Respiratory Rate (RPM)
●
Temperature (°C)
Changes from Baseline in vital sign values will be summarized by n, mean, standard 
deviation, minimum value, median, and maximum value for each treatment group.
The number and percentage of subjects meeting the criteria for potentially clinically 
significant (PCS) vital sign values will also be summarized.
The criteria for potentially clinically significant vital sign findings are presented in 
Table 8.


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
49
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ! 90 mmHg and/or decrease ∀20 mmHg from Baseline
High
Value ∀180 mmHg and/or increase ∀20 mmHg from Baseline
Diastolic blood pressure
Low
Value ! 50 mmHg and/or decrease ∀15 mmHg from Baseline
High
Value ∀105 mmHg and/or increase ∀15 mmHg from Baseline
Pulse
Low
Value ! 50 bpm and/or decrease ∀15 mmHg from Baseline
High
Value ∀120 mmHg and/or increase ∀15 mmHg from Baseline
Vital sign results meeting the criteria for PCS findings will be identified in a listing.
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
Under Section 10.2 Efficacy Analyses, there was a typo for the endpoint "Proportion of 
subjects with CDAI < 150 at Week 4 and SES-CD ≤ 4 and at least 2 point reduction 
versus baseline and no subscore greater than 1 in any individual variable at Week 56."  It 
should be Week 56 for CDAI < 150, not Week 4.  The endpoint has been updated in the 
SAP to "Proportion of subjects with CDAI < 150 at Week 56 and SES-CD ≤ 4 and at least 
2 point reduction versus baseline and no subscore greater than 1 in any individual variable 
at Week 56."
Under Section 10.2 Efficacy Analyses, the following explanatory endpoints are added:
●
Proportion of subjects who achieve endoscopic remission (SES-CD ≤ 4 and at 
least a 2 point reduction versus Induction Baseline and no subscore greater 
than 1 in any individual variable) at Week 56 among subjects with endoscopic 
response at Week 12.
●
Proportion of subjects with endoscopic response, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.
●
Proportion of subjects with endoscopic remission, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.


Adalimumab
M14-115 – Statistical Analysis Plan for the Double-Blind Maintenance Study
Version 1.0 – 15 November 2019
50
●
Proportion of subjects with clinical remission, and ≥ 50% decrease from 
Induction Baseline in hs-CRP or fecal calprotectin at Week 56.
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
This is the first version of the SAP.
13.0
Appendix
14.0
References
1.
Devlin NJ, Shah KK, Feng Y, et al.  Valuing health-related quality of life:  an 
EQ-5D-5L value set for England.  Health Econ.  2018;27(1):7-22.


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Statistical Analysis Plan for the 12-Week 
Double-Blind Induction Study
Study M14-115
A Multicenter, Randomized, Double-Blind Study to 
Evaluate Higher Versus Standard Adalimumab 
Dosing Regimens for Induction and Maintenance 
Therapy in Subjects with Moderately to Severely 
Active Crohn's Disease and Evidence of Mucosal 
Ulceration
Date:  22 Feb 2019
Version 4.0


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