Clinical trial NCT02065622
Conditions: Ulcerative Colitis (UC)
Keywords: Ulcerative Colitis
Sponsor: AbbVie
Start date: 2014-03-27; Completion date: 2019-11-11
Enrollment: 952 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate safety and efficacy of two adalimumab dosing regimens for induction and maintenance (standard and higher dosing) in achieving clinical remission in subjects with moderately to severely active ulcerative colitis.

Detailed description:

Arms: arm 1: Induction Standard Dose: Double-blind adalimumab regimen of 160 mg at Week 0 followed by 80 mg at Week 2, 40 mg at Week 4, and 40 mg at Week 6. arm 2: Induction Higher Dose: Double-blind adalimumab regimen of 160 mg at Weeks 0, 1, 2, and 3 followed by 40 mg at Week 4, and 40 mg at Week 6. arm 3: Maintenance Standard Dose: Double-blind adalimumab 40 mg every other week (eow), for 44 weeks. arm 4: Maintenance Higher Dose: Double-blind adalimumab 40 mg every week (ew) for 44 weeks. arm 5: Double-blind adalimumab 40 mg eow at Week 8 and Week 10, with possible dose adjustments at Weeks 12, 24, and 37 based on criteria assessing blinded adalimumab serum concentration and rectal bleeding subscore (RBS) assessments.
Interventions: intervention 1: Adalimumab intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_002.pdf: 
Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
1
1.0
Title Page
Clinical Study Protocol M14-033
A Double-Blind, Randomized, Multicenter Study of 
Higher Versus Standard Adalimumab Dosing 
Regimens for Induction and Maintenance Therapy in 
Subjects with Moderately to Severely Active 
Ulcerative Colitis
Incorporating Administrative Change 1, 
Amendment 1, Administrative Change 2, 
Administrative Change 3, and Amendments 2 and 3
AbbVie Investigational
  Product:
Adalimumab 
Date:
16 June 2016
Development Phase:
3
Study Design:
This is a double-blind, randomized, multicenter study of higher versus 
standard adalimumab dosing regimens for induction and maintenance 
therapy in subjects with moderately to severely active ulcerative colitis.
EudraCT Number:
2013-001682-16
Investigator:
Multicenter:  Investigator information is on file at AbbVie
Sponsor:*
For non-EU Countries, 
Excluding Japan:
AbbVie
1 North Waukegan Rd.
North Chicago, IL  60064 
USA
For EU Countries:
AbbVie Deutschland
GmbH & Co. KG 
Knollstrasse
Ludwigshafen 67061
Germany
Japan:
AbbVie GK
3-5-27, Mita, Minato-ku
Tokyo 108-6302, Japan
NCT02065622


Adalimumab
M14-033 Protocol Amendment 3
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Sponsor/Emergency
  Contact:
All Participating Countries
 MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Office:
Mobile:
Fax:
Email:
Secondary Japan Contact:
MD, PhD
Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory 
requirements, including the archiving of essential documents.
*The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
11 December 2013
Administrative Change 1
21 March 2014
Amendment 1
02 June 2014
Administrative Change 2
02 December 2014
Administrative Change 3
29 May 2015
Amendment 2
03 December 2015
The purpose of this Amendment is to:
●
Section 1.0, Title Page, Section 6.1.5, Adverse Event Reporting, Section 7.0,
Protocol Deviations, Appendix K, Japan Sub-Study, Section 6.1.5, Adverse 
Event Reporting, Change in SDP title and Department name
Rationale:  Company updates
●
Section 1.0, Title Page, Section 6.1.5, Adverse Event Reporting, Change in 
Secondary Japan Contact
Rationale:  Company updates
●
Section 1.2, Synopsis, updated to match with protocol changes
Rationale: Align with study changes
●
Section 1.2, Synopsis, Section 8.1.4.1, Primary Efficacy Variables, 
Appendix K, Japan Sub-Study, Section 8.1.4.1, Primary Efficacy Variables, 
typo correction from CRP to hs-CRP
Rationale: Typo correction
●
Section 1.3, List of Abbreviations and Definition of Terms, Section 8.1.4.1, 
Primary Efficacy Variables, Section 8.1.4.2, Secondary Efficacy Variables, 
Section 8.1.7, Interim Analysis, Appendix K, Japan Sub-Study, Section 8.1, 
Statistical and Analytical Plans, Section 8.1.1, Analysis Population, 
Section 8.1.3, Demographics and Baseline Characteristics, Section 8.1.4.1, 
Primary Efficacy Variables, Section 8.1.4.2, Secondary Efficacy Variables, 


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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updated to include updated names of statistical groups due to statistical 
changes in protocol
Rationale:  Align with study changes
●
Section 1.3, List of Abbreviations and Definition of Terms, updated to include 
three (3) additional abbreviations.
Rationale:  For consistency of section
●
Section 1.3, List of Abbreviations and Definition of Terms, updated to include 
three (3) additional definitions
Rationale:  For clarification purposes
●
Section 3.0, Introduction, Section 3.1, Differences Statement, Section 5.1, 
Overall Study Design and Plan: Description, Table 1, TDM Arm Dose 
Adjustment Criteria, Section 5.3.4, Pharmacokinetic Variables, Section 5.5.1,
Treatments Administered, Section 5.5.3, Method of Assigning Subjects to 
Treatment Regimens, Section 5.6.1, Discussion of Study Design and Choice of 
Control Regimens, Section 5.6.4, Selection of Doses in the Study, 
Section 8.1.1, Analysis Population, Section 8.1.3, Demographics and Baseline 
Characteristics, Section 8.1.7, Interim Analysis, Section 8.1.8, 
Pharmacokinetic Analyses, Section 8.2, Determination of Sample Size, 
Section 8.3, Randomization Methods, Appendix K, Japan Sub-Study, 
Section 5.1 Overall Study Design and Plan:  Description, Table 2, Study 
Activities, Section 5.5.1, Treatments Administered, Section 5.5.3, Method of 
Assigning Subjects to Treatment Regimens, Section 8.1.3, Demographics and 
Baseline Characteristics, Section, 8.1.4.1 Primary Efficacy Variables, 
Section 8.3, Randomization Methods, Section 8.2, Determination of Sample 
Size, updated terminology from "arm" to "regimen," "dosing regimen" or 
"treatment group" as appropriate and introduce terminology Induction Study 
and Maintenance Study
Rationale:  Align with study changes
●
Section 3.0, Introduction, Section 3.1, Differences Statement, Section 5.1,
Overall Study Design and Plan: Description, Appendix K, Japan Sub-Study, 
Section 5.1, Overall Study Design and Plan: Description, Added clarification 
that both main and sub study have an Induction Study and a Maintenance 
Study.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
5
Rationale:  Align with study changes
●
Section 4.0, Study Objective, Section 5.6.1, Discussion of Study Design and 
Choice of Control Regimens, Appendix K, Japan Sub-Study, Section 4.0, 
Study Objective of Japan Sub-Study, removed "primary"
Rationale:  Align with study changes
●
Section 5.1, Overall Study Design and Plan: Description, Figure 1, Study 
Schematic, Section 5.2, Selection of Study Population, Section 8.2,
Determination of Sample Size, Appendix K, Japan Sub-Study, Section 5.1,
Overall Study Design and Plan: Description, Appendix K, Japan Sub-Study, 
Study Schematic, Appendix K, Japan Sub-Study, Section 8.2, Determination 
of Sample Size, updated with new study enrollment numbers
Rationale:  Align with study changes
●
Section 5.1, Overall Study Design and Plan: Description, added language to 
clarify collection of PG sample
Rationale:  To align with protocol changes made in Amendment 2
●
Section 5.1, Overall Study Design and Plan: Description, Figure 1, Study 
Schematic, Section 5.3.1, Efficacy and Safety Measurements Assessed and 
Flow Chart, Table 2, Study Activities, Appendix K, Japan Sub-Study, 
Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow Chart, 
Table 2, Study Activities, Updates throughout protocol to note terminology 
change from "Period" to "Study"
Rationale:  Align with study changes
●
Section 5.1, Overall Study Design and Plan, 8-Week Double-Blind Induction 
Study, clarified corticosteroid language 
Rationale:  updated for consistency with rest of protocol
●
Section 5.1, Overall Study Design and Plan: Description, Table 1, TDM Arm 
Dose Adjustment Criteria, added clarification to serum concentration in TDM 
regimen to mean adalimumab serum concentration
Rationale:  For clarification purposes
●
Section 5.2.2, Exclusion Criteria, Exclusion Criteria 25, Section 5.3.1.1, Study 
Procedures, Hepatitis B Testing, Appendix K, Japan Sub-Study, Section 5.2.2, 


Adalimumab
M14-033 Protocol Amendment 3
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Exclusion Criteria, added clarification to the results when testing for 
hepatitis B surface antibody
Rationale:  Due to changes in central laboratory
●
Section 5.2, Selection of Study Population, updated to convey that 
840 subjects will be enrolled at up to 125 sites in the Main Study sites
Rationale:  For clarification purposes
●
Section 5.3.2, Drug Concentration Measurements and Appendix K, Japan Sub-
Study, Section 5.3.2, Drug Concentration Measurements, updates made to total 
number of PK samples
Rationale:  Updated to reflect new enrollment numbers
●
Section 5.2.3.2, Concomitant Therapy, clarified assessment rules
Rationale:  The study now has 2 distinct studies, each with its own endpoints; 
this re-wording removes ambiguity
●
Section 5.3.1.1, Efficacy and Safety Measurements Assessed and Flow Chart, 
Table 2, Study Activities, Appendix K, Japan Sub-Study, Section 5.3.1,
Efficacy and Safety Measurements Assessed and Flow Chart, Table 2, Study 
Activities, footnote "j." expanded to remind sites to refer to the Lab Manual for 
this process.
Rationale:  For clarification purposes
●
Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow Chart, 
Table 2, Study Activities, Appendix K, Japan Sub-Study, Section 5.3.1,
Efficacy and Safety Measurements Assessed and Flow Chart, Table 2, Study 
Activities, footnote "m." added language to match the rest of the protocol.
Rationale: For consistency throughout protocol
●
Section 5.3.1.1, Study Procedures, TB Screening, For the PPD Test, language 
added to clarify how previous TB medications should be collected and added 
to the eCRF.
Rationale:  For clarification purposes
●
Section 5.3.2.3, Disposition of Samples, removed the word "onsite"
Rationale:  typo correction


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
7
●
Section 5.3.3.1, Primary Variables, Section 8.1.4.1, Primary Efficacy Variable, 
primary variables explained for Induction Study and Maintenance Study
Rationale:  To reflect that the study now has 2 distinct studies that each have 
their own endpoints
●
Section 5.3.3.2, Secondary Variables, Section 8.1.4.2, Secondary Efficacy 
Variables, variables updated for Induction Study and Maintenance Study
Rationale:  To reflect that the study now has 2 distinct studies that each have 
their own endpoints
●
Section 5.3.3.3, Additional Variables, variables updated for Induction Study 
and Maintenance Study
Rationale:  To reflect that the study now has 2 distinct studies that each have 
their own endpoints
●
Section 5.5.1, Treatments Administered, Appendix K, Japan Sub-Study, 
Section 5.5.1, Treatments Administered, updated to reflect Week 52 or 
Premature Discontinuation
Rationale:  For clarification purposes
●
Section 5.5.4, Selection and Time of Dose for Each Subject and Section 5.5.6,
Treatment Compliance, clarified this instruction is for home dosing
Rationale:  For clarification purposes
●
Section 6.1.4, Adverse Event Reporting, added clarification that medications 
for AEs/SAEs should be collected during 70-day follow-up phone call and that 
all 70-day follow-up phone call data is to be entered in the eCRF and recorded 
in source documentation
Rationale:  For clarification purposes
●
Section 6.1.5, Adverse Event Reporting, Appendix K, Japan Sub-Study, 
Section 6.1.5, Adverse Event Reporting – update department number for 
Safety Team
Rationale:  Company changes
●
Section 8.1, Statistical and Analytical Plans, additional information added on 
the Safety Analysis Plan between the main and sub studies.
Rationale:  For clarification purposes


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
8
●
Section 8.1.4.1, Primary Efficacy Variables, Appendix K, Japan Sub-Study, 
Section 8.1.4.1, typo correction from IMM to Immunosuppressant
Rationale:  Typo correction
●
Section 8.1.4.1, Primary Efficacy Variables, Appendix K, Japan Sub-Study, 
Section 8.1.4.1, Added language about the method and interpretation between 
the dosing regimens.
Rationale:  To reflect that the study now has 2 distinct studies, each with its 
own set of endpoints.
●
Section 8.1.5, Statistical Analyses of Safety, Clarified statistical analysis 
delineating between Induction and Maintenance Studies.
Rationale:  To reflect that the study now has 2 distinct studies
●
Section 8.1.7, Interim Analyses, updated noting that interim analysis may be 
performed via a database cut
Rationale: To more accurately reflect a possibility to perform an interim 
analysis and clarify the process
●
Section 8.2, Determination of Sample Size, updated to provide scientific 
justification of the increase in the number of patients
Rationale:  To provide scientific justification of the increase in the number of 
patients
●
Section 8.2, Determination of Sample Size, Appendix K, Japan Sub-Study, 
Section 8.2, Determination of Sample Size, updated power of statistical 
analyses
Rationale:  Sample size increased to reflect the lower than expected rate in a 
blinded review of Week 8 response status, and to increase the power for the 
primary endpoint at Week 52 which is previously a secondary endpoint.
●
Section 11.0, Data Quality Assurance, updated section to give more detail per 
standard language
Rationale:  For clarification purposes
●
Appendix B, List of Protocol Signatories, updated per current study team
Rationale:  Study team changes


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
9
●
Appendix J, 70-Day Follow-Up Phone Call, Sample updated to collect date of 
last study drug administration, collect reason if 70-day follow-up call was not 
performed, and add additional help text
Rationale:  To reduce site confusion in completing the form and facilitate 
whether further follow-up is required
●
Appendix K, Japan Sub-Study, Section 8.1.2, Planned Methods of Statistical 
Analysis, deleted
Rationale:  The information was the same in the main study Section 8.1.2 so 
Appendix K Section 8.1.2 was redundant
●
Appendix K, Japan Sub-Study, Section 8.1.7, Interim Analyses, updated 
noting that interim analysis will be performed only if performed for the main 
study
Rationale:  To more accurately reflect a possibility to perform an interim 
analysis
An itemized list of all changes made to this protocol amendment can be found in 
Appendix L.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
10
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-033
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  16 June 2016
Protocol Title:  A Double-Blind, Randomized, Multicenter Study of Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Ulcerative Colitis
Objective:  The objective is to evaluate safety and efficacy of higher induction and maintenance dosing 
regimens in subjects with moderately to severely active Ulcerative Colitis (UC).  
Investigators:  Multicenter Trial (Investigator information on file at AbbVie).
Study Sites:  Approximately 125 sites for the main study and approximately 21 sites for the Japan 
sub-study.
Study Population:  Male and female subjects ≥ 18 and ≤ 75 years of age with a diagnosis of moderately 
to severely active UC (up to 25% infliximab-experienced).
Number of Subjects to be Enrolled:  For the main Induction Study, approximately 840 subjects 
(504 subjects in the higher induction dose regimen and 336 subjects in the standard induction dose 
regimen) will be enrolled at approximately 125 sites worldwide.  All subjects who complete the 
Induction Study (regardless of achievement of response at Week 8) will continue into the Maintenance 
Study.  An additional 100 Japanese subjects (60 in the higher induction dose regimen and 40 in the 
standard induction dose regimen) in a Japan sub-study will be enrolled at 21 Japan sites.  In both the 
main study and Japan sub study, up to 25% of subjects with previous infliximab exposure may be 
enrolled.
Methodology:
This Phase 3 study design includes the Screening Period followed by an 8-Week double blind Induction 
Study and a 44-Week double blind Maintenance Study.   
The Induction Study:  will evaluate the efficacy and safety of a higher induction dosing regimen of 
adalimumab versus standard induction dosing in inducing clinical remission at Week 8 in subjects with 
moderately to severely active UC.  
The Maintenance Study:  will evaluate the safety and efficacy of 44 weeks of three maintenance dosing 
regimens of adalimumab in achieving clinical remission at Week 52 (from the Induction Study Baseline) 
in subjects with moderately to severely active UC who achieved clinical response at Week 8 of the 
Induction Study.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
11
Methodology (Continued):
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 8 will represent the final assessment in the 
Induction Study.  Week 52 will represent the final assessment in the Maintenance Study (representing 
44 weeks of maintenance treatment in the Maintenance Study).  Subjects will have moderately to 
severely active UC as defined by a Mayo Score of 6 to 12 points with an endoscopy subscore of 2 or 3, 
confirmed by a central reader.  For all Mayo Score evaluations throughout the entire study, the stool 
frequency and the rectal bleeding subscores will be calculated based on entries recorded into the 
subject's diary.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
Induction Study.  During the Induction Study, subjects will be randomized at Baseline to one of 
2 double-blinded adalimumab induction regimens (higher dose or standard dose) in a 3:2 ratio, as shown 
in the following figure.  Use of the 3:2 randomization scheme allows for collection of additional safety 
data with the higher induction dose regimen.  The randomization will be stratified by previous infliximab 
use and Baseline corticosteroid use.
8-Week Double-Blind Induction Study
The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg at Weeks 4 
and 6 leads to a total adalimumab dose over 8 weeks that is approximately twice that of the standard 
induction dose regimen (720 mg versus 320 mg).  The higher induction dose regimen was designed for 
rapid attainment of higher adalimumab serum concentrations in order to rapidly control inflammation.  
Pre dosing serum samples for infliximab concentration and human antichimeric antibodies (HACAs) 
will be collected at Week 0.  Pre-dosing serum samples for adalimumab drug levels will be collected at 
Weeks 0, 2, 4, and 8.  Pre-dosing serum samples for anti-adalimumab antibodies will be collected at 
Weeks 0, 4, and 8.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
12
Methodology (Continued):
At Week 4, all subjects who are taking oral corticosteroids from Baseline will have their corticosteroid 
therapy tapered according to the proposed tapering schedule specified in the 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.
At the conclusion of the 8-Week Induction Study, all subjects will be re-randomized into the 44-week 
Maintenance Study.  Re-randomization into the Maintenance Study will be stratified by induction 
treatment regimen in the Induction Study and response status (per Full Mayo Score) at Week 8.  Among 
the responders at Week 8, the re-randomization will be further stratified by remission status (per Full 
Mayo score) at Week 8.  All subjects in the main study who complete the Induction Study) will be re-
randomized into one of three blinded treatment groups in a 2:2:1 ratio:

Adalimumab 40 mg every other week (eow)

Adalimumab 40 mg every week (ew)

Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory)*
*
1) All subjects in the TDM dosing regimen will receive 40 mg eow at Week 8 and Week 10. At 
Weeks 12, 24, and 37, the regimen will be adjusted for subjects meeting the dose adjustment 
criteria (see table below) based on blinded serum concentrations at the prior visit (Weeks 10, 22 and 
35, respectively) and rectal bleeding subscore at the prior and current visits as follows:

Subjects receiving 40 mg eow who meet the dose adjustment criteria will escalate to 40 mg 
weekly.

Subjects receiving 40 mg ew who meet the dose adjustment criteria will receive a one-time dose 
of 160 mg at the visit, and resume 40 mg ew starting the following week.
2) Japan sub-study does not have TDM dosing regimen.  Subjects will be re-randomized into 
Adalimumab 40 mg eow treatment group or Adalimumab 40 mg ew treatment group in a 1:1 ratio.
Pre-dosing serum samples for adalimumab drug levels will be collected in all subjects at Weeks 10, 12, 
16, 22, 24, 29, 35, 37, 42, 48, 52/Premature Discontinuation (PD), and unscheduled visits.  Pre-dosing 
serum samples for anti-adalimumab antibodies will be collected at Weeks 12, 24, 37, 52/PD, and 
unscheduled visits.
The goal of the TDM dosing regimen is to attain serum adalimumab levels within a targeted 
concentration range (selected based on exposure-response analyses from Study M06-827) while 
avoiding excessively high concentrations.  During maintenance therapy in Study M06-827, 
concentrations ranged from 0 to 39.3 µg/mL with eow dosing and 0 to 38.0 µg/mL with ew dosing.  The 
lower bound (10 µg/mL) of the targeted concentration range for the TDM dosing regimen is similar to 
the median concentrations observed over time for the subjects in remission at Week 52 of 
Study M06-827 (11.4, 10.6, and 10.8 µg/mL, for Weeks 8, 32, and 52, respectively).  Use of this 
concentration as the minimum threshold to trigger dose escalation will lead to the majority of subjects 
achieving concentrations greater than 10 µg/mL.  Since serum adalimumab concentrations roughly 
double with a doubling of dose, an upper bound of 20 µg/mL is expected to achieve maximal trough 
concentrations in the range of the highest trough concentrations observed in Study M06-827.  It is 
expected that approximately 60% of subjects in the TDM dosing regimen will escalate to ew dosing and 
15% or fewer will receive reinduction using this concentration range plus the Rectal Bleeding Subscore 
(RBS) criteria outlined in the table below as a guide to adjust adalimumab dosing.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
13
Methodology (Continued):
TDM Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/ml to 20 µg/mL
< 1
No
10 µg/ml to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for 
the Rectal Bleeding Subscore for each study visit.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose 
of 160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing regimens.
  
Study visits for clinical and safety assessments will be performed at Baseline (Week 0), Weeks 1, 2, 4, 8, 
10, 12, 16, 22, 24, 29, 35, 37, 42, 48, and 52/PD.  All subjects will be provided with a Subject Diary 
where they will record ulcerative colitis-related symptoms (daily stool frequency, abdominal discomfort, 
number of bloody stools, fecal urgency, and general well-being), use of anti-diarrheals, use of 
medications for endoscopy preparation, and study drug dosing information throughout the study.  Blood 
samples will be collected for hs-CRP, adalimumab serum concentrations, anti-adalimumab antibody 
(AAA) levels, and other biomarker analyses.  In addition, stool samples for calprotectin and microbiota 
metagenomic analyses will be collected.  The stool samples should be taken before starting bowel 
preparations for endoscopy.  Subjects will undergo an endoscopy (colonoscopy or flexible 
sigmoidoscopy) with biopsy for histologic assessment during Screening, at Week 8 and at Week 52/PD 
(for subjects who remain in the study through at least Week 24) with local investigator assessment for 
Mayo endoscopic subscore confirmed by a central reader.  The central reviewer scoring will be used for 
all efficacy assessments.  The endoscopy subscore result from the central reviewer during the screening 
period will be used to evaluate the eligibility of a subject to enroll in the study.
Subjects who consent to participate in the optional pharmacogenetic (PG) analysis should have an 
additional blood sample drawn at Baseline and at Week 52/PD.  If the sample is not collected at 
Baseline, preferably it should be collected at the next study visit.
Subjects will be discontinued if they withdraw consent or if they are deemed unsuitable to continue for 
any reason by the Investigator.  Subjects experiencing an active infection or those for whom the 
investigator feels dose escalation is not advisable should contact the Study Designated Physician.


Adalimumab
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14
Methodology (Continued):
Subjects will only be allowed to change the dosage of UC-specific concomitant medications as specified 
below:

At Week 4, all subjects who are taking oral corticosteroids from Baseline will have their 
corticosteroid therapy tapered according to the proposed tapering schedule specified in the 
Protocol.  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.

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.
Subjects in whom UC-related medications (defined as oral or rectal aminosalicylates, systemic or rectal 
corticosteroids, or systemic medications affecting the immune system, including thiopurines, MTX, and 
agents listed in the study exclusion criteria) 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.
Immunosuppressant, corticosteroid, and aminosalicylate doses may be decreased or terminated in the 
event of moderate-to-severe treatment-related toxicities.
Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion criteria are for subjects enrolled in the main study.  Separate 
Inclusion/Exclusion criteria for subjects recruited in Japan will be followed in the Japan sub-study.
Main Inclusion:
1.
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.
2.
Male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3.
Subject with a diagnosis of UC for 90 days or greater prior to Baseline, confirmed by endoscopy 
(colonoscopy or flexible sigmoidoscopy) during the Screening Period, with exclusion of current 
infection, dysplasia and/or malignancy.  Appropriate documentation of biopsy results consistent with 
the diagnosis of UC, in the assessment of the Investigator, must be available.


Adalimumab
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15
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
4.
Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to 3 (confirmed by 
central reader) 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 or immunosuppressants as 
defined below):

Subject taking oral corticosteroids, excluding budesonide or beclomethasone:
o
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);

For subject 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 subject 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 subject 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 subject 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.

Subject taking oral beclomethasone:
o
Dose must not exceed 5 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.
or,

At least a consecutive 42-day course of azathioprine, 6-mercaptopurine (6-MP) or injectable 
methotrexate (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 dosing and duration of use criteria.  Oral MTX use is allowed during 
the study (at a stable dose for 28 days prior to Baseline), however prior or current 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.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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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 for their UC from infliximab 
and discontinued its use due to a subsequent loss of response (i.e., judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of UC related symptoms) or intolerance (i.e., in the opinion of the investigator therapy 
was discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication).  Confirmed documentation indicating loss of response or lack of tolerability will be 
required.
6.
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 and correctly 
are (see local informed consent for more detail):

Implants, injectables, some, intrauterine devices (IUDs), intrauterine hormone-releasing system 
(IUS);

Sexual abstinence (when in line with preferred and usual lifestyle of the subject);

A vasectomized partner;

Hormonal contraceptives for at least 90 days prior to study drug administration.
Note:  low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 
0.5 mg are not considered adequate.
7.
If female, subject is not breast-feeding throughout the study and for 150 days after last dose.
8.
Subject has a negative tuberculosis (TB) Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a 
full course of TB prophylaxis, prior to Baseline.
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, chest x-ray, 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 diagnosis and/or history of Crohn's disease (CD) or diagnosis of indeterminate colitis 
(IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
4.
Received therapeutic enema or suppository, other than required for endoscopy, within 7 days prior 
to the Screening endoscopy and during the remainder of the Screening Period.
5.
History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Kock pouch, or 
ileostomy or is planning bowel surgery.
6.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
7.
Positive pregnancy test at Screening (serum) or Baseline (urine).
8.
Female who is breast-feeding or considering becoming pregnant during the study.


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M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
9.
History of clinically significant drug or alcohol abuse in the last 12 months.
10. Subject on azathioprine, 6-MP, 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.
11. Subject on oral aminosalicylates who:

Has not been on stable doses of these medications for at least 14 days prior to Baseline; or

Has discontinued use of aminosalicylates within 14 days of Baseline.
12. Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on oral budesonide 
> 9 mg/day; or subject on oral beclomethasone > 5 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 of at least 14 days in 
duration 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 oral 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 of at least 14 days in duration 
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 has not been a current steroid course of at least 14 days in duration 
prior to Baseline; or

Subject taking oral beclomethasone:
o
has not been on a stable dose for at least 7 days prior to Baseline; or
o
but has not been on a current steroid course of at least 14 days in duration prior to Baseline; 
or
Has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) 
simultaneously
and/or 
Has discontinued use of corticosteroids within 14 days of Baseline.
13. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
14. Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening Period.
15. Currently receiving total parenteral nutrition (TPN).


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
16. Subject who received any investigational agent or procedure (including previous fecal microbial 
transplantation) within 30 days or 5 half-lives prior to Week 0 (Baseline), whichever is longer.
17. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
18. 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.
19. 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®]) or previous participation in an adalimumab clinical study.  Prior exposure to any 
anti-tumor necrosis factor (TNF) agent other than infliximab (including but not limited to 
adalimumab [Humira®], etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).
20. Subject with known hypersensitivity to the excipients of adalimumab (see Protocol).
21. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
22. 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.  If the Screening endoscopy shows evidence of current 
dysplasia or malignancy, subject may not be enrolled in the study.
23. History of invasive infection (e.g., listeriosis and histoplasmosis), human immunodeficiency virus 
(HIV).
24. Subject with any active viral infection that based on the investigator's clinical assessment makes the 
subject an unsuitable candidate for the study.
25. 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.
26. Chronic recurring infections or active TB.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
27. History of moderate to severe congestive heart failure (NYHA class III or IV), recent 
cerebrovascular accident and/or any other condition which would put the subject at risk by 
participation in the study.
28. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
29. 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.
Investigational Products:
Adalimumab
Induction Study: 
Double-Blind Induction 
Doses:
NOTE:  In order to retain 
blinding, all subjects in the 
Standard Induction Dose 
Regimen will receive 
matching placebo injections 
in addition to the adalimumab 
injection at Weeks 1, 2 and 3.
Subjects will be randomized to receive one of 2 double-blind 
adalimumab induction dosing regimens.
Standard Induction Dose Regimen:  160 mg at Week 0 and matching 
placebo at Week 1.  Subjects will receive 80 mg at Week 2 and 
matching placebo at Week 3.  Subjects will receive 40 mg at Week 4 
and Week 6.
Higher Induction Dose Regimen:  160 mg at Weeks 0, 1, 2, and 3.
Subjects will receive 40 mg at Week 4 and Week 6.


Adalimumab
M14-033 Protocol Amendment 3
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Maintenance Study:
Double-Blind Maintenance 
Doses:
Subjects will be re-randomized to receive one of 3 double-blind 
adalimumab maintenance dosing regimens.
Adalimumab 40 mg eow Regimen:  40 mg every other week, starting at 
Week 8 until Week 50.  Matching Placebo will be administered every 
other week, starting at Week 9 until Week 51.  No dose will be 
administered at Week 52.
Adalimumab 40 mg ew Regimen:  40 mg every week, starting at 
Week 8 until Week 51.  No dose will be administered at Week 52.
Adalimumab TDM Regimen:  40 mg eow at Week 8 and Week 10.  
Matching placebo at Week 9 and Week 11.  At Weeks 12, 24 and 37, 
the regimen will be adjusted for subjects meeting specified criteria.  
Subjects receiving 40 mg eow and meeting the regimen adjustment 
criteria will escalate to 40 mg weekly.  Subjects receiving 40 mg ew and 
meeting the regimen adjustment criteria will receive a one-time dose of 
160 mg at the visit, followed by 40 mg ew starting the following week.  
Subjects receiving 40 mg eow who do not meet the regimen adjustment 
criteria will receive adalimumab 40 mg eow and placebo at alternative 
weeks.  No dose will be administered at Week 52.
NOTE:  In order to retain blinding, all subjects in the 40 mg eow and 
40 mg ew regimen groups and subjects who do not meet the criteria for 
dose escalation in the TDM regimen group will receive matching 
placebo injections in addition to the adalimumab injection (placebo 
reinduction) at Weeks 24 and 37.
Mode of Administration:
Subcutaneous injection (SC)
Duration of Treatment:  The overall study treatment duration is 52 weeks (8 weeks of induction 
therapy during the Induction Study followed by 44 weeks of maintenance therapy during the 
Maintenance Study).  There will be a 70-day follow-up phone call for subjects who complete the study 
or discontinue from the study prematurely.  The 70-day follow-up phone call will not be required for any 
subject who initiates commercial adalimumab.
Criteria for Evaluation:
The following analysis is for subjects recruited in the main study.  A separate statistical analysis will be 
performed for subjects recruited in the Japan sub-study and for all subjects recruited in the main study 
and the Japan sub-study.
Efficacy:
For the Induction Study endpoints, the subjects receiving the higher adalimumab induction dose regimen 
will be compared to subjects receiving the standard adalimumab induction dose regimen.  For the 
Maintenance Study endpoints, the subjects receiving the eow regimen will be compared to subjects 
receiving the ew regimen.  The TDM regimen will be used for exploratory analyses.  For the primary 
endpoints, clinical remission or response will be evaluated using Full Mayo Score.  Exploratory analysis 
will also be performed using Full Mayo Score excluding PGA (Adapted Mayo Score) and Full Mayo 
Score excluding Endoscopy Subscore (Partial Mayo Score).


Adalimumab
M14-033 Protocol Amendment 3
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Criteria for Evaluation (Continued):
Efficacy (Continued):
The primary efficacy endpoint for the Induction Study is:

Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with no 
subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:

Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full Mayo 
score of ≥ 3 points and ≥ 30% from Baseline Plus a decrease in the rectal bleeding subscore 
[RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full Mayo score) at 
Week 52.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the Induction Study 
are:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 0 or 1) at 
Week 8.
2.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.
3.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) at Week 8.
4.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
5.
Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
Additional pre-specified endpoints in the Induction Study include but are not limited to the following:

Assessment of the relationship between adalimumab serum concentrations and efficacy during 
the Induction Study

All-cause and UC-related hospitalization and surgery rates during Weeks 0 – 8.

Change from Baseline in histologic score at Week 8.

Proportion of subjects achieving clinical remission per Adapted Mayo Score (defined as stool 
frequency subscore ≤ 1, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1) at Week 8.

Proportion of subjects achieving Full Mayo score, excluding the PGA subscore, ≤ 2 with no 
subscore > 1 at Week 8.

Relationship between histologic scores and endoscopic improvement (endoscopy subscore of 0 
or 1) at Week 8.

Relationship between histologic scores and endoscopic subscore of 0 at Week 8.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the Maintenance 
Study are:
1.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
2.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are steroid 
free for at least 90 days at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are steroid 
free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
4.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission (per Full Mayo 
score) at Week 52.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Criteria for Evaluation (Continued):
Efficacy (Continued):
5.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are steroid-
free for at least 90 days at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are steroid-
free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
8.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response (increase of IBDQ ≥ 16 
from Baseline) at Week 52.
9.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
10. Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
11. Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.
12. Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.  
Additional pre-specified endpoints in the Maintenance Study include but are not limited to the following:  

Assessment of the relationship between adalimumab serum concentrations and efficacy during 
the Maintenance Study by Week 8 response status.

Proportion of Week 8 responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic improvement at 
Week 52.

All cause and UC-related hospitalization and surgery rates during Weeks 8 – 52.

Change from Baseline in histologic score at Week 52.

Proportion of Week 8 responders per Adapted Mayo Score (defined as decrease from Baseline 
in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal 
bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1) achieving clinical remission per Adapted 
Mayo Scores at Week 52.

Proportion of Week 8 responders (per Full Mayo score) achieving Full Mayo score, excluding 
the PGA subscore, ≤ 2 with no subscore > 1 at Week 52.

Relationship between histologic scores and endoscopic improvement (endoscopy subscore of 0 
or 1) at Week 52.

Relationship between histologic scores and endoscopic subscore of 0 at Week 52.

Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are 
steroid free for at least 180 days and in clinical remission (per Full Mayo score) at Week 52.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Criteria for Evaluation (Continued):
Efficacy (Continued):
The following additional pre-specified endpoints will also be analyzed in both the Induction Study and 
the Maintenance Study.

Analysis of the impact of immunogenicity on safety, pharmacokinetics, and efficacy.

Proportion of subjects who are taking corticosteroids at Baseline and are steroid-free over time.

Evaluation of adalimumab concentrations and immunogenicity at the time of loss of clinical 
remission.

Proportion of subjects achieving clinical remission per Partial Mayo (defined as a Partial Mayo 
score ≤ 2 with no subscore > 1) score over time.

Proportion of subjects achieving clinical response per Partial Mayo score (defined as a decrease 
in Partial Mayo score of ≥ 2 points and ≥ 30% from Baseline Plus a decrease in the rectal 
bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) over time.

Change from Baseline in hs-CRP over time.

Change from Baseline in corticosteroid dose over time.

Change from Baseline in IBDQ score over time.

Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores over time.

Change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, hematocrit, 
albumin, total protein concentration, and weight).

Change from Baseline in subject-reported stool frequency (absolute values).

Change from Baseline in work productivity and impairment questionnaire (WPAI) scores over 
time.

Change from Baseline in SF-36 score over time.

Change from Baseline in fecal calprotectin over time.

Time to achievement of remission (per Partial Mayo score).

Time to achievement of response (per Partial Mayo score).

Time to loss of response and factors associated with loss of response.

Change in presence of extraintestinal manifestations over time.
Pharmacokinetics:  
Blood samples will be collected for the measurement of serum adalimumab concentrations just prior to 
dosing at Baseline and Weeks 2, 4, 8, 10, 12, 16, 22, 24, 29, 35, 37, 42, 48, 52 (or at the PD visit if the 
subject discontinues prior to Week 52), and unscheduled visits.  Pre-dosing serum samples for HACAs 
and infliximab concentrations will be collected at Week 0.
Blood samples will be collected for the measurement of AAA just prior to dosing at Baseline and 
Weeks 4, 8, 12, 24, 37, 52 (or at the PD visit if the subject discontinues prior to Week 52), and 
unscheduled visits.
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.


Adalimumab
M14-033 Protocol Amendment 3
EudraCT 2013-001682-16
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Statistical Methods:
The following statistical analysis plan is for subjects recruited in the main study.  A separate statistical 
analysis plan will be provided for subjects recruited in the Japan sub-study and for all the subjects 
recruited in the main study and the Japan sub-study (See Appendix K).
Efficacy:
For the Induction Study, a total of 840 subjects will be allocated to the adalimumab higher induction 
dosing regimen and the adalimumab standard induction dosing regimen in a 3:2 ratio (504 and 
336 subjects in each regimen, respectively).  The sample size for the Induction Study is based on the 
expected proportions of subjects who achieve clinical remission at Week 8.  Assuming the clinical 
remission rate of 35% in the adalimumab higher induction dosing regimen and 20% in the adalimumab 
standard induction dosing regimen at Week 8, this sample size will provide > 95% power to detect a 
difference of 15% between the two treatment groups for the primary endpoint of the Induction Study 
using two-sided Fisher's Exact test at a 0.05 significance level.  The efficacy analysis will be based on 
intent-to-treat analysis set.  The intent-to-treat analysis set includes all randomized subjects who receive 
at least one dose of study drug in the Induction Study 1 (ITT1).  The difference between the higher 
induction dosing regimen group versus the standard induction dosing regimen group in the proportion of 
subjects achieving clinical remission at Week 8 will be assessed using Cochran-Mantel-Haenszel (CMH) 
test adjusted for previous infliximab use and Baseline corticosteroid use.  A CMH based two-sided 95% 
confidence interval for the difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary endpoint data at 
Week 8 will be classified as "no clinical remission" (non-responder imputation [NRI] method) for the 
Week 8 endpoint.  Subjects with missing Mayo score data at Week 8 will be classified as Week 8 non-
responders for the Week 52 Maintenance Study analyses.  As sensitivity analyses, logistic regression 
including treatment, the randomization stratification factors and additional clinically important factors 
such as Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline will also 
be performed for the primary endpoint.  
For the Maintenance Study, the sample size is based on the expected proportions of subjects who 
achieve clinical remission at Week 52.  Assuming the average response rate at Week 8 in the Induction 
Study is 50%, a total of 420 Week 8 responders will be re-randomized to adalimumab 40 mg eow, 
adalimumab 40 mg ew, and TDM regimen in a ratio of 2:2:1; i.e., 168 subjects each in the eow and ew 
groups and 84 subjects in the TDM regimen.  Assuming the Week 52 clinical remission rate of 48% in 
the ew group and 30% in the eow group among Week 8 responders, this sample size will provide 90% 
power to detect a treatment difference of 18% between the two groups using two-sided Fisher's Exact 
test at a 0.05 significance level.  The efficacy analysis will be based on intent-to-treat analysis set.  The 
intent-to-treat analysis set includes all re-randomized subjects who receive at least one dose of study 
drug in the Maintenance Study (ITT2).  The difference between the adalimumab eow regimen versus the 
adalimumab ew regimen in the proportion of subjects achieving clinical remission at Week 52 among 
Week 8 responders will be assessed using Cochran-Mantel-Haenszel (CMH) test adjusted for the 
induction treatment regimen dosing and remitter status at Week 8 (per Full Mayo score utilizing the 
Week 8 endoscopy subscore provided by the site).  A CMH based two-sided 95% confidence interval for 
the difference between treatment groups will be calculated.  Breslow-Day test for homogeneity of odds 
ratios will be performed as well.  Subjects with missing primary endpoint data at Week 52 will be 
classified as "no clinical remission" (non-responder imputation [NRI] method) for the Week 52 
endpoint.


Adalimumab
M14-033 Protocol Amendment 3
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Statistical Methods (Continued):
Efficacy (Continued): 
As sensitivity analyses, logistic regression including treatment, the randomization stratification factors 
and additional clinically important factors such as Immunosuppressant use at Baseline, Baseline hs-CRP, 
and disease severity at Baseline will also be performed for the primary endpoint.
The secondary efficacy variables of the Induction Study and the Maintenance Study are divided into 
two groups.  The first group includes ranked secondary endpoints, which are ranked by clinical 
importance.  Statistical significance is assessed at an alpha level of 0.050 (two-sided) in ranked endpoint 
order until the significant level exceeds 0.05.  No additional statistically significant treatment differences 
could be declared if the preceding ranked endpoint fails to achieve 0.05.  The second group includes all 
other additional secondary variables.  For the Induction Study Week 8 endpoints, the difference between 
the higher adalimumab induction dosing regimen versus the standard adalimumab induction dosing 
regimen will be assessed using ITT1 analysis set.  For the Maintenance Study Week 52 endpoints, the 
difference between the eow group versus the ew group will be assessed using ITT2 analysis set.  
Categorical data will be described by frequency and percentage; continuous data will be described by 
mean, standard deviation, minimum, median, and maximum.  In general, the secondary endpoints at 
Week 8 for the Induction Study that are of the binary type will be analyzed using a two-sided CMH test 
adjusted for previous infliximab use and Baseline corticosteroid use using the ITT1 analysis set, and the 
secondary endpoints at Week 52 for the Maintenance Study that are of the binary type will be analyzed 
using a two-sided CMH test adjusted for induction treatment regimen and remitter status (per Full Mayo 
score) at Week 8 (where applicable) using the ITT2 analysis set.  Additionally, the two-sided 95% 
confidence interval for the difference in proportions will be provided.  Continuous secondary efficacy 
variables will be analyzed using Analysis of Covariance (ANCOVA) with factor for treatment group, 
stratification variables and Baseline values.  NRI for missing data will be used for categorical endpoints.  
Procedures for handling missing data for continuous endpoints will be described in the Statistical 
Analysis Plan.
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 positivity 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 for both Induction and Maintenance Studies using the safety 
analysis set, which includes all subjects who receive at least one dose of study medication in each Study, 
respectively.  Treatment-emergent adverse events will be tabulated by system organ class and by 
MedDRA preferred term by treatment group for the Induction Study and the Maintenance Study, and for 
any adalimumab over the entire study.  Mean changes in vital signs, physical examination results, ECGs, 
and clinical laboratory values will be analyzed.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
AAA
Anti-adalimumab Antibody
ADA
Adalimumab
AE
Adverse event
ALT
Alanine Transaminase
ANA
Antinuclear Antibody
AST
Aspartate Transaminase
BCG
Bacillus Calmette-Guérin
BUN
Blood Urea Nitrogen
CD
Crohn's Disease
CDC
Centers for Disease Control and Prevention
CMH
Cochran-Mantel-Haenszel
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
DNA
Deoxyribonucleic Acid
dsDNA
Double-stranded DNA
EC 
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
EIMs
Extra-Intestinal Manifestations
eow
every other week
ew
every week
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HACA
Human Antichimeric Antibody
HBs Ab
Hepatitis B surface antibodies
HBs Ag
Hepatitis B surface antigen
HBc Ab
Hepatitis B core antibodies
HBV
Hepatitis B Virus


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hs-CRP
high-sensitivity C-Reactive Protein
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
I-ITT1
Integrated Intent-To-Treat Induction Study
I-ITT2
Integrated Intent-To Treat Maintenance Study
IM
Intramuscular
IRB
Institutional Review Board
ITT1
Intent-To-Treat Induction Study
ITT2
Intent-to-Treat Maintenance Study
IRT
Interactive Response System
J-ITT1
Japan Integrated Intent-To-Treat Induction Study
J-ITT2
Japan Integrated Intent-To-Treat Maintenance Study
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTX
Methotrexate
PGA
Physician's Global Assessment
PA
Posteroanterior
PBO
Placebo
PD
Premature Discontinuation
PG
Pharmacogenetic
PK
Pharmacokinetics
POR
Proof of Receipt
PML
Progressive Multifocal Leukoencephalopathy
PMS
Partial Mayo Score
PPD
Purified Protein Derivative
RBS
Rectal Bleeding Subscore
SAE
Serious Adverse Event
SFS
Stool Frequency Subscore
SC
Subcutaneous
SDP
Study Designated Physician
TDM
Therapeutic Drug Monitoring
TB
Tuberculosis


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TNF
Tumor Necrosis Factor
TPN
Total Parenteral Nutrition
UC
Ulcerative Colitis
WPAI
Work Productivity and Impairment Questionnaire
Definition of Terms
Adapted Mayo Score
Full Mayo Score minus the Physician's Global Assessment (PGA)
Remission per Adapted Mayo Score
An Adapted Mayo Score ≤ 2, with stool frequency subscore ≤ 1, 
rectal bleeding subscore of 0, and endoscopic subscore ≤ 1
Remission per Full Mayo Score
A Full Mayo score ≤ 2 with no subscore > 1 
Remission per Partial Mayo Score
A Partial Mayo score ≤ 2 with no subscore > 1
Response per Adapted Mayo Score
A decrease in the Adapted Mayo Score ≥ 2 points and ≥ 30% 
from baseline, PLUS a decrease in rectal bleeding subscore 
(RBS) ≥ 1 or an absolute RBS ≤ 1
Response per Full Mayo Score
A decrease in Full Mayo score of ≥ 3 points and ≥30% from 
Baseline PLUS a decrease in the rectal bleeding subscore [RBS] 
≥ 1 or an absolute RBS of 0 or 1
Response per Partial Mayo Score
A decrease in Partial Mayo score ≥ 2 points and ≥30% from 
Baseline PLUS a decrease in the RBS ≥1 or an absolute RBS of 
0 or 1
IBDQ Response
An increase of ≥ 16 points from Baseline in total Inflammatory 
Bowel Disease Questionnaire (IBDQ) score
Endoscopic Improvement
Endoscopy subscore of 0 or 1


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis ...................................................................................................10
1.3
List of Abbreviations and Definition of Terms........................................26
2.0
Table of Contents...................................................................29
3.0
Introduction ...........................................................................34
3.1
Differences Statement..............................................................................36
3.2
Benefits and Risks....................................................................................37
3.3
Adalimumab Overview............................................................................37
3.4
Safety Information ...................................................................................38
4.0
Study Objective......................................................................39
5.0
Investigational Plan...............................................................39
5.1
Overall Study Design and Plan:  Description ..........................................39
5.2
Selection of Study Population..................................................................47
5.2.1
Inclusion Criteria .....................................................................................47
5.2.2
Exclusion Criteria ....................................................................................50
5.2.3
Prior and Concomitant Therapy...............................................................55
5.2.3.1
Prior Therapy ...........................................................................................55
5.2.3.2
Concomitant Therapy...............................................................................56
5.2.3.3
Prohibited Therapy...................................................................................58
5.3
Efficacy, Pharmacokinetic, and Safety Assessments/Variables ..............59
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................59
5.3.1.1
Study Procedures .....................................................................................66
5.3.1.2
Blood Sample for Pharmacogenetic Analysis..........................................83
5.3.1.3
Blood Samples for Biomarker Analysis...................................................83
5.3.2
Drug Concentration Measurements .........................................................84
5.3.2.1
Collection of Samples for Analysis .........................................................84
5.3.2.2
Handling/Processing of Samples .............................................................85
5.3.2.3
Disposition of Samples ............................................................................86
5.3.2.4
Measurement Methods.............................................................................86
5.3.3
Efficacy Variables....................................................................................86


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5.3.3.1
Primary Variables ....................................................................................86
5.3.3.2
Secondary Variables ................................................................................86
5.3.3.3
Additional Variables ................................................................................88
5.3.3.4
Safety Variables .......................................................................................91
5.3.4
Pharmacokinetic Variables ......................................................................91
5.3.5
Pharmacogenetic and Serologic Variables...............................................91
5.3.5.1
Pharmacogenetic Variables......................................................................91
5.3.5.2
Serologic Variables..................................................................................92
5.4
Removal of Subjects from Therapy or Assessment .................................92
5.4.1
Discontinuation of Individual Subjects....................................................92
5.4.2
Discontinuation of Entire Study...............................................................94
5.5
Treatments................................................................................................94
5.5.1
Treatments Administered.........................................................................94
5.5.2
Identity of Investigational Products .........................................................96
5.5.2.1
Packaging and Labeling...........................................................................97
5.5.2.2
Storage and Disposition of Study Drug(s)...............................................97
5.5.3
Method of Assigning Subjects to Treatment Regimens ..........................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 Regimens .............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 ...........................................................................104
6.1
Medical Complaints...............................................................................104
6.1.1
Definitions..............................................................................................105
6.1.1.1
Adverse Event........................................................................................105
6.1.1.2
Serious Adverse Events .........................................................................105
6.1.2
Adverse Event Severity..........................................................................107


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6.1.3
Relationship to Study Drug....................................................................107
6.1.4
Adverse Event Collection Period...........................................................108
6.1.5
Adverse Event Reporting.......................................................................109
6.1.6
Pregnancy...............................................................................................110
6.1.7
Toxicity Management ............................................................................111
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
Analysis Population ...............................................................................114
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 Variables....................................................................115
8.1.4.2
Secondary Efficacy Variables................................................................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 .....................................................................118
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 .................................................................122
9.3
Subject Information and Consent...........................................................122
10.0
Source Documents and Case Report Form 
Completion ...........................................................................123
10.1
Source Documents .................................................................................123
10.2
Case Report Forms.................................................................................123


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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...............................................................127
13.0
Completion of the Study .....................................................128
14.0
Investigator's Agreement....................................................130
15.0
Reference List ......................................................................131
List of Tables
Table 1.
TDM Dose Adjustment Criteria...............................................................46
Table 2.
Study Activities........................................................................................60
Table 3.
Clinical Laboratory Tests.........................................................................76
Table 4.
Study Drugs .............................................................................................97
List of Figures
Figure 1.
Study Schematic.......................................................................................41
Figure 2.
8-Week Double-Blind Induction Study ...................................................43
Figure 3.
Drug Monitoring (TDM) Regimen ..........................................................45
Figure 4.
Adverse Event Collection ......................................................................108
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................133
Appendix B.
List of Protocol Signatories....................................................................135
Appendix C.
Script for Collection of Mayo Scores for Use in Study M14-033 .........136
Appendix D.
Sample WPAI Work Productivity and Activity Impairment 
Questionnaire:  Ulcerative Colitis V2.0 (WPAI:UC) ............................140
Appendix E.
Sample Injection Instructions – Pre-Filled Syringe ...............................142
Appendix F.
Sample Quality of Life in Inflammatory Bowel Disease 
Questionnaire (IBDQ)............................................................................149
Appendix G.
Sample SF-36 v2 Acute, US Version 2.0...............................................167


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Appendix H.
Guidelines to Evaluate Loss of Response and Intolerance to 
Infliximab...............................................................................................173
Appendix I.
Sample Bristol Stool Chart ....................................................................174
Appendix J.
70-Day Follow-Up Phone Call – Sample ..............................................175
Appendix K.
Japan Sub-Study.....................................................................................177
Appendix L.
Protocol Amendment:  List of Changes.................................................208


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3.0
Introduction
Ulcerative colitis (UC) is one of the two primary forms of idiopathic inflammatory bowel 
disease.  It is postulated that UC is caused by unregulated and exaggerated local immune 
response to environmental triggers in genetically susceptible individuals.1  UC is a chronic, 
relapsing inflammatory disease of the large intestine characterized by inflammation and 
ulceration of the mucosal and submucosal intestinal layers.  The incidence in North 
America is estimated at 2.2 to 14.3 cases per 100,000 person-years with a prevalence of 
37 to 246 cases per 100,000 persons.2  The burden of UC on the healthcare system is 
profound, accounting for nearly 500,000 physician visits and more than 
46,000 hospitalizations per year in the United States (US) alone.3
The hallmark clinical symptoms include bloody diarrhea associated with rectal urgency 
and tenesmus.  The clinical course is marked by exacerbation and remission.  The 
diagnosis of UC is suspected on clinical grounds and supported by diagnostic testing, and 
elimination of infectious causes.4
The most severe intestinal manifestations of UC are toxic megacolon and perforation.  
Extraintestinal complications include arthritis (sacroiliitis and ankylosing spondylitis), 
dermatological conditions (erythema nodosum, aphthous stomatitis, and pyoderma 
gangrenosum), inflammation of the eye (uveitis), and liver dysfunction (primary 
sclerosing cholangitis).  Patients with UC are at an increased risk for colon cancer, and the 
risk increases with the duration of disease as well as extent of colon affected by the 
disease.5
The aim of medical treatment in UC is to control inflammation and reduce symptoms.  
Available pharmaceutical therapies are limited, do not always completely abate the 
inflammatory process, and have significant adverse effects.  Therapies for mildly to 
moderately active UC include 5-aminosalicylic acid (5-ASA) derivatives and 
immunosuppressants.  Corticosteroids are used in patients with more severe symptoms but 
are not useful for longer term therapy.6  The frequency and severity of corticosteroid 
toxicities are significant, including infections, emotional and psychiatric disturbances, 


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skin injury, and metabolic bone disease.  Corticosteroids are not effective for the 
maintenance of remission and the UC practice guidelines from the American College of 
Gastroenterology recommend against chronic steroid treatment.7
Patients with moderate to severe symptoms may derive some benefits from 
immunomodulatory agents (azathioprine [AZA], 6-mercaptopurine [6-MP] or 
methotrexate [MTX]); however, the use of these agents is limited by slow onset of action 
(3 to 6 months) and adverse events (AEs), including bone marrow suppression, infections, 
hepatotoxicity, pancreatitis, and malignancies.7,8  Removal of the colon/rectum can 
eliminate the source of the inflammatory process but may be accompanied by significant 
morbidity.
The safety and efficacy of adalimumab for the induction and maintenance of clinical 
remission in adult subjects with moderately to severely active UC has been studied in 
two completed clinical trials (Study M06-826 and Study M06-827) and an ongoing 
open-label study (Study M10-223).9-11  In addition, adalimumab was associated with 
statistically significant and clinically relevant results in multiple other endpoints, 
including response, endoscopic improvement, and improvements in Inflammatory Bowel 
Disease Questionnaire (IBDQ) scores compared to placebo for up to 52 weeks in these 
subjects.11
The purpose of this study is to evaluate a higher induction and maintenance regimen, 
including an exploratory dosing regimen evaluating a therapeutic drug monitoring 
strategy, than the standard approved adalimumab induction regimen (160 mg at Week 0 
and 80 mg at Week 2, followed by 40 mg every other week [eow] beginning at Week 4) 
for induction and maintenance therapy in adult patients with moderately to severely active 
ulcerative colitis.  This study is designed to fulfill the following two post-marketing 
requirements (PMR) that were part of the US approval of adalimumab in adult patients 
with UC:


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●
PMR 5:  Conduct a trial in moderately to severely active ulcerative colitis 
patients to evaluate the safety of induction regimens of adalimumab at doses 
higher than 160/80 mg.  In this trial, the efficacy of Humira (adalimumab) 
should also be assessed, both during induction treatment as well as during 
continued treatment after induction, and pharmacokinetic measurements 
should be conducted for exposure-response analysis.  In this trial, collecting 
samples for immunogenicity testing (utilizing a validated anti-adalimumab 
antibody assay as described in PMR 3 above) and conducting analyses of the 
impact of immunogenicity on safety, pharmacokinetics, and efficacy is 
important.  The protocol should be agreed upon by the agency prior to the 
initiation of the trial.
●
PMR 6:  A safety and pharmacokinetic trial as a sub-study of the trial 
described in PMR 5 above to evaluate trough concentrations of adalimumab 
and antibody levels (utilizing a validated anti-adalimumab antibody assay as 
described in PMR 3 above) at the time of loss of clinical remission in patients 
whose physicians plan to escalate the dose (e.g., decrease the dosing interval 
to weekly or increase the dosage) in response to loss of remission.  Trough 
concentrations will be evaluated to determine whether patients who have low 
adalimumab exposures benefit from dose escalation without increasing risk of 
serious adverse events.  The protocol should be agreed upon by the agency 
prior to initiation of the trial.
This study is constructed of a main study and a Japan sub-study.  Both the main study and 
Japan sub-study include an Induction Study and a Maintenance Study.  The protocol 
indicates the method for the main study and is to be followed for the Japan sub-study 
except as indicated in Appendix K.
3.1
Differences Statement
The differences between Study M14-033 and the other UC studies (Study M06-826 and 
Study M06-827), are the inclusion of a higher induction dose, a higher maintenance dose 
(weekly dosing) and an adjustable dosing regimen based on therapeutic drug monitoring 
during the Maintenance Study, which will allow for a greater range of exposure and 
ultimately provide greater precision around adalimumab dosing/exposure and 


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efficacy/safety relationships in subjects with moderately to severely active ulcerative 
colitis.  The pharmacokinetic profile of adalimumab during Induction and Maintenance 
Studies and its relationship to efficacy in adult subjects with moderately to severely active 
ulcerative colitis will be characterized.
In addition, the methodology differs from the registration trials in that the endoscopy was 
not read centrally in the registration trials, and Study M06-827 included 40% of subjects 
previously treated with an anti-tumor necrosis factor (TNF) agent compared to a 
maximum of 25% in the present trial.
3.2
Benefits and Risks
Extensive clinical and postmarketing experience exists with adalimumab in a wide range 
of disease states, including Crohn's disease and 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 UC have not altered this safety 
profile and demonstrated a positive benefit/risk balance.  Conditions which may present a 
risk specifically for patients with UC 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 1330 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 TNF, and human IgG1 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 


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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 
in 2002 and 2003, respectively, and subsequently by the Pharmaceuticals and Medical 
Devices Agency in Japan in 2008.  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 the EU, 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 based on 
extensive postmarketing experience and continued clinical trial subject 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-wide exploration of the rare appearance of malignancy in subjects who are 30 years 
old 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 


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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 study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, double-blind, randomized, multicenter study of higher versus standard 
adalimumab dosing regimens for induction and maintenance therapy in subjects with 
moderately to severely active UC (Mayo Score of 6 to 12 points with an endoscopy 
subscore of 2 or 3, confirmed by a central reader).  For all Mayo Score evaluations 
throughout the study, the stool frequency and the rectal bleeding subscore will be 
calculated according to Appendix C.
The study was designed to enroll 840 subjects in the main study (504 subjects in the 
higher induction dose regimen and 336 subjects in the standard induction dose regimen) at 
approximately 125 sites worldwide to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  There 
also will be 100 Japanese subjects (60 subjects in the higher induction dose regimen and 
40 subjects in the standard induction dose regimen) in a Japan sub-study to be enrolled at 
21 Japan sites.  The Japan sub-study will be conducted utilizing the same design as 
outlined in the main study with the exceptions that are outlined in Appendix K.  If the 
target number of subjects has been enrolled, there is a possibility that additional subjects 
in screening will not be enrolled.
This study will include:
●
A 3-Week Screening Period


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●
An 8-Week Double-Blind Induction Study
●
A 44-Week Double-Blind Maintenance Study
●
A 70-Day Follow-Up Period
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 8 will represent the final 
assessment in the Induction Study and the beginning of the Maintenance Study.  Week 52 
will represent the final assessment in the Maintenance Study (representing 44 weeks of 
maintenance treatment in the Maintenance Study).  A subject's participation in the study is 
anticipated to be up to 65 weeks.  There is a ± 3-day window for all study visits.  An 
effort will be made to bring subjects back to their original scheduled visit (calculated from 
Baseline) if they are out of the visit window.
Study visits for clinical and safety assessments will be performed at Baseline (Week 0), 
Weeks 1, 2, 4, 8, 10, 12, 16, 22, 24, 29, 35, 37, 42, 48 and 52/PD.  All subjects will be 
provided with a subject diary at Screening where they will record ulcerative colitis-related 
symptoms (stool frequency, abdominal discomfort, number of bloody stools, fecal 
urgency, and general well-being), use of anti-diarrheals, use of medications for endoscopy 
preparation, and study drug dosing information) throughout the study.  Blood samples will 
be collected for high-sensitivity C-reactive protein (hs-CRP), adalimumab serum 
concentrations, anti-adalimumab antibody (AAA) levels, and other biomarker analyses as 
indicated in Table 2.  In addition, stool samples for calprotectin, and microbiota 
metagenomic analyses will be collected.  The stool samples should be taken before 
starting bowel preparations for endoscopy. Subjects will undergo an endoscopy 
(colonoscopy or flexible sigmoidoscopy) with biopsy for histologic assessment during 
Screening, at Week 8 and Week 52/PD (for subjects who remain in the study through at 
least Week 24), with local investigator assessment for Mayo endoscopic subscore 
confirmed by a central reader.  Subjects who consent to participate in the optional 
pharmacogenetic (PG) analysis should have an additional blood sample drawn at Baseline 


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and at Week 52/PD.  If the sample is not collected at Baseline, it should be collected at the 
next study visit.
A schematic of the study design is presented in Figure 1.
Figure 1.
Study Schematic
Screening Period
The Screening Period begins at the Screening Visit and continues through to Baseline 
Visit (Week 0).  Screening Assessments will include medical history, physical 
examination, chest x-ray, endoscopy (colonoscopy or flexible sigmoidoscopy), 
electrocardiogram (ECG), diary review and laboratory results including pregnancy testing, 
all of which will be reviewed by the study site to confirm selection criteria are met prior to 
enrolling the subject.
Subjects who meet all eligibility criteria during the Screening Period (refer to 
Section 5.2.1) will enter the 8-Week Double-Blind Induction Study.  The length of time 
between screening and the 8-Week Double-Blind Induction Study Baseline Visit must 
allow time for endoscopy central reading and lab results.  The Screening period


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(1 – 3 weeks, ±3 days is granted around all study visits) 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).
Subjects who initially screen fail for the study may be permitted to re-screen following 
re-consent.  There is no minimum period of time a subject must wait to re-screen for the 
study.  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.  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, and 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.  An endoscopy 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 
30 days have passed between the endoscopy date and the rescreening date.  All other 
screening procedures will be repeated.  As appropriate, sites should contact the AbbVie 
SDP to confirm if subjects may be re-screened.
8-Week Double-Blind Induction Study
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the 8-Week Induction Study.  In both the main study and the Japan sub-study 
populations, up to 25% of subjects with previous infliximab exposure may be enrolled.
Subjects will be randomized via interactive response system (IRT) at Baseline (Week 0) 
to one of 2 double-blinded adalimumab induction regimens (higher dose or standard dose) 
in a 3:2 ratio.  Use of the 3:2 randomization scheme allows for collection of additional 
safety data with the higher induction dose regimen.  The randomization will be stratified 
by:
●
Previous infliximab use


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and
●
Baseline corticosteroid use.
The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg 
at Weeks 4 and 6 leads to a total adalimumab dose over 8 weeks that is approximately 
twice that of the standard induction regimen (720 mg versus 320 mg) as shown in 
Figure 2 below.
Figure 2.
8-Week Double-Blind Induction Study
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit as outlined in Section 5.3.1.1.
At Week 4, all subjects who are on oral corticosteroids from Baseline will have their 
corticosteroid dose tapered according to the proposed tapering schedule outlined in the 
protocol.  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.


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44-Week Double-Blind Maintenance Study
At the conclusion of the 8-Week Double-Blind Induction Study, subjects will return to the 
study site and will be re-randomized via IRT into the 44-Week Double-Blind 
Maintenance Study to one of three treatment groups in a 2:2:1 ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
●
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory).  See 
Figure 3.  (The Japan sub-study does not have a TDM regimen.  Subjects will 
be randomized into Adalimumab 40 mg eow treatment group or Adalimumab 
40 mg ew treatment group in a 1:1 ratio.)
At Week 8, subjects will be re-stratified by:
●
Treatment regimen in the Induction Study
and
●
Response status (per Full Mayo score utilizing the Week 8 endoscopy subscore 
provided by the site) at Week 8.  Among the responders at Week 8, the re-
randomization will be further stratified by remission status (per Full Mayo 
score utilizing the Week 8 endoscopy subscore provided by the site) 
determined at Week 8.


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Figure 3.
Drug Monitoring (TDM) Regimen
Subjects in the adalimumab 40 mg eow treatment group will continue to receive 40 mg 
eow until the end of the study.  Subjects in the adalimumab 40 mg ew treatment group 
will start 40 mg ew at Week 8 until the end of the study.
All subjects in the TDM regimen will receive 40 mg eow at Week 8 and Week 10, and 
may have their adalimumab dose adjusted at Weeks 12, 24, and 37 based on criteria 
assessing blinded adalimumab serum concentration at the prior visit (Weeks 10, 22, and 
35, respectively, Table 1) and rectal bleeding subscore (RBS) at the prior and current 
visits as follows:
●
Subjects receiving 40 mg eow and meeting the regimen adjustment criteria will 
escalate to 40 mg weekly.


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●
Subjects receiving 40 mg ew and meeting the regimen adjustment criteria will 
receive a one-time dose of 160 mg at the visit, followed by 40 mg ew starting 
the following week.
Table 1.
TDM Dose Adjustment Criteria
TDM Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/mL to 20 µg/mL
< 1
No
10 µg/mL to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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 SDP.
b.
Measured from the adalimumab serum concentration taken at the prior study visit.
c.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for the 
Rectal Bleeding subscore for each study visit, Appendix C.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose of 
160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing groups.
Throughout the study, subjects will only be allowed to change the dosage of UC-specific 
concomitant medications as specified in Section 5.2.3.2.
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit as outlined in Section 5.3.1.1.  Site staff to ensure all data needed to complete 
Weeks 12, 24 and 37 is available prior to the subject arriving at the site.  Notify the 
Clinical Research Associate (CRA) should any needed reports be missing.  No study drug 
will be administered or injected at the final visit.
70-Day Follow-Up/Premature Discontinuation
Subjects may discontinue adalimumab treatment at any time during study participation 
(Section 5.4).  Subjects who end study participation early will have a premature 
discontinuation (PD) Visit.  All subjects will have a follow-up phone call approximately 
70 days after the last administration of study drug to obtain information on any new or 


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ongoing AEs.  The 70-day follow-up phone call will not be required for any subject who 
initiates commercial adalimumab.
5.2
Selection of Study Population
Eight hundred and forty (840) subjects will be enrolled at up to 125 sites in the Main 
Study.
An additional 100 subjects will be enrolled at approximately 21 sites in Japan as part of a 
separate Japan sub-study outlined in Appendix K.
Adult male and female subjects who meet all of the inclusion criteria specified in 
Section 5.2.1 and none of the exclusion criteria specified in Section 5.2.2 of the protocol 
are eligible to be enrolled into the study.
5.2.1
Inclusion Criteria
1.
Subject must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol.
2.
Male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3.
Subject with a diagnosis of Ulcerative Colitis for 90 days or greater prior to 
Baseline, confirmed by endoscopy (colonoscopy or flexible sigmoidoscopy) during 
the Screening Period with exclusion of current infection, dysplasia and/or 
malignancy.  Appropriate documentation of biopsy results consistent with the 
diagnosis of UC, in the assessment of the Investigator, must be available.
4.
Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to 
3 (confirmed by central reader) 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 or immunosuppressants as defined below):
●
Subject taking oral corticosteroids, excluding budesonide or beclomethasone:
○
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);


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●
For subject 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 subject 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 subject 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 subject 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.
●
Subject taking oral beclomethasone:
○
Dose must not exceed 5 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.
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 


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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.
5.
Subject may be included if they have previously experienced a benefit for their UC 
from infliximab and discontinued its use due to a subsequent loss of response
(i.e., judged by the Investigator to have responded to infliximab in the past and 
subsequently experienced an overall lack of improvement or worsening of UC 
related symptoms) or intolerance (i.e., in the opinion of the investigator therapy 
was discontinued as a result of a significant acute or delayed 
infusion/administration reaction to the medication).  Confirmed documentation 
indicating loss or response or lack of tolerability will be required, see Section 10.1
and Appendix H.
6.
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 and 
correctly are (see local informed consent for more detail):
●
Implants, injectables, some  intrauterine devices (IUDs), intrauterine 
hormone-releasing system (IUS);
●
Sexual abstinence (when in line with preferred and usual lifestyle of the 
subject);
●
A vasectomized partner;


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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.
7.
If female, subject is not breast-feeding throughout the study and for 150 days after 
last dose.
8.
Subject has a negative TB Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 2 weeks 
(or per local guidelines, whichever is longer) of an ongoing TB prophylaxis or have 
documented completion of a full course of TB prophylaxis, prior to Baseline (see 
Section 5.3.1.1).
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, chest x-ray, and a 12-lead ECG performed during Screening.
10.
Subject must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections.
Rationale for the Inclusion Criteria
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 diagnosis and/or history of Crohn's disease (CD) or diagnosis of 
indeterminate colitis (IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the 
screening endoscopy.


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4.
Received therapeutic enema or suppository, other than required for endoscopy, 
within 7 days prior to the Screening endoscopy and during the remainder of the 
Screening Period.
5.
History of subtotal colectomy with ileorectostomy or colectomy with ileoanal 
pouch, Kock pouch, or ileostomy or is planning bowel surgery.
6.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior 
to Baseline.
7.
Positive pregnancy test at Screening (serum) or Baseline (urine).
8.
Female who is breast-feeding or considering becoming pregnant during the study.
9.
History of clinically significant drug or alcohol abuse in the last 12 months.
10.
Subject on azathioprine, 6-MP, 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.
11.
Subject on oral aminosalicylates who:
●
Has not been on stable doses of these medications for at least 14 days prior to 
Baseline; or
●
Has discontinued use of aminosalicylates within 14 days of Baseline.
12.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on 
oral budesonide > 9 mg/day; or subject on oral beclomethasone > 5 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 of at least 
14 days in duration prior to Baseline; or


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○
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 oral 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 of at least 
14 days in duration 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 has not been a current steroid course of at least 
14 days in duration prior to Baseline; or
●
Subject taking oral beclomethasone:
○
has not been on a stable dose for at least 7 days prior to Baseline; or
●
but has not been on a current steroid course of at least 14 days in 
duration prior to Baseline; or
Has been taking, both oral budesonide (or oral beclomethasone) and oral prednisone 
(or equivalent) simultaneously.
and/or
Has discontinued use of corticosteroids within 14 days of Baseline.
13.
Received intravenous corticosteroids within 14 days prior to Screening or during 
the Screening Period.
14.
Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening 
Period.
15.
Currently receiving total parenteral nutrition (TPN).


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16.
Subject who received any investigational agent or procedure (including previous 
fecal microbial transplantation) within 30 days or 5 half-lives prior to Week 0 
(Baseline), whichever is longer.
17.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the 
Baseline Visit.
18.
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.
19.
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®]) or 
previous participation in an adalimumab clinical study.  Prior exposure to any 
anti-TNF agent other than infliximab (including but not limited to adalimumab 
[Humira®], etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or 
vedolizumab (Entyvio®).
20.
Subject with known hypersensitivity to the excipients of adalimumab as stated in 
the prescribing information.
21.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
22.
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.  If the 


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Screening endoscopy shows evidence of current dysplasia or malignancy, subject 
may not be enrolled in the study.
23.
History of invasive infection (e.g., listeriosis and histoplasmosis), human 
immunodeficiency virus (HIV).
24.
Subject with any active viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study.
25.
Subjects with a positive result for 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.
26.
Chronic recurring infections or active TB.
27.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and/or any other condition which would put the
subject at risk by participation in the study.
28.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
29.
Screening laboratory and other analyses show any of the following abnormal 
results:


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●
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.
Rationale for the Exclusion Criteria
Criteria
Rationale
1, 2, 3, 5
To avoid medical conditions that may compromise the ability to identify subjects with 
the correct diagnosis or to interpret medical importance of clinical results.
7, 8, 14, 17, 
21 – 27, 29
To reduce the risk to subjects or others and/or to exclude underlying conditions that 
would compromise the subject's safety.
28
To maintain the integrity of other aspects of study conduct, including, subject sampling, 
treatment procedures, etc.
4, 6, 10 – 13, 
15 – 16, 19
To avoid bias for the evaluation of efficacy and safety by concomitant or prior use of 
other medications or treatments.
9, 18, 20
To exclude subjects who maybe at increased risk for protocol non-adherence or 
premature discontinue.
5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any non-UC related medication or vaccine (including over-the-counter or prescription 
medicines, vitamins and herbal supplements) that the subject is receiving within 30 days 
prior to Baseline, is receiving at the time of Enrollment, and/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).
UC-specific medications (including but not limited to oral corticosteroids, oral or rectal 
aminosalicylates, and immunosuppressant agents) that the subject has received within 
90 days of Baseline should be recorded on the appropriate page of the eCRF and should 


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include the dates of administration and dosages.  Antibiotics taken for any reason 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 (within the past 1 year) or were intolerant (within the past 5 years) to treatment 
with oral corticosteroids, or immunosuppressants will have the last dosage, dates of 
administration, maximum dose, and reasons for discontinuation recorded in appropriate 
eCRF.
If subjects have/had ever been treated with azathioprine, 6-MP, or methotrexate, the 
duration of therapy, maximum dose, reason for use and reason(s) for termination of 
treatment will be recorded in appropriated eCRF.  For subjects previously treated with 
infliximab, the infliximab history will be recorded, including the duration of therapy, 
maximum dose, reason for use and reason(s) for termination of treatment.  The AbbVie 
SDP identified in Section 6.1.5 should be contacted if there are any questions regarding 
concomitant or prior therapies.
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 labels 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.
5.2.3.2
Concomitant Therapy
Doses of immunosuppressants (including but not limited to azathioprine, 6-MP, and 
MTX) and aminosalicylates taken at Baseline will be continued.  Doses must remain 
stable from Baseline throughout the duration of the study.  Doses may be decreased or 


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terminated in the event of moderate-to-severe treatment-related toxicities (e.g., leukopenia 
or elevated liver enzymes) in the opinion of the investigator.
Doses of oral corticosteroids taken at Baseline (as outlined in inclusion criterion 4 in 
Section 5.2.1) will be continued.  Subjects may not be on both oral budesonide (or oral 
beclomethasone) and oral prednisone (or equivalent) simultaneously.  Subjects may not 
change the corticosteroid 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 oral corticosteroid therapy at 
Baseline will have their corticosteroid therapy tapered according to the proposed tapering 
schedule specified 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.
●
For steroids other than budesonide, a reduction of 5 mg prednisone (or
equivalent) per day for doses > 10 mg/day of prednisone (or equivalent) every 
week until a 10 mg/day (or equivalent) dose is reached, then a weekly decrease 
by 2.5 mg (or equivalent) per day until discontinuation.
●
For budesonide, a weekly decrease by 3 mg/day of budesonide until
discontinuation.
●
For beclomethasone, discontinue.
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.


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Subjects in whom the following UC-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.
Subjects who enter the study on probiotics may continue this therapy provided doses 
remain stable from Baseline throughout the duration of the study.
Changes in all concomitant medications will be assessed at each study visit from Baseline 
(Week 0) through Week 52/PD Visits.  Any changes will be documented in the source 
documents and captured on the appropriate eCRF page.
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®);
○
Infliximab (Remicade®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Efalizumab (Raptiva®);
○
Golimumab (Simponi®);
○
Certolizumab pegol (Cimzia®);
○
Ustekinumab (Stelara®);


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○
Belimumab (Benlysta®);
○
Vedolizumab (Entyvio®).
●
Live vaccines (during the study and for 70 days after the last dose of study 
drug).
●
Cyclosporine, tacrolimus, or mycophenolate mofetil (within 30 days prior to 
Baseline and during the study).
●
Tofacitinib (Xeljanz®).
●
Recreational or medical marijuana use 14 days 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 7 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 or investigational procedures 
(including previous fecal microbial transplantation)  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 SDP 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 into the study.


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Table 2.
Study Activities
Screening 
Period 
(21 days)
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Informed Consent
X
Inclusion/Exclusion
X
Xb
Medical/Surgical History
X
Xb
Previous and 
Concomitant Medication
X
Xb
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
X
Schedule Endoscopy
X
X
X
Endoscopy/Biopsyd
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/Hematologyi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisi,j
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
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Pregnancy Testk
X
X
X
Hepatitis B Screen, HIVl
X
hs-CRP
X
X
X
X
X
X
X
X
X
X
X
C. difficile Toxin
X
Provide Stool Kit m
X
X
X
X
X
X
X
Stool Sample (Fecal 
Calprotectin)m
X
X
X
X
X
X
X
Stool Sample (Microbiota 
Metagenomic Analysis)m
X
X
X
X
X
Bristol Stool Chart m
X
X
X
X
X
Antinuclear antibody 
(ANA)/ 
Anti-Double-Stranded 
DNA (anti-dsDNA)n
X
Human Antichimeric 
Antibodies (HACA)/ 
Infliximab Concentrations
X


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Table 2.
Study Activities (Continued)
Screening 
Period
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Adalimumab 
Concentrationo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AAA Concentrationo
X
X
X
X
X
X
X
X
Pharmacogenetic 
(optional)p
X
X
Serologic 
Markers/mRNA
X
X
X
X
X
X
Inflammatory Bowel 
Disease Questionnaire 
(IBDQ)
X
X
X
X
X
X
X
X
Partial Mayo Score
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mayo Score
X
X
X
SF-36
X
X
X
Work Productivity and 
Impairment 
Questionnaire (WPAI)
X
X
X


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Table 2.
Study Activities (Continued)
Screening 
Period
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Start Corticosteroid 
Taperq
X
Monitor Adverse Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Daily Diarys
X
Daily Diarys
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Trained on 
Self-Administration of 
Injections
X
Study Drug Dispensing/ 
Administrationt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
The 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.


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Table 2.
Study Activities (Continued)
d.
Subjects will undergo an endoscopy (colonoscopy or flexible sigmoidoscopy) with biopsy for histologic assessment during Screening, at Week 8 and at Week 52/PD (for 
subjects who remain in the study through at least Week 24).  A full colonoscopy will be performed at Screening unless the subject underwent a full colonoscopy within 
12 months prior to Screening and appropriate documentation is available (to confirm the diagnosis and extent of disease and no current evidence of dysplasia and colon 
cancer).  In this case, the screening endoscopy may be either a full colonoscopy or a flexible sigmoidoscopy.  Appropriate documentation of biopsy results consistent with the 
diagnosis of UC, 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 colon must be performed during the Screening endoscopy and evaluated by a qualified local pathologist and the 
results reviewed by the Investigator.  Biopsies to rule out current dysplasia and colon cancer may be taken during any study endoscopy per the Investigator's discretion and 
evaluated by the local pathologist.  The Week 8 and Week 52/PD endoscopies may be either full colonoscopies or flexible sigmoidoscopies.  During all endoscopies, 
2 biopsies for histologic evaluation by a central laboratory will be taken from each observed colonic segment (see Section 5.3.1.1 for details about biopsy sampling).
e.
Physical examinations performed at Screening, Week 8 and Week 52/PD Visits are full physical examinations which must include an assessment of extra-intestinal 
manifestations (EIMs).  Physical exams performed at all other visits are symptom-based.
f.
Subjects with negative latent TB test(s) (In cases where a subject received both a PPD test and IGRA, both must be negative) within 90 days of Screening will not require a 
repeat latent TB 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 will not require a repeat chest x-ray, if 
documentation is available.
h.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.
i.
Laboratory 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.
A serum pregnancy test will be performed on all women of childbearing potential at Screening.  Urine pregnancy test will be performed at Baseline Visit, and at the Week 
52/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 Section 5.3.1.1 in the Hepatitis B testing section 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.


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Table 2.
Study Activities (Continued)
m.
If a sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit (supplieswill be provided at the time-points indicated).  The 
stool from which these samples are prepared should be scored using the Bristol stool chart by the site.  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:  TheScreening stool sample may be taken anytime during 
the Screening period but should be collected prior to any bowel prep.  Remaining sample will be stored for potential researchtesting.
n.
Anti-dsDNA performed if ANA result is positive.
o.
Blood samples for the measurement of adalimumab, AAA concentrations, serologic markers and mRNA will be collected prior to dosing.  All adalimumab samples should 
be shipped the same day they are collected at Weeks 10, 22 and 35 to ensure adequate processing time to determine blinded serum concentration levels needed for 
dosing adjustments, where applicable, at Weeks 12, 24 and 37.  Note:  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.
p.
Verify subject has signed consent for optional pharmacogenetic sample prior to the sample drawn.  If the sample is not collected at Baseline, preferably it should be collected 
at the next study visit.
q.
Subjects will begin the 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 Serious Adverse Events (SAEs) begins the day the subject signs the informed consent.
s.
Subjects will be dispensed the subject 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, including during hospitalizations whenever possible.  The diary will be reviewed by site personnel 
with the subject at each visit and collected at the Final/PD visit.
t.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
u.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who continue on adalimumab 
therapy after the end of study participation.
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.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 2 are discussed in detail in this section, with the 
exception of drug and HACA/Infliximab concentration measurements, antibody 
measurements, and serologic and mRNA biomarkers (discussed in Section 5.3.2, 
Section 5.3.1.3, and Section 5.3.5.2), 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 (including Medication) and Surgical History
A complete medical and surgical history (which includes UC-onset date), 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.
Prior azathioprine or 6-MP use or MTX (since birth) will be asked.  If subjects have/had 
ever treated with azathioprine or 6-MP or MTX, the duration of therapy, maximum dose, 
reason for use and reason(s) for termination of treatment with azathioprine and/or 6-MP 
and/or MTX will be recorded in the appropriate eCRF.


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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 H.
A detailed medical history with respect to TB exposure also needs to be documented.  
This information needs to include Bacillus Calmette-Guérin (BCG) vaccination, 
cohabitation with individuals who have had TB, and/or residence or work in TB-endemic 
locations.
Vital Signs
Vital sign determinations of sitting blood pressure (diastolic and systolic), pulse rate, 
respiratory rate, body temperature, and body weight will be obtained at each visit prior to 
blood draws.  Weight measurements of subjects (with clothes on) should be obtained at 
each visit using the same measuring instrument.  Height will be measured at the Screening 
Visit only.  All measurements will be recorded in metric units when applicable.
Endoscopy
All endoscopies should be recorded in a video format at the time points noted in Table 2.  
Endoscopies will be reviewed by a primary central reviewer who is blinded to the 
subject's clinical data, the site's endoscopy assessment and the subject's therapy.  If, in the 
assessment of the endoscopist, the Screening endoscopy does not indicate an endoscopy 
subscore of 2 or 3 per eligibility requirements, the subject should be screen-failed and the 
video should not be sent for central review.  The endoscopy during the Screening period, 
at Week 8 and Week 52/PD Visit (for subjects who remain in the study through at least 
Week 24) will be used for calculation of the endoscopy subscore of the Mayo Score, refer 
to Appendix C.  The endoscopy subscore will be documented by the endoscopist at the 
site and maintained in the subject's source documents.  The endoscopist will also 
document the presence or absence of friability in the subject's source documents and 
eCRF.


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Screening endoscopy:  A full colonoscopy will be performed at Screening unless the 
subject underwent a full colonoscopy within 12 months prior to Screening and appropriate 
documentation is available (to confirm the diagnosis and extent of disease and no 
evidence of current dysplasia and colon cancer).  In this case, the screening endoscopy 
may be either a full colonoscopy or a flexible sigmoidoscopy.
The endoscopy subscore result from the central reviewer will be entered into the eCRF by 
the site and used to evaluate the eligibility of a subject at Baseline for the study.  A second 
central read (adjudication) of the screening endoscopy will be required if the subject's 
eligibility for the study is discrepant between the site and central reader.  For instance, if a 
site endoscopist scores the endoscopy subscore of 2 and the central reader provides a 
score of 1, the subject's ability to be enrolled would be in question and that would lead to 
an adjudication using a second central reader as outlined in the endoscopy central reader 
manual.  The adjudicator will perform an independent review with read-only access to 
both site and central assessments (blinded to the source of assessments).  The adjudicator
will not provide an assessment but will select the assessment with whom he/she agrees.  
The adjudicator's assessment will be considered final.
Week 8 and Week 52/PD endoscopy:  The Week 8 and Week 52/PD endoscopies may be 
either full colonoscopies or flexible sigmoidoscopies.  The site's endoscopist scoring will 
be entered into the eCRF by the site and used for the Mayo score calculation for the 
purposes of re-randomization.  The central reader's assessment will be used for the Mayo 
scores used in all efficacy endpoint assessments.
Only endoscopists designated to take part in the study will perform the endoscopies. 
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of UC, 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 colon must be performed during the Screening 


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endoscopy and read by a qualified local pathologist and the results reviewed by the 
Investigator.  Biopsies to rule out dysplasia and colon cancer may be taken during any 
study endoscopy per the Investigator's discretion and evaluated by the local pathologist.
The signed pathology reports confirming the diagnosis and when appropriate, ruling out 
current dysplasia/malignancy will be monitored by the responsible CRA and kept with the 
subject's source documents onsite.  Subjects will not be enrolled if colon dysplasia or 
colon cancer is discovered at the Screening endoscopy.  If a diagnosis of colon dysplasia 
or colon cancer 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.
Additional tissue biopsy sample(s) will be collected from each observed bowel segment 
(rectum, sigmoid, descending colon, transverse colon, ascending colon/cecum) and stored 
for histologic analysis by a central laboratory, as described below.
Up to 10 biopsy specimens per subject should be obtained at each endoscopy for 
histologic assessment.  Two (2) biopsies should be taken from each observed segment of 
the colon (rectum, sigmoid, descending colon, transverse colon, ascending colon/cecum).  
One biopsy should be taken from the area of most inflammation (if the area is ulcerated, 
the sample should be obtained from the edge of the ulcer).  The second biopsy should be 
taken from an area that is representative of the general degree of mucosal inflammation 
present in that segment.
For all histology biopsies, the location of the biopsy specimen (distance from the anal 
margin) should be recorded.
In the absence of any visible lesions or areas of general inflammation characteristic of 
ulcerative colitis, one biopsy specimen should be collected from normal mucosa in the 
same segments as noted above.


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Biopsy Sample Collection, Storage and Shipping:
Biopsies performed to confirm the diagnosis of UC or to rule out current 
dysplasia/malignancy should be processed and read locally per site standards.
Up to 10 biopsy specimens per subject should be obtained by endoscopy for histologic 
assessment at Screening, Week 8, and Week 52/PD.  Using routine forceps for tissue 
collection, obtain the required number of biopsy specimens from each of the identified 
regions and process the specimens following the instructions in the Investigator Manual 
provided by the laboratory.
Tissue Analysis
The following analyses will be sent to the central laboratory and performed on 
formalin-fixed samples:
1.
Qualitative ulcerative colitis histological assessment for the colon using a 
histologic scoring system.
2.
These samples may not be read in real time, however if unexpected findings, such 
as dysplasia, are noted on the histology biopsies, the central laboratory will contact 
the Investigator to inform him/her about the unexpected finding.  Subjects who are 
found to have dysplasia on the submitted biopsy will be terminated from the trial at 
the time the dysplasia is discovered.  Unexpected findings should be recorded as an 
adverse event.
3.
Any remaining tissue (per local requirements) 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, and/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.  The samples will be retained for no longer than 20 years after 
completion of the study (where allowed by local requirements).


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Physical Examination
A physical exam will be performed at the designated study visits as outlined in Table 2.  
Physical examinations performed at Screening, Week 8 and Week 52/PD Visits are full 
physical examinations and must include an assessment of extra-intestinal manifestations 
(EIMs).  Physical exams performed at all other visits are symptom-based.
Physical examination findings that are related to or part of each subject's medical history 
should be captured on the appropriate medical history eCRF.
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.)
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.


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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 chest x-ray 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 chest x-ray 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 test is positive, the subject will be 
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 


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test.  If the second IGRA test 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 in 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 residence 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.
Chest X-Ray
All subjects will undergo a standard chest x-ray (PA and lateral views) at the Screening 
Visit to rule out the presence of TB or other clinically relevant findings.  The chest x-ray 
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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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.
Subjects can have a repeat chest x-ray at any time during the study as warranted based on 
the opinion of the Investigator.
12-Lead ECG
A resting 12-lead ECG will be performed at the designated study visits in Table 2.  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.
Laboratory Assessments
Samples obtained for the laboratory tests will be collected as indicated in Table 2.  Blood 
draws should be performed after efficacy assessments and vital sign determinations are 


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made.  Additional laboratory tests may be obtained when clinically warranted.  Should a 
laboratory test value be outside the reference range and be considered by the Investigator 
to be clinically significant, the test should be repeated to verify the result.  All laboratory 
test results that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution.
The Central Laboratory chosen for the study will process the samples and provide results 
for the clinical laboratory tests indicated in Table 3.
The last clinical laboratory test value obtained prior to randomization will serve as the 
baseline laboratory test values.  Laboratory abnormalities are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events.
The laboratory results will be sent from the central laboratory to the investigative site 
where they will be reviewed, signed and dated by the Investigator.  The central laboratory 
will provide instructions regarding the collection, processing, and shipping of 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 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 will not be made aware of 
any positive result.


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Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysisa
Hematocrit
Hemoglobin
Red Blood Cell count
White Blood Cell 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
Additional Blood Samples Collected
Stool Samples Collected
Pharmacokinetic
hs-CRP
Pharmacogenetic (optional)
mRNA
HACA
Infliximab
Serologic Biomarkers 
ANA
anti-dsDNA – if ANA positive
β-HCG
HBV
HIV, if applicable (testing to be conducted at local lab)
C. Difficile toxin
Fecal calprotectin
Microbiota metagenomic 
analyses
a.
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 2.  
A microscopic analysis will be performed by the central laboratory, in the event the 


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dipstick results show protein, ketones or blood greater than negative or glucose greater 
than normal.
Pregnancy Tests
A serum pregnancy test will be performed on all women of childbearing potential at 
Screening.  Urine pregnancy tests will be performed locally by designated study personnel 
at the Baseline Visit, and at the Week 52/PD for all women of childbearing potential.  The 
frequency can be increased up to every visit as per local regulations.
If any urine pregnancy test is positive, a serum pregnancy test will be performed by the 
central laboratory.  A lactating or pregnant female will not be eligible for participation or 
continuation in this study.
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.
hs-CRP
Blood samples for hs-CRP will be obtained as indicated in Table 2.


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Blood draws should always be performed after all efficacy assessments and questionnaires, 
vital sign determinations are obtained and before study drug administration during a visit.
Antinuclear Antibody and Anti-Double-Stranded DNA
ANA will be performed and if positive, anti-dsDNA will be performed as indicated in 
Table 2.
Pharmacogenetic Sample
Samples will be obtained for pharmacogenetic analysis at the designated study visits in 
Table 2 These analyses are described in more detail in Section 5.3.1.2.
Other Laboratory Assessments
Stool Sample (Fecal Calprotectin, C. Difficile, and Metagenomic Analyses)
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, 
fecal calprotectin and microbiota metagenomic analyses.  Subjects will be sent home with 
a stool sample supply kit as indicated in Table 2 if a sample cannot be obtained during the 
site visit.  The site will give instructions to the subjects with the collection procedures.  
The fecal calprotectin sample collected during the Screening period will be used as the 
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.  All microbiota metagenomic 
analyses stool samples should be scored using the Bristol stool chart (Appendix I) by site 
staff.  A central laboratory(s) will be utilized to process these laboratory samples.  The 
samples must be shipped to the central laboratory using dry ice.  Additional information is 
available in the Investigator Manual provided by the central laboratory.  Subjects can 
Re-screen if they have a positive C. difficile at Screening, are treated appropriately, and 
have a negative C. difficile upon completion of treatment.


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Fecal calprotectin and microbiota metagenomic analysis will be performed for all subjects 
as indicated in Table 2.  Fecal calprotectin and microbiota metagenomic results will 
remain blinded to the Investigator, study site personnel and the subject throughout the 
study.
Any remaining stool (per local requirements) 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, and/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.  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.
Outcome Assessments
IBDQ
IBDQ will be completed at the time points indicated in Table 2 (Appendix F).
Mayo Score/Partial Mayo Score 
Data from the patient diaries will be collected so Mayo score/Partial Mayo Score may be 
calculated at the time points indicated in Table 2.
Whenever possible, the same physician (investigator or subinvestigator) should determine 
the Physician's Global Assessment (PGA) subscore for an individual subject through the 
duration for the study.  The directions for capturing the stool frequency subscore, rectal 
bleeding subscore, and PGA subscores of the Mayo score are described in Appendix C.


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SF-36v2™ Health Status Survey
The SF-36v2™ form contains 36 total questions targeting a subject's functional health and 
well-being, as well as his/her psychometric physical and mental health.  Subjects will 
complete the SF-36 at the visits indicated in Table 2 (Appendix G).
Work Productivity and Impairment Questionnaire (WPAI)
Subjects will complete the WPAI Questionnaire at the time-points indicated in Table 2.  
The data in the subject-completed questionnaire will be transferred to the appropriate 
eCRF by the site personnel at each study visit (Appendix D).
Corticosteroid Therapy
At and after Week 4, subjects who are on oral prednisone (or equivalent) or budesonide or 
beclomethasone will initiate a taper of their corticosteroid dose.  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 tapering schedule is shown below.
Dose
Rate
Prednisone (or equivalent)
> 10 mg/day
≤ 10 mg/day
5 mg/day/week
2.5 mg/day/week
Beclomethasone
5 mg/day
Discontinue
Dose
Rate
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 (or oral beclomethasone) 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 
subject 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 E.
Adalimumab injections occurring during study visits will be performed at the visit by the 
subject or his/her 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 first four doses of study drug will be administered on site the same day at the 
Baseline Visit and Week 1 Visit.  On Week 2, 24 and 37 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.  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.
A ± 3-day dosing window is allowable for scheduled study dosing dates.  For subjects 
who deviate from this dosing window, every effort should be made to bring the subject 
back to the original dosing schedule as soon as possible.  For situations where bringing 
the subject back on the original dosing schedule will cause the dose to be out of the 
± 3-day dosing window, please contact the Monitor 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 medication 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 his/her 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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5.3.1.2
Blood Sample for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected per Table 2 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.
5.3.1.3
Blood Samples for Biomarker Analysis
Collection of Samples for Serologic Markers
Two 5 mL blood samples for serologic markers analysis (refer to Section 5.3.5.2) will be 
collected at the time points indicated in Table 2.  Please refer to the laboratory manual for 
instructions.
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.


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Collection of Samples for mRNA Assays
Two 2.5 mL blood samples for mRNA (refer to Section 5.3.5.2) will be collected at the 
time points indicated in Table 2.  Please refer to the laboratory manual for 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 mRNA samples to AbbVie or specified lab for 
testing.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for adalimumab, AAA, infliximab, and HACA assays will be obtained at 
the time points as indicated in Table 2.
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.


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A maximum of 22 samples (not including unscheduled visit sample collections) are 
planned to be collected per subject for adalimumab (15 samples) and AAA (7 samples) 
assays.  The total number of samples planned (not including unscheduled visit sample 
collections) will not exceed 12,600 (15 samples × 840 subjects) for the adalimumab assay 
and 5,880 (7 samples × 840 subjects) for the AAA assay for the main study.
Collection of Samples for Infliximab and HACA Assays
Blood samples for infliximab and HACA assay will be collected at Week 0 (Baseline) by 
venipuncture into appropriately labeled 4-mL evacuated serum collection tube 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 1,680 (2 samples × 840 subjects) for 
the main study.
5.3.2.2
Handling/Processing of Samples
The blood samples for adalimumab, AAA, infliximab and HACA assays will be labeled 
with the type of sample, the protocol number, the subject number, the week and the 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.
IMPORTANT:  All adalimumab samples should be shipped the same day they are 
collected at Weeks 10, 22 and 35 to ensure adequate processing time to determine 
blinded serum concentration levels needed for dosing adjustments, where applicable 
at Weeks, 12, 24, and 37.


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5.3.2.3
Disposition of Samples
Frozen 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 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.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variables
The primary efficacy variable for the Induction Study is the proportion of subjects 
achieving clinical remission (defined as a Full Mayo score ≤ 2 with no subscore > 1) at 
Week 8.
The primary efficacy variable for the Maintenance Study is the proportion of Week 8 
responders (per Full Mayo score, defined as a decrease in Full Mayo score of ≥ 3 points 
and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) achieving clinical remission (per Full Mayo score) at Week 52.
5.3.3.2
Secondary Variables
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Induction Study are:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 
0 or 1) at Week 8.
2.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.


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3.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) 
at Week 8.
4.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
5.
Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Maintenance Study are:
1.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
2.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
4.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission 
(per Full Mayo score) at Week 52.
5.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
8.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response 
(increase of IBDQ ≥ 16 from Baseline) at Week 52.


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9.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
10.
Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
11.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
12.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
The steroid-free endpoints require subjects to have discontinued steroids for at least 
90 days.  While steroid therapy is associated with significant toxicity, durable steroid-free 
status may be more clinically meaningful than discontinuation evaluated simply at a 
single point in time.  A position paper on endpoints in ulcerative colitis trials suggested 
that the minimal clinically significant corticosteroid-free duration is unclear, but the 
authors suggested that 3 months or longer represented a clinically meaningful endpoint in 
therapeutic trials.14  The duration of steroid-free status should also be considered within
the context of the duration of the clinical study, the maximum allowed steroid dose at 
Baseline, and the tapering schedule.  Based on these factors, 90 days was felt to be 
clinically meaningful and therefore this duration was selected for the ranked secondary 
endpoints that evaluate steroid-free status in this study.
5.3.3.3
Additional Variables
Additional pre-specified endpoints in the Induction Study include but are not limited to 
the following:
●
Assessment of the relationship between adalimumab serum concentrations and 
efficacy during the Induction Study.
●
All-cause and UC-related hospitalization and surgery rates during Weeks 0 – 8.
●
Change from Baseline in histologic score at Week 8.


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●
Proportion of subjects achieving clinical remission per Adapted Mayo Score 
(defined as stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1) at Week 8.
●
Proportion of subjects achieving Full Mayo score excluding the PGA subscore, 
≤ 2 with no subscore > 1 at Week 8.
●
Relationship between histologic subscores and endoscopic improvement 
(endoscopy subscore of 0 or 1) at Week 8.
●
Relationship between histologic scores and endoscopic subscore of 0 as 
Week 8.
Additional pre-specified endpoints in the Maintenance Study include but are not limited to 
the following:
●
Assessment of the relationship between adalimumab serum concentrations and 
efficacy during the Maintenance Study by Week 8 response status.
●
Proportion of Week 8 responders (per Full Mayo score) with clinical response 
at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with clinical 
response at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic 
improvement at Week 52.
●
All cause and UC-related hospitalization and surgery rates during Weeks 8 –
52.
●
Change from Baseline in histologic score at Week 52.
●
Proportion of Week 8 responders per Adapted Mayo score (defined as decrease 
from Baseline in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, 
PLUS a decrease in rectal bleeding subscore (RBS) ≥1 or an absolute RBS 
≤1) achieving clinical remission per Adapted Mayo scores at Week 52.
●
Proportion of Week 8 responders (per Full Mayo score) achieving Full Mayo 
Score, excluding the PGA subscore ≤ 2 with no subscore > 1 at Week 52.
●
Relationship between histologic scores and endoscopic improvement 
(endoscopy subscore of 0 or 1) at Week 52.


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●
Relationship between histologic scores and endoscopic subscore of 0 at 
Week 52.
●
Proportion of Week 8 responders (per Full Mayo score) taking steroids at 
Baseline who are steroid-free for at least 180 days and in clinical remission 
(per Full Mayo score) at Week 52.
The following additional pre-specified endpoints will also be analyzed in both the 
Induction Study and the Maintenance Study.
●
Analysis of the impact of immunogenicity on safety, pharmacokinetics, and 
efficacy.
●
Proportion of subjects who are taking corticosteroids at Baseline and are 
steroid free over time.
●
Evaluation of adalimumab concentrations and immunogenicity at the time of 
loss of clinical remission.
●
Proportion of subjects achieving clinical remission per Partial Mayo (defined 
as a Partial Mayo score ≤ 2 with no subscore > 1) score over time.
●
Proportion of subjects achieving clinical response per Partial Mayo score 
(defined as a decrease in Partial Mayo score of ≥ 2 points and ≥ 30% from 
Baseline Plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) over time.
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in corticosteroid dose over time.
●
Change from Baseline in IBDQ score over time.
●
Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores 
over time.
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight).
●
Change from Baseline in subject-reported stool frequency (absolute values).
●
Change from Baseline in work productivity and impairment questionnaire 
(WPAI) scores over time.


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●
Change from Baseline in SF-36 score over time.
●
Change from Baseline in fecal calprotectin over time.
●
Time to achievement of remission (per Partial Mayo score)
●
Time to achievement of response (per Partial Mayo score)
●
Time to loss of response and factors associated with loss of response.
●
Change in presence of extraintestinal manifestations over time.
5.3.3.4
Safety Variables
Safety will be assessed by adverse events, physical examination, vital signs and laboratory 
data during the entire study.
5.3.4
Pharmacokinetic Variables
Serum concentrations of adalimumab at each scheduled sampling time will be 
summarized and stratified by treatment regimen.  The number and percentage of subjects 
who develop AAA will be determined.  The adalimumab concentration data may be 
analyzed using a nonlinear mixed effects model (population PK analysis).  The 
relationship of response (primary efficacy variables and other responses of interest) with 
study drug exposure will be explored.
5.3.5
Pharmacogenetic and Serologic Variables
5.3.5.1
Pharmacogenetic Variables
Samples may be sequenced and data analyzed for DNA sequences contributing to the 
disease or to the 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.


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5.3.5.2
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, adverse events, 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.
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.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie SDP (see Section 5.2 and Section 7.0).


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●
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 medication.
●
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 PD 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 PD.  The information will be recorded on the appropriate eCRF page.
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.


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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
Double-Blind Induction Study
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction dosing regimens.
Subjects assigned to the standard induction dosing regimen will receive adalimumab 
160 mg (4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  
At Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes) At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction dosing regimen will receive 160 mg (4 syringes) 
at Weeks 0, 1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Study
At Week 8, subjects will be re-randomized to receive 1 of 3 double-blind adalimumab 
treatment maintenance regimens in a 2:2:1 ratio.


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Subjects assigned to the adalimumab 40 mg eow regimen will receive 40 mg (1 syringe) 
at Weeks 8, 10, 12, 14, 16, 18, 20, 22, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 50.  
Subjects will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24.  At Week 37, 
subjects will receive matching placebo (4 syringes).  Matching Placebo (1 syringe) will be 
administered at Weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 39, 41, 43, 45, 
47, 49, 51.  No dose will be administered at Week 52/Premature Discontinuation.
Subjects assigned to the adalimumab 40 mg ew regimen will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 
32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  Subjects will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Weeks 24 and 37.  No dose will be 
administered at Week 52/Premature Discontinuation.
Subjects assigned to the TDM regimen will receive adalimumab 40 mg eow (1 syringe) at 
Week 8 and Week 10.  Matching placebo (1 syringe) will be administered at Weeks 9 and 
11.  At Weeks 12, 24 and 37, the regimen will be adjusted for subjects meeting specified 
criteria in Table 1.
Subjects who don't dose escalate at Week 12 will receive 40 mg eow (1 syringe) at 
Weeks 12, 14, 16, 18, 20, and 22 and placebo (1 syringe) at Weeks 13, 15, 17, 19, 21 and 
23.  Subjects who escalate at Week 12 will receive 40 mg ew (1 syringe) at Weeks 12, 13, 
14, 15, 16, 17, 18, 19, 20, 21, 22 and 23. 
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg eow 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 
eow (1 syringe) at Weeks 26, 28, 30, 32, 34, and 36 and placebo (1 syringe) at Weeks 25, 
27, 29, 31, 33 and 35.  Subjects who escalate at Week 24 and were receiving adalimumab 
40 mg eow will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed 
by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 


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ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.  Subjects who 
escalate at Week 24 and were receiving adalimumab 40 mg ew will receive 160 mg 
(4 syringes) at Week 24, followed by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 
30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg eow 
will receive placebo (4 syringes) at Week 37, followed by 40 mg eow (1 syringe) at 
Weeks 38, 40, 42, 44, 46, 48, and 50 and placebo (1 syringe) at Weeks 39, 41, 43, 45, 47, 
49, 51.  No dose will be administered at Week 52/Premature Discontinuation.
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg eow will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg ew 
(1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52/Premature Discontinuation.
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg 
ew (1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52/Premature Discontinuation.
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg ew will receive 
160 mg (4 syringes) at Week 37, followed by 40 mg ew (1 syringe) at Weeks 38, 39, 40, 
41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose will be administered at 
Week 52/Premature Discontinuation.
5.5.2
Identity of Investigational Products
The individual study drug information is presented in Table 4.


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Table 4.
Study Drugs
Drug
Dosage Form
Device
Formulation
Manufacturer
Adalimumab
Parenteral
Pre-filled 
syringe
40 mg/0.8 mL solution for injection 
Adalimumab/Mannitol, Citric acid 
monohydrate, Sodium citrate, 
Disodium phosphate dihydrate, 
Sodium dihydrogen phosphate 
dihydrate, Sodium chloride, 
Polysorbate 80, Water for injections, 
Sodium hydroxide added as necessary 
to adjust pH
AbbVie
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.
All labels must remain affixed to study medication 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 E.
5.5.2.2
Storage and Disposition of Study Drug(s)
Adalimumab/placebo pre-filled syringes are to be stored protected from light at 2° to 
8°C/36° to 46°F.  Study medication drug must not be frozen at any time.  A storage 


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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 must be reported to the Sponsor immediately.  
Study medication should be quarantined and not dispensed until AbbVie GPRD or 
AbbVie Temperature Excursion Management System (ATEMS) or other 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 Inc.
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 Regimens
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 Induction Study.  Subjects who enter the Induction Study 
will be randomized at Week 0 in a 3:2 ratio into the criteria-driven regimens using the 
IRT, which will assign a randomization number according to the randomization scheme, 
generated by AbbVie before the start of the study.  The randomization will be stratified by 
previous infliximab use and Baseline corticosteroid use.  The criteria-driven regimen 
assignment will be maintained by the IRT.  Subjects will be referred to by the subject 
number assigned at Screening.
Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Study at the conclusion of the Week 8 Visit to one of three 
treatment regimens in a 2:2:1 ratio.  Subjects will be re-stratified by:  induction treatment 
regimen and response status (per Full Mayo Score) at Week 8.  Among Week 8 
responders, the randomization will be further stratified by remission status (per Full Mayo 
Score) at Week 8.


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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 IRT will be 
provided to each site.  Study drug will be dispensed/administered at the study visits 
summarized in Table 2.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study medication as outlined in Section 5.5.1.  If a subject should 
forget to administer the injection of study medication on his/her regularly scheduled 
dosing date, he or she should take the forgotten injection as soon as they remember the 
dose was missed up to the day of his/her next scheduled dose.  The subject should not 
administer two doses on the same day.  
In the event the incorrect dose is taken or a dose is missed, the subject should be 
instructed to contact the site to determine how to proceed with dosing.  The subject must 
record all home 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 his/her 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 the AbbVie Drug Supply Management Team) the Investigator, 
study site personnel and the subject will remain blinded to each subject's treatment 
throughout the blinded period of the study.  The IRT 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 


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(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 and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than that described in the protocol.
The subject or his/her 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 administered at home.  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 (or information is not available 
electronically), 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 or available electronically 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 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.


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In addition, an accurate running inventory of study drug will be kept by the site on a Site 
Drug Accountability log including date received, the lot number, kit number(s), date 
dispensed, subject number, and the identification with date of the person dispensing the 
drug.  For this study, unless otherwise prohibited locally, these records will be maintained 
electronically as part of the IVRS/IWRS system.
All empty IP boxes and used pre-filled syringes will be inventoried by the site.  Each 
subject will be given his/her 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 medication accountability via study medication 
logs, source documents, subject diary, 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 
Regimens
Study M14-033 is a global, randomized, multicenter study of standard versus higher 
adalimumab dosing regimens for induction and maintenance therapy in subjects with 
moderately to severely active UC.  No placebo regimen is planned due to documented 
efficacy of adalimumab in UC and the purpose of this study is to investigate whether 
greater efficacy is achieved with the higher dose than with the standard dose, and to 
compare safety outcomes.  Additionally, since subjects will have evidence of endoscopic 
damage confirmed by a central reader and clinical symptoms consistent with moderately 


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to severely active UC, it would be not medically acceptable to deny those subjects 
effective treatment and it would be difficult to enroll subjects in the trial when the drug is 
available to be prescribed for UC.
The study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active UC.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  The 
clinical efficacy measurement used in this study (Mayo Score) has been used in multiple 
pivotal clinical trials in assessing disease activity in subjects with UC.12,13  All clinical and 
laboratory procedures in this study are standard and generally accepted.
5.6.3
Suitability of Subject Population
Subjects with moderately to severely active UC who meet all inclusion criteria and none 
of the exclusion criteria are eligible for this study.  The specific subject population chosen 
was based on unmet medical needs of currently available medical therapies as well as 
previous anti-TNF studies that demonstrated effectiveness in UC.13
5.6.4
Selection of Doses in the Study
Dose regimens and numbers of subjects were determined based on efficacy and safety 
data from the adult UC population from Study M06-827, PK/pharmacodynamic modeling 
using PK and efficacy data from Study M06-827 and observed safety data from high dose 
adalimumab IV studies in rheumatoid arthritis.
Induction Dose Selection
The use of higher induction doses than 160/80 mg in adult subjects with moderately to 
severely active UC is supported by exposure-efficacy analyses from Study M06-827.  At 
Week 8 of Study M06-827, serum trough adalimumab concentrations ranged from 0 to 
22.8 μg/mL following dosing with 160/80 mg at Weeks 0 and 2 and 40 mg at Weeks 4 


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and 6.  The highest rate of remission (25.4%) was observed in subjects in the highest 
concentration quartile, in which most observed concentrations ranged from 12 to 
16 μg/mL.  The higher induction regimen selected for testing represents an approximate 
doubling in adalimumab exposure over the first 8 weeks compared to the standard dose, 
and is expected to achieve a higher rate of remission at Week 8 compared to the standard 
approved induction dose regimen.
Maintenance Dose Selection
In order to test the efficacy and safety of a wide range of adalimumab exposure during 
maintenance therapy for UC three dosing strategies will be tested.  Two fixed doses, 
40 mg eow (the currently approved maintenance dose) and 40 mg weekly will be tested.  
An exploratory regimen evaluating a TDM strategy will also be evaluated.  The goal of 
the TDM maintenance dosing regimen is to analyze the feasibility, efficacy, and safety of 
aiming for serum adalimumab levels within a targeted concentration range for making 
decisions regarding dosing.
The targeted concentration range selected for the TDM dosing regimen was based on 
serum concentrations observed during Study M06-827 and the mean serum concentrations 
observed in subjects who achieved remission during this study.  During maintenance 
therapy in Study M06-827, concentrations with maintenance dosing ranged from 0 to 
39.3 μg/mL with eow dosing and 0 to 38.0 μg/mL with 40 mg weekly dosing.  The lower 
bound of the targeted concentration range (10 μg/mL) for the TDM regimen is based on 
serum concentrations in Week 52 remitters in Study M06-827.  In those subjects, the 
median concentrations observed over time were 11.4, 10.6, and 10.8 μg/mL, for Weeks 8, 
32, and 52, respectively. 
Use of this concentration minimum threshold to trigger dose escalation is expected to lead 
to the majority of subjects achieving concentrations greater than 10 μg/mL.  Since serum 
adalimumab concentrations roughly double with a doubling of dose, an upper bound of 
20 μg/mL is expected to achieve maximal trough concentrations in the range of highest 
trough concentrations observed in Study M06-827.  Based on observed adalimumab 


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pharmacokinetics in Study M06-827, it is expected that approximately 60% of subjects in 
the TDM dosing regimen will escalate to 40 mg weekly dosing, and approximately 15% 
will receive re-induction thereafter using this concentration range and the RBS criteria 
described in Table 1 as a guide to adjust dosing.
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).
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 6.1.1
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.


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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 
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, (refer Section 6.1.7 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.


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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).
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.


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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.
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, an Other cause of event must be provided by the investigator for the serious 
adverse event.


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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 who continue on 
adalimumab therapy after the end of study participation.  These subjects are not required 
to complete the 70-day follow-up and any new Adverse Events should be reported 
through the mechanism used for all post marketing adverse experiences.
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 4).  Thus, all SAEs and non-
serious AEs, as defined by AbbVie, as well as the medication for AEs/SAEs, reported 
during the 70-day follow-up phone call must be captured in the clinical database via the 
eCRF and also recorded in source documentation (Appendix J).  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 4.
Figure 4.
Adverse Event Collection
SAEs
SAEs and Non-Serious AEs
Elicited and/or Spontaneously Reported




Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
70 Days After 
Study Drug 
Stopped


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6.1.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any non-serious event of 
malignancy in subjects 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 SAE or non-serious event of 
malignancy in subjects 30 years of age and younger data into the electronic data capture 
(EDC) system.  Serious adverse events and non-serious events of malignancy in subjects 
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.
Email:  
FAX to:  
For safety concerns, contact the Immunology Safety Management Team at:
Immunology Safety Team
Office:
Email:


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For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician
MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Contact Information:
Phone:
Mobile:
Fax:
Email:
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 Humira 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).


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Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a SAE 
and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
6.1.7
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 6.1.1 for definitions).  Study medication may be 
restarted once the physician determines that the infection has been successfully treated.  
Otherwise prohibited concomitant medications may be given if medically necessary.  
Prior to use, every attempt should be made to contact the AbbVie Study Physician for 
direction on re-introduction of adalimumab therapy after prohibited medication 
administration.
If the subject must undergo elective surgery, the study injections must be interrupted 
two weeks prior to the surgery.  If the subject must undergo emergency surgery, the study 
injections must be interrupted at the time of the surgery.  The injectable study medication 
can recommence at least two weeks after surgery once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
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 
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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.
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).  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 


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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
IEC/Independent Review Board (IRB) regulatory authorities (as applicable), and their 
assigned Clinical Monitor or the following AbbVie Clinical Monitor(s):
Primary Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
United States
Telephone Contact Information:
Office:
Email:
Alternate Contact:
 MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Telephone Contact Information:
Office: 
Mobile:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objectives of the statistical analyses are to evaluate the efficacy and safety of 
adalimumab for the induction and maintenance of clinical remission in subjects with 
moderately to severely active ulcerative colitis.  The following statistical analysis plan is 
for subjects recruited in the main study.  A separate statistical analysis plan will be 
provided for subjects recruited in the Japan sub-study and for all the subjects recruited in 
the main study and the Japan sub-study (See Appendix K).


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Complete, specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP) for the main study and the Japan 
sub-study.  The SAPs will be finalized prior to the database lock.
8.1.1
Analysis Population
The following populations will be used for analyses in this study: 
Intent-to-Treat (ITT1) population includes all subjects who were randomized at Baseline.  
ITT1 subjects will be analyzed as randomized.  ITT1 is the primary population for the 
efficacy analysis at Week 8 during the Induction Study.
Intent-to-Treat maintenance (ITT2) population includes all subjects who are re-
randomized at Week 8 to the Maintenance Study.  ITT2 subjects will be analyzed as 
randomized.  ITT2 is the primary population for the efficacy analysis at Week 52 during 
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 


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using the analysis of variance (ANOVA), and discrete variables will be analyzed using the 
chi-square test or Fisher's exact test.
8.1.4
Statistical Analyses of Efficacy
8.1.4.1
Primary Efficacy Variables
The primary efficacy endpoint for the Induction Study is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full 
Mayo score of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding 
subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full 
Mayo score) at Week 52.
The primary analysis of the Induction Study will compare the subjects in the higher 
adalimumab induction regimen versus the standard adalimumab induction regimen in the 
ITT1 analysis set.  The difference between the treatment regimens in the proportion of 
subjects achieving clinical remission at Week 8 will be assessed using Cochran-Mantel-
Haenszel (CMH) test adjusted for previous infliximab use and Baseline corticosteroid use 
at Baseline.  A CMH based two sided 95% confidence interval for the difference between 
treatment groups will be calculated.  Breslow-Day test for homogeneity of odds ratios will 
be performed as well.  Subjects with missing primary endpoint data at Week 8 will be 
classified as "no clinical remission" (non-responder imputation [NRI] method) for the 
Week 8 endpoint.  Subjects with missing Mayo score data for Week 8 will also be 
classified as Week 8 non responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as 


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Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline 
will also be performed for the primary endpoint for the Induction Study.
The primary analysis of the Maintenance Study will compare the Week 8 responders (per 
Full Mayo Score) in the eow regimen versus the subjects in the ew regimen in the ITT2 
analysis set.  The difference between the treatment regimens in the proportion of subjects 
achieving clinical remission at Week 52 will be assessed using Cochran-Mantel-Haenszel 
(CMH) test adjusted for Induction treatment regimen and the remitter status (per Full 
Mayo Score) at Week 8.  A CMH based two-sided 95% confidence interval for the 
difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 52 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method) for the Week 52 endpoint.  Subjects with missing Mayo score 
data for Week 52 will also be classified as Week 52 non-responders.
The TDM regimen will be used for exploratory analyses.
8.1.4.2
Secondary Efficacy Variables
The 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 an alpha level of 0.050 (two-sided) in ranked endpoint order 
until the significant level exceeds 0.05.  No additional statistically significant treatment 
differences could be declared if the preceding ranked endpoint fails to achieve 0.05.  The 
second group includes all other additional secondary variables.  For the Induction Study 
endpoints, the difference between the higher adalimumab induction regimen versus the 
standard adalimumab induction regimen will be assessed using ITT1 analysis set.  For the 
Maintenance Study endpoints, the difference between the eow dosing regimen versus the 
ew doing regimen will be assessed using Intent-to-Treat maintenance (ITT2) analysis set 
where Week 8 responder/remitter status will be determined based on the Full Mayo score 
using endoscopy subscore from the central reader.  Categorical data will be described by 
frequency and percentage; continuous data will be described by mean, standard deviation, 


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minimum, median, and maximum.  In general, the secondary endpoints at Week 8 that are 
of the binary type will be analyzed using a two-sided CMH test adjusted for previous 
infliximab use and Baseline corticosteroid use in the ITT1 analysis set, and the secondary 
endpoints at Week 52 that are of the binary type will be analyzed using a two-sided CMH 
test adjusted for induction treatment regimen, and remitter status (per Full Mayo score) at 
Week 8 (where applicable) in the ITT2 analysis set.  Additionally, the two-sided 95% 
confidence interval for the difference in proportions will be provided.  Continuous 
secondary efficacy variables will be analyzed using Analysis of Covariance (ANCOVA) 
with factor for treatment regimen, stratification variables and Baseline values.  NRI for 
missing data will be used for categorical endpoints.  Procedures for handling missing data 
for continuous endpoints will be described in the Statistical Analysis Plan.
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 
Studies using the safety analysis set which includes all subjects who receive at least 
one dose of study medication in each Study respectively.  Treatment-emergent AEs, will 
be tabulated by MedDRA preferred term by treatment group for the Induction Study and 
the Maintenance Study, and for any adalimumab over the entire study.  Mean changes in 
vital signs, physical examination results, ECGs, and clinical laboratory data values will be 
analyzed.
8.1.6
Other Statistical Analyses of Efficacy
The subgroups listed below will be used in subgroup analyses of the primary endpoints.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline Mayo Score (≤ 9, > 9)


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●
Baseline Mayo Score (≤ median, > median)
●
Prior exposure to anti-TNF (yes, no)
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Baseline hs-CRP (≤ median, > median)
●
Baseline Albumin (≤ median, > median)
●
Region (US versus non-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 8 may be performed after the last subject in ITT1 population completes the 
8-week double-blind Induction Study of the main 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 primary efficacy endpoint of the Induction Study, no 
adjustment of alpha-level is necessary.
8.1.8
Pharmacokinetic Analyses
Adalimumab trough serum concentrations will be summarized by treatment regimen 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.


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8.2
Determination of Sample Size
When Protocol M14-033 was initially designed, AbbVie used an assumption regarding 
induction response rate in order to calculate the expected number of Week 8 responders 
that would comprise the analysis set used to compare the Week 52 remission rates in the 
adalimumab 40 mg every other week and 40 mg weekly groups.  AbbVie assumed that 
the overall response rate (per Full Mayo Score) at Week 8 would be 60%, which would 
provide 315 Week 8 responders for the analysis of Week 52 remission (126 in the every 
other week dosing group, 126 in the every week dosing group, and 63 in the exploratory 
TDM group, based upon a 2:2:1 randomization scheme) from the 525 randomized 
induction subjects.  This sample size would provide 80% power to detect a treatment 
difference of 18%, assuming an expected Week 52 remission rate of 48% in the 
adalimumab weekly dosing group and 30% in the adalimumab every other week dosing 
group.
Considering the uncertainty in the Week 8 response rate may be caused by the impact of 
central reading on the endoscopic subscore, based on the ozanimod Phase 2 
TOUCHSTONE trial data presented in early 2015, AbbVie re-estimated the Week 8 
response rate to be 50% instead of 60%.  Under this assumption, if the sample remains 
525, a smaller size of the Week 52 analysis set than was original predicted, and thus an 
insufficient power (72%) for the analysis of the Week 52 remission endpoint is expected.  
Furthermore, Week 52 remission rate will be the primary endpoint of the Maintenance 
Study.  AbbVie proposes to increase the power for this endpoint from 80% as originally 
designed to 90% retaining the currently assumed treatment difference.  The combined 
impact of these changes (i.e., increased power plus higher uncertainty in Week 8 response 
rate) results in an increase in the overall Study M14-033 sample size from 525 subjects to 
a total of 840 subjects.
Subjects will be randomized to the adalimumab higher induction regimen and the 
adalimumab standard induction regimen in a 3:2 ratio.  The sample size calculations for 
the main study are based on a two sided Fisher's exact test at a significance level of 0.05.  
Assuming an expected Week 8 endoscopic improvement rate of 60% in the adalimumab 


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higher induction dosing regimen and 45% in the adalimumab standard induction dosing 
regimen, 804 subjects (504 subjects in the higher induction dosing regimen and 
336 subjects in the standard induction dosing regimen) will provide 90% statistical power 
to detect the difference between the two induction treatment regimens.  This sample size 
of 804 subjects in the main study will provide at least 95% power to detect a treatment 
difference of 15% for the primary endpoint of clinical remission, assuming an expected 
Week 8 clinical remission rate of 35% in the adalimumab higher induction regimen and 
20% in the adalimumab standard induction regimen.
Assuming the average response rate at Week 8 in the adalimumab induction dosing 
regimens in the main study is 50%, there will be 420 responders for the analysis of 
Week 52 clinical remission among the Week 8 responders (168 in the higher maintenance 
dosing regimen, 168 in the standard maintenance dosing regimen, and 84 in the TDM 
regimen).  This sample size will provide 90% power to detect a treatment difference of 
18%, assuming an expected Week 52 clinical remission rate of 48% in the adalimumab 
higher maintenance dosing regimen and 30% in the adalimumab standard maintenance 
dosing regimen. 
The sample size calculations for the Japan sub-study are described in Appendix K.
8.3
Randomization Methods
At Baseline, subjects will be randomized 3:2 to one of two double-blinded adalimumab 
induction regimens (higher dose or standard dose).  The randomization will be stratified 
by previous infliximab use and Baseline corticosteroid use.  In both the main study and 
the Japan sub-study populations, up to 25% of subjects with previous infliximab exposure 
may be enrolled.
At the conclusion of the 8-week Induction Study, all subjects will be re-randomized into 
the 44-week Maintenance Study.  Re-randomization will be stratified by induction 
treatment regimen and response status (per Full Mayo Score utilizing the Week 8 
endoscopy subscore provided by the site) at Week 8.  Among Week 8 responders, the 


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randomization will be further stratified by remission status (per Full Mayo Score utilizing 
the Week 8 endoscopy subscore provided by the site) at Week 8.  All subjects will be 
randomized into one of three blinded treatment regimens in a 2:2:1 ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg ew
●
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory).  
(The Japan sub-study does not have a TDM regimen.  Subjects will be 
randomized into Adalimumab 40 mg eow or Adalimumab 40 mg ew treatment 
regimens in a 1:1 ratio.)
The randomization schedule will be prepared by the Statistics Department of AbbVie.  
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
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 


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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.
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.
Any optional testing will only be performed if the subject has voluntarily given 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.  Subject consent must be signed 
before the optional testing is performed.  If the subject does not consent to the optional 
testing, it will not affect 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 


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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.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
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
CRFs 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 


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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.  eCRF data required by this protocol will be 
recorded by investigative site personnel in the EDC system, except for subject-completed 
questionnaires, which will be completed on paper by the subject then transcribed into the 
EDC system.  All data entered into the eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or AbbVie's representatives).  AbbVie (or AbbVie's 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
●
SF-36 acute recall version 2.0
●
WPAI


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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 
documentation.  
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 


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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 (stool frequency, abdominal discomfort, number of bloody stools, fecal 
urgency, use of anti-diarrheals, use of medications used for endoscopy preparation, 
general well-being and dosing information) 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.  The subject's dosing information will be used as confirmation for the site and site 
staff will need to add the information to the appropriate eCRF.  To calculate the Partial 
Mayo score, the site will be able to use the subscores from ePRO to manually enter into 
the eCRF.
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.


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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.
Data from the central laboratory and the imaging vendor will be electronically transferred 
to the study database.
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 
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.


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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 pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or subject management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic 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 AbbVie's representative.


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The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
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 Double-Blind, Randomized, Multicenter Study of Higher Versus 
Standard Adalimumab Dosing Regimens for Induction and 
Maintenance Therapy in Subjects with Moderately to Severely 
Active Ulcerative Colitis
Protocol Date:
16 June 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Hanauer SB.  Update on the etiology, pathogenesis and diagnosis of ulcerative 
colitis.  Nat Clin Pract Gastroenterol Hepatol.  2004;1:26-31.
2.
Loftus EV.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  2004;126:1504-17. 
3.
Sandler RS, Everhart JE, Donowitz M, et al.  The burden of selected digestive 
diseases in the United States.  Gastroenterology.  2002;122:1500-11. 
4.
Dignass A, Eliakim R, Magro F, et al.  Second European evidence-based consensus 
on the diagnosis and management of ulcerative colitis Part 1:  Definitions and 
diagnosis.  J Crohn's Colitis.  2012;6:965-90.
5.
Rutter M, Saunders B, Wilkinson K, et al.  Severity of inflammation is a risk factor 
for colorectal neoplasia in ulcerative colitis.  Gastroenterology.  2004;126:451-9.
6.
Truelove SC, Witts LJ.  Cortisone and corticotrophin in ulcerative colitis.  
Br Med J.  1959;34:387-94. 
7.
Kornbluth A, Sachar DB; the Practice Parameters Committee of the American 
College of Gastroenterology.  Ulcerative colitis practice guidelines in adults:  
American College of Gastroenterology, Practice Parameters Committee.  Am J 
Gastroenterol.  2010;105:501-23.
8.
Beaugerie L, Brousse N, Bouvier AM, et al.  Lymphoproliferative disorders in 
patients receiving thiopurines for inflammatory bowel disease: a prospective 
observational cohort study.  Lancet.  2009;374:1617-25. 
9.
Reinisch W, Sandborn WJ, Hommes DW, et al.  Adalimumab for induction of 
clinical remission in moderately to severely active ulcerative colitis:  results of a 
randomised controlled trial.  Gut.  2010;60:780-7.
10.
Reinisch W, Sandborn WJ, Panaccione R, et al.  52-Week efficacy of adalimumab 
in patients with moderately to severely active ulcerative colitis who failed 
corticosteroids and/or immunosuppressants.  Inflamm Bowel Dis.  
2013;10.1097/MIB.0b013e318281f2b7.


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11.
Sandborn WJ, Van Assche G, Reinisch W, et al.  Adalimumab induces and 
maintains clinical remission in patients with moderate-to-severe ulcerative colitis.  
Gastroenterology.  2012;142:257-65. 
12.
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis.  N Engl J Med 
1987;317:1625-29.
13.
Rutgeerts P, Sandborn WJ, Feagan BG, et al.  Infliximab for induction and 
maintenance therapy for ulcerative colitis.  N Engl J Med.  2005;353:2462.
14.
D'Haens G, Sandborn WJ, Feagan BG, et al.  A review of activity indices and 
efficacy end points for clinical trials of medical therapy in adults with ulcerative 
colitis.  Gastroenterology.  2007;132(2):763-86.
15.
YAKUSHOKUSHINSA Notification No. 0928010 dated on September 28, 2007, 
issued by Director of Evaluation and Licensing Division, Pharmaceutical and Food 
Safety Bureau, Ministry of Health, Labour and Welfare.


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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
Clinical
Data and Statistical Sciences
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical
Bioanalysis


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Appendix C.
Script for Collection of Mayo Scores for Use in Study M14-033
The Mayo Score is a composite of the following subscores:  Stool Frequency subscore, 
Rectal Bleeding subscore, Endoscopy subscore, and Physician's Global Assessment 
subscore.
The Partial Mayo Score is a composite of the following subscores:  Stool Frequency 
subscore, Rectal Bleeding subscore, and Physician's Global Assessment subscore.
Stool Frequency Subscore
The stool frequency subscore is calculated by comparing the stool frequency to a 
reference number.  The reference number is the number of stools per day (24 hours) that is 
typical for the subject when having active UC but not experiencing a flare and needs to be 
designated once prior to enrollment.  The reference number should represent a full 
number of at least 1.
Subjects will record the daily number of stools throughout the trial.  Using these numbers, 
the Stool Frequency subscore will be assessed for each study day as follows: 
A number of bowel movements lower than or equal to the reference number of bowel 
movements should be scored as 0 = Normal.
One or 2 bowel movements more than the reference number of bowel movements should 
be scored as 1.
Three or 4 bowel movements more than the reference number of bowel 
movements should be scored as 2.
Five or more bowel movements more than the reference number of bowel 
movements should be scored as 3.
The Stool Frequency subscores based on 5 days prior to each study visit will be averaged 
and used for the Stool Frequency subscore for each study visit.  


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The Stool Frequency subscore during days which the subject received anti-diarrheal 
medication will be scored as a 3.
Diary entries for stool frequency should not be included in the 5 days prior to the visit that 
are evaluated for the Stool Frequency subscore for the following days:  (1) the day the 
subject received medication for bowel preparation prior to endoscopy, (2) the day the 
subject underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier diary 
entries will be used accordingly in order to provide the most recent data for 5 days prior to 
the respective study visit.
Rectal Bleeding Subscore
Subjects will be assigned a daily rectal bleeding subscore value as follows:
No visible blood with stool during the respective day should be scored as 0.
Visible blood with stool less than half the time during the respective day should be 
scored as 1.
Visible blood with stool at least half the time during the respective day should be 
scored as 2.
A score of 3 for bleeding requires subjects to have at least 50% of bowel 
movements accompanied by visible blood and at least one bowel movement with 
blood alone.
The score entries into subject's diary based on 5 days prior to each study visit will be 
averaged and used for the Rectal Bleeding subscore for each study visit.  
Diary entries for rectal bleeding should not be included in the 5 days prior to the visit that 
are evaluated for the Rectal Bleeding  subscore for the following days:  (1) the day the 
subject received medication for bowel preparation prior to endoscopy, (2) the day the 
subject underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier diary 


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entries will be used accordingly in order to provide the most recent data for 5 days prior to 
the respective study visit.
Physician's Global Assessment Subscore
The physician's global assessment acknowledges the 2 subject-reported subscores, the 
endoscopy subscore as applicable, the subject's daily record of abdominal discomfort and 
general well-being during based on the 5 days prior to the visit, and other observations 
such as physical findings, and the subject's performance status in order to assess disease 
activity as follows:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Endoscopy Subscore
The endoscopist should evaluate each observed segment of the colon (rectum, sigmoid, 
descending colon, transverse colon, ascending colon/cecum) by using the classification as 
follows:
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
The endoscopic subscore for the subject will be the worst score of the observed segments.


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The local endoscopist should also separately assess presence or absence of friability 
(yes/no).
The endoscopy will be recorded (not a still image) and will undergo a central review
process for endoscopy subscore assessment.
Sources:
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-ASA therapy for mildly to moderately active 
ulcerative colitis.  N Engl J Med.  1987;317(26):1625-9.
Lewis JD, Chuai S, Nessel L, et al.  Use of the noninvasive components of the Mayo Score to assess clinical 
response in ulcerative colitis.  Inflamm Bowel Dis.  2008;14(12):1660-6.


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Appendix D.
Sample WPAI Work Productivity and Activity Impairment 
Questionnaire:  Ulcerative Colitis V2.0 (WPAI:UC)
The following questions ask about the effect of your ulcerative colitis on your ability to 
work and perform regular activities.  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 ulcerative colitis?  Include hours you missed on sick 
days, times you went in late, left early, etc., because of your ulcerative colitis.  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 ulcerative colitis 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 usual.  If ulcerative colitis affected your work only a little, 
choose a low number.  Choose a high number if ulcerative colitis affected your 
work a great deal.


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Consider only how much ulcerative colitis affected 
productivity while you were working.
Ulcerative colitis 
had no effect on 
my work
Ulcerative 
colitis 
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 ulcerative colitis 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 ulcerative colitis affected your activities only a little, 
choose a low number.  Choose a high number if ulcerative colitis affected your 
activities a great deal.
Consider only how much ulcerative colitis affected your ability 
to do your regular daily activities, other than work at a job.
Ulcerative colitis 
had no effect on 
my daily 
activities
Ulcerative 
colitis 
completely 
prevented me 
from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
f:\institut\cultadap\project\3052\study3052\final_versions\wpai-ucoriq.doc-18/08/2006


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Appendix E.
Sample Injection Instructions – Pre-Filled Syringe
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M14-033
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 this study:
●
Baseline visit (the first visit to receive study medication for this study), 
Week 1 and Week 2 you will receive 4 injections (2 kits) at the clinic.
●
Week 3 you will administer 4 injections (2 kits) at home.
●
Weeks 4, 8, 10, 12, 16, 22, 29, 35, 42, and 48 you will receive 1 injection at 
the clinic.
●
Weeks 6, 9, 11, 13, 14, 15, 17-21, 23, 25-28, 30 – 34, 36, 38 –41, 43 – 47, and 
49 – 51 you will administer 1 injection at home.
●
Weeks 24 and 37 you will receive 4 injections at the clinic.
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.
Remember to complete your 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.
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.


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●
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 F.
Sample Quality of Life in Inflammatory Bowel Disease 
Questionnaire (IBDQ)
INSTRUCTIONS FOR SELF-ADMINISTERED INFLAMMATORY BOWEL 
DISEASE QUESTIONNAIRE (IBDQ)
This questionnaire is designed to measure the effects of your inflammatory bowel disease 
on your daily function and quality of life.  You will be asked about symptoms you have 
been having as a result of your bowel disease, the way you have been feeling in general, 
and how your mood has been.
There are two versions of this questionnaire, the IBDQ and IBDQ-Stoma.  If you have a 
colostomy or ileostomy, you should complete the IBDQ-Stoma.  Questions 1, 5, 17, 22, 
24 and 26 are slightly different in each version.  Be sure you have the correct 
questionnaire.
On this questionnaire there are 32 questions.  Each question has graded response choices 
numbered from 1 to 7.  Please read each question carefully and answer the number which 
best describes how you have been feeling in the past 2 weeks.
EXAMPLE
How often have you felt unwell as a result of your bowel problem in the past 2 weeks?
1.
ALL OF THE TIME
2.
MOST OF THE TIME
3.
A GOOD BIT OF THE TIME
4.
SOME OF THE TIME
5.
A LITTLE OF THE TIME
6.
HARDLY ANY OF THE TIME
7.
NONE OF THE TIME
If you are having trouble understanding a question, STOP for a moment!  Think about 
what the question means to you.  How is it affected by your bowel problem?  Then answer 


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the question as best you can.  You will have the chance to ask the nurse questions after 
completing the questionnaire.  This takes only a few minutes to complete.
This questionnaire is designed to find out how you have been feeling during the last 
2 weeks.  You will be asked about symptoms you have been having as a result of your 
Ulcerative Colitis disease, the way you have been feeling in general, and how your mood 
has been.
1.
How frequent have your bowel movements been during the last 2 weeks?  Please 
indicate how frequent your bowel movements have been during the last 2 weeks by 
picking one of the options from:
1. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE 
EVER BEEN
2. EXTREMELY FREQUENT
3. VERY FREQUENT
4. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS


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2.
How often has the feeling of fatigue or of being tired and worn out been a problem 
for you during the last 2 weeks?  Please indicate how often the feeling of fatigue or 
tiredness has been a problem for you during the last 2 weeks by picking one of the 
options from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
3.
How often during the last 2 weeks have you felt frustrated, impatient, or restless?  
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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4.
How often during the last 2 weeks have you been unable to attend school or do 
your work because of your bowel problem?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
5.
How much of the time during the last 2 weeks have your bowel movements been 
loose?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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6.
How much energy have you had during the last 2 weeks?  Please choose an option 
from:
1. NO ENERGY AT ALL
2. VERY LITTLE ENERGY
3. A LITTLE ENERGY
4. SOME ENERGY
5. A MODERATE AMOUNT OF ENERGY
6. A LOT OF ENERGY
7. FULL OF ENERGY
7.
How often during the last 2 weeks did you feel worried about the possibility of 
needing to have surgery because of your bowel problem.  Please choose an option 
from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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8.
How often during the last 2 weeks have you had to delay or cancel a social 
engagement because of your bowel problem?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
9.
How often during the last 2 weeks have you been troubled by cramps in your 
abdomen?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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10.
How often during the last 2 weeks have you felt generally unwell?  Please choose 
an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
11.
How often during the last 2 weeks have you been troubled because of fear of not 
finding a washroom?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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12.
How much difficulty have you had, as a result of your bowel problems, doing 
leisure or sports activities you would have liked to have done during the last 
2 weeks?  Please choose an option from:
1. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2. A LOT OF DIFFICULTY
3. A FAIR BIT OF DIFFICULTY
4. SOME DIFFICULTY
5. A LITTLE DIFFICULTY
6. HARDLY ANY DIFFICULTY
7. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS 
OR LEISURE ACTIVITIES
13.
How often during the last 2 weeks have you been troubled by pain in the abdomen?  
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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14.
How often during the last 2 weeks have you had problems getting a good night's 
sleep, or been troubled by waking up during the night?  Please choose an option 
from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
15.
How often during the last 2 weeks have you felt depressed or discouraged?  Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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16.
How often during the last 2 weeks have you had to avoid attending events where 
there was no washroom close at hand?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
17.
Overall, in the last 2 weeks, how much of a problem have you had with passing 
large amounts of gas?  Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE 
7. NO TROUBLE


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18.
Overall, in the last 2 weeks, how much of a problem have you had maintaining or 
getting to, the weight you would like to be at?  Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE 
7. NO TROUBLE
19.
Many patients with bowel problems often have worries and anxieties related to 
their illness.  These include worries about getting cancer, worries about never 
feeling any better, and worries about having a relapse.  In general, how often 
during the last 2 weeks have you felt worried or anxious?  Please choose an option 
from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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20.
How much of the time during the last 2 weeks have you been troubled by a feeling 
of abdominal bloating?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
21.
How often during the last 2 weeks have you felt relaxed and free of tension?  
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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22.
How much of the time during the last 2 weeks have you had a problem with rectal 
bleeding with your bowel movements?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
23.
How much of the time during the last 2 weeks have you felt embarrassed as a result 
of your bowel problem?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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24.
How much of the time during the last 2 weeks have you been troubled by a feeling 
of having to go to the bathroom even though your bowels were empty?  Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
25.
How much of the time during the last 2 weeks have you felt tearful or upset?  
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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26.
How much of the time during the last 2 weeks have you been troubled by 
accidental soiling of your underpants?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
27.
How much of the time during the last 2 weeks have you felt angry as a result of 
your bowel problem?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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28.
To what extent has your bowel problem limited sexual activity during the last 
2 weeks?  Please choose an option from:
1. NO SEX AS A RESULT OF BOWEL DISEASE
2. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4. SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7. NO LIMITATION AS A RESULT OF BOWEL DISEASE
29.
How much of the time during the last 2 weeks have you been troubled by nausea or 
feeling sick to your stomach?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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30.
How much of the time during the last 2 weeks have you felt irritable? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
31.
How often during the past 2 weeks have you felt a lack of understanding from 
others?  Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME


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32.
How satisfied, happy, or pleased have you been with your personal life during the 
past 2 weeks?  Please choose one of the following options from:
1. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2. GENERALLY DISSATISFIED, UNHAPPY
3. SOMEWHAT DISSATISFIED, UNHAPPY
4. GENERALLY SATISFIED, PLEASED
5. SATISFIED MOST OF THE TIME, HAPPY
6. VERY SATISFIED MOST OF THE TIME, HAPPY
7. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY 
OR PLEASED
Copyright© 1989 McMaster University, Hamilton, Ontario, Canada 
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of McMaster 
University (Copyright© 1989, McMaster University).  The IBDQ has been provided under license from McMaster 
University and must not be copied, distributed or used in any way without the prior written consent of McMaster 
University.  Contact the McMaster Industry Liaison Office at McMaster University, email: milo@mcmaster.ca for 
licensing details.
IBDQ – United Kingdom-English – Version of 09 May 08 – Mapi Research Institute. 
ID4529/IBDQ_AU2.0_eng-GB.doc


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Appendix G.
Sample SF-36 v2 Acute, US Version 2.0
Your Health and Well-Being
This survey asks for your views about your health.  This information will help keep 
track of how you feel and how well you are able to do your usual activities.  Thank 
you for completing this survey!
For each of the following questions, please mark an 
in the box that best describes 
your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
1
2
3
4
5
2.
Compared to one year ago, how would you rate your health in general now?
Much better 
now than 
one year ago
Somewhat 
better now than 
one year ago
About the same 
as one year ago
Somewhat 
worse now than 
one year ago
Much worse 
now than 
one year ago
1
2
3
4
5


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3.
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much?
Yes,
limited
a lot
Yes,
limited
a little
No, not
limited
at all
a  Vigorous activities, such as running, lifting 
   heavy objects, participating in strenuous 
   sports
1
2
3
b   Moderate activities, such as moving a table, 
   pushing a vacuum cleaner, bowling, or 
   playing golf
1
2
3
c   Lifting or carrying groceries
1
2
3
d   Climbing several flights of stairs
1
2
3
e   Climbing one flight of stairs
1
2
3
f   Bending, kneeling, or stooping
1
2
3
g   Walking more than a mile
1
2
3
h   Walking several hundred yards
1
2
3
i  Walking one hundred yards
1
2
3
j   Bathing or dressing yourself
1
2
3


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4.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a result 
of your physical health?
All of the 
time
Most of 
the time
Some 
of the 
time
A little 
of the 
time
None of the 
time
a   Cut down on the amount of time you 
   spent on work or other activities
1
2
3
4
5
b   Accomplished less than you would like
1
2
3
4
5
c   Were limited in the kind of work or 
   other activities
1
2
3
4
5
d   Had difficulty performing the work or 
   other activities (for example, it took extra
   effort) 
1
2
3
4
5


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5.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a result 
of any emotional problems (such as feeling depressed or anxious)?
All of 
the 
time
Most 
of the 
time
Some 
of the 
time
A little 
of the 
time
None 
of the 
time
a   Cut down on the amount of time you spent 
    on work or other activities
1
2
3
4
5
b   Accomplished less than you would like
1
2
3
4
5
c   Did work or other activities less carefully 
    than usual
1
2
3
4
5
6.
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
1
2
3
4
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
1
2
3
4
5
6


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8.
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
1
2
3
4
5
9.
These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time during 
the past 4 weeks:
All of the 
time
Most of 
the time
Some of 
the time
A little 
of the 
time
None of 
the time
a   Did you feel full of life?
1
2
3
4
5
b   Have you been very nervous?
1
2
3
4
5
c   Have you felt so down in the dumps 
that nothing could cheer you up?
1
2
3
4
5
d   Have you felt calm and peaceful?
1
2
3
4
5
e   Did you have a lot of energy?
1
2
3
4
5
f   Have you felt downhearted and 
depressed?
1
2
3
4
5
g   Did you feel worn out?
1
2
3
4
5
h   Have you been happy?
1
2
3
4
5
i   Did you feel tired?
1
2
3
4
5


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10.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)?
All of the
time
Most of the
time
Some of the
time
A little of the 
time
None of the
time
1
2
3
4
5
11. How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly
true
Don't
know
Mostly
false
Definitely 
false
a   I seem to get sick a little 
easier than other people
1
2
3
4
5
b   I am as healthy as  anybody I know
1
2
3
4
5
c   I expect my health to get worse
1
2
3
4
5
d   My health is excellent
1
2
3
4
5
THANK YOU FOR COMPLETING THESE QUESTIONS
SF-36v2Health Survey© 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.
SF-36® is a registered trademark of Medical Outcomes Trust
(SF-36v2 Standard, US Version 2.0)


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Appendix H.
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 I.
Sample Bristol Stool Chart


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Appendix J.
70-Day Follow-Up Phone Call – Sample
Site Name/Site Number:  ____________________________
Subject Number:  __________________
Date of last study drug administration (DD/MMM/YY): __________________
Please contact subjects who discontinue adalimumab 70 days following study drug 
discontinuation.
Note:  Subjects who continue commercial adalimumab do not require a 70-day follow-up call.
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
AEs/SAEs Reported
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.)  Any medications taken as a result of the events should also be entered on the eCRF.


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If events are listed above, your monitor will review and retrieve the appropriate eCRF pages during their 
next visit.
If 70-day follow-up call was not performed:
Subject continued adalimumab therapy after the end of their study participation
Other, describe below:
Please fax all completed forms to:
Fax:  
Email:
Subject line:  PI NAME_Subject number_70 day followup


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Appendix K.
Japan Sub-Study
There will be a Japan sub-study that includes only Japanese subjects enrolled from sites in 
Japan.  The subjects enrolled under the Japan sub-study will not be included in the 
primary analyses of the main study nor used for regulatory applications outside of Japan.  
The Japan sub-study will, however, allow the integration of clinical data obtained from all 
other subjects in the main study to support a future regulatory application in Japan.
The main study is to be followed for the Japan sub-study except where indicated as 
outlined below.
4.0
Study Objective of Japan Sub-Study
The study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis and to show the consistency of efficacy between Japanese population and 
integrated population of Japanese and western subjects.
5.0
Investigational Plan of Japan Sub-Study
5.1
Overall Study Design and Plan: Description
The primary analysis for the Japan sub-study during the Induction Study will be an 
analysis of subjects achieving clinical remission (per Full Mayo Score) at Week 8.  The 
primary analysis for the Japan sub-study during the Maintenance Study will be an analysis 
of subjects is the proportion of Week 8 responders achieving clinical remission (per Full 
Mayo score) at Week 52.
The analysis will include approximately 100 subjects (60 in the higher induction dose 
regimen and 40 in the standard induction dose regimen) from 21 Japanese sites and 
approximately 840 subjects from all other sites in the main study.


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44-Week Double-Blind Maintenance Study
The TDM regimen in the maintenance period will not be applied to the Japan sub-study 
because of logistical challenges in obtaining adalimumab serum concentration results 
within the time period specified in the main study.  At the conclusion of the 8-Week 
Double-Blind Induction Study, subjects will return to the study site and will be re 
randomized using the same stratification variables as the main study via IRT into the 
44-Week Double-Blind Maintenance Study to one of two treatment groups in a 1:1 ratio 
with the same stratification from the main study:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
Screening 
Period
Up to 21 days
Double-Blind 
Induction
Study
8 weeks
Double-Blind Maintenance Study
44 weeks
Follow-up
0*  1   2      4             8     10    12            16                     22   24              29                     35    37            42                      48                    52
Week
RR
RR
ADA 40 eow
ADA 40 ew
Std (N=40)
High 
(N=60)
Re-Randomization of all 
subjects
* Randomization
Subjects in the adalimumab 40 mg eow treatment group will continue to receive 40 mg 
eow until the end of the study.  Subjects in the adalimumab 40 mg ew treatment group 
will start 40 mg ew at Week 8 until the end of the study.
5.2.1
Inclusion Criteria
Differences from main study are underlined.


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1.
Subject must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol. If the subject is < 20 years old, a 
subject's parent or legal guardian must be willing to give written informed consent.
2.
Japanese male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3.
Subject with a diagnosis of Ulcerative Colitis for 90 days or greater prior to 
Baseline, confirmed by endoscopy (colonoscopy or flexible sigmoidoscopy) during 
the Screening Period with exclusion of infection, current dysplasia and/or 
malignancy.  Appropriate documentation of biopsy results consistent with the 
diagnosis of UC, in the assessment of the Investigator, must be available.
4.
Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to 3 
(confirmed by central reader) 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 or immunosuppressants as defined below):
●
Subject taking oral corticosteroids, excluding budesonide or beclomethasone:
○
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
●
For subject 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 subject 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 subject 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 subject 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.
●
Subject taking oral beclomethasone:


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○
Dose must not exceed 5 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.
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.
5.
Subject may be included if they have previously experienced a benefit for their UC 
from infliximab and discontinued its use due to a subsequent loss of response 
(i.e., judged by the Investigator to have responded to infliximab in the past and 
subsequently experienced an overall lack of improvement or worsening of UC 
related symptoms) or intolerance (i.e., in the opinion of the investigator therapy 
was discontinued as a result of a significant acute or delayed 


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infusion/administration reaction to the medication).  Confirmed documentation 
indicating loss or response or lack of tolerability will be required, see Section 10.1
and Appendix H.
6.
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 and 
correctly are (see local informed consent for more detail):
●
Implants, injectables, some intrauterine devices (IUDs), intrauterine 
hormone-releasing system (IUS);
●
Sexual abstinence (when in line with preferred and usual lifestyle of the 
subject;
●
A vasectomized partner;
●
Hormonal contraceptives for at least 90 days prior to study drug administration.  
Note:  low-dose progestin-only oral contraceptives such as norethindrone 
0.35 mg and lynestenol 0.5 mg are not considered adequate.
7.
If female, subject is not breast-feeding throughout the study and for 150 days after 
last dose.
8.
Subject has a negative TB Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 21 days of 
an ongoing TB prophylaxis or have documented completion of a full course of TB 
prophylaxis, prior to Baseline (see Section 5.3.1.1).
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, chest x-ray, and a 12-lead ECG performed during Screening.
10.
Subject must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections.


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Rationale for the Difference from Main Study:
The lower doses of azathioprine and 6-MP are recommended for Japanese IBD patients 
because of the difference of TPMT activity between Japanese and western IBD patients.  
The 6-TGN (active metabolite of azathioprine and 6-MP) concentration in Japanese 
patients with IBD on the specified doses of azathioprine and 6-MP therapy is considered 
to be comparable to those reported from Western countries.
5.2.2
Exclusion Criteria
Differences from main study are underlined.
1.
Subject with diagnosis and/or history of Crohn's disease (CD) or diagnosis of 
indeterminate colitis (IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the 
screening endoscopy.
4.
Received therapeutic enema or suppository, other than required for endoscopy, 
within 7 days prior to the Screening endoscopy and during the remainder of the 
Screening Period.
5.
History of subtotal colectomy with ileorectostomy or colectomy with ileoanal 
pouch, Kock pouch, or ileostomy or is planning bowel surgery.
6.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior 
to Baseline.
7.
Positive pregnancy test at Screening (serum) or Baseline (urine).
8.
Female who is breast-feeding or considering becoming pregnant during the study.
9.
History of clinically significant drug or alcohol abuse in the last 12 months.
10.
Subject on azathioprine, 6-MP, MTX, or another immunosuppressant 
(e.g., thalidomide) who:


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●
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.
11.
Subject on oral aminosalicylates who:
●
Has not been on stable doses of these medications for at least 14 days prior to 
Baseline; or
●
Has discontinued use of aminosalicylates within 14 days of Baseline.
12.
Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on 
oral budesonide > 9 mg/day; or subject on oral beclomethasone > 5 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 of at least 
14 days in duration 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 oral 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 of at least 
14 days in duration 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 has not been a current steroid course of at least 
14 days in duration prior to Baseline; or
●
Subject taking oral beclomethasone:
○
has not been on a stable dose for at least 7 days prior to Baseline; or


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●
but has not been on a current steroid course of at least 14 days in 
duration prior to Baseline; or
Has been taking, both oral budesonide (or oral beclomethasone) and oral 
prednisone (or equivalent) simultaneously.
and/or
Has discontinued use of corticosteroids within 14 days of Baseline
13.
Received intravenous corticosteroids within 14 days prior to Screening or during 
the Screening Period.
14.
Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening 
Period.
15.
Currently receiving total parenteral nutrition (TPN).
16.
Subject who received any investigational agent or procedure (including previous 
fecal microbial transplantation) within 30 days or 5 half-lives prior to Week 0 
(Baseline), whichever is longer.
17.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the 
Baseline Visit.
18.
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.
19.
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®]) or 
previous participation in an adalimumab clinical study.  Prior exposure to any 
anti-TNF agent other than infliximab (including but not limited to adalimumab 


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[Humira®], etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or 
vedolizumab (Entyvio®).
20.
Subject with known hypersensitivity to the excipients of adalimumab as stated in 
the prescribing information.
21.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
22.
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.  If the 
Screening endoscopy shows current evidence of dysplasia or malignancy, subject 
may not be enrolled in the study.
23.
History of invasive infection (e.g., listeriosis and histoplasmosis), human 
immunodeficiency virus (HIV).
24.
Subject with any active viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study.
25.
Subjects with a positive result for 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* (+)


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*
For HBs Ab test results, a (–) result is equivalent to nonreactive and a (+) result is 
equivalent to reactive.
26.
Chronic recurring infections or active TB.
27.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and/or any other condition which would put the 
subject at risk by participation in the study.
28.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
29.
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.
30.
Received cytoapheresis treatment (GCAP, LCAP etc.) within 8 weeks prior to 
Baseline.
31.
Received ATM treatment (antibiotic combination therapy with amoxicillin, 
tetracycline and metronidazole) during the Screening Period.
Rationale for the Difference from Main Study:
Concomitant therapies for UC (cytoapheresis treatment and ATM therapy) that are 
possibly used in Japan should be prohibited to avoid bias for the evaluation of efficacy 
and safety by concomitant use of other medications or treatments.
5.2.3.3
Prohibited Therapy
In Japan, the following therapies are also prohibited during the study:


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●
Cytoapheresis treatment (GCAP, LCAP etc.)
●
ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline 
and metronidazole)
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 into the study.


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Table 2.
Study Activities
Screening 
Period 
(21 days)
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Informed Consent
X
Inclusion/Exclusion
X
Xb
Medical/Surgical History
X
Xb
Previous and 
Concomitant Medication
X
Xb
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
X
Schedule Endoscopy
X
X
X
Endoscopy/Biopsyd
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/Hematologyi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisi,j
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
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Pregnancy Testk
X
X
X
Hepatitis B Screen, HIVl
X
hs-CRP
X
X
X
X
X
X
X
X
X
X
X
C. difficile Toxin
X
Provide Stool Kit m
X
X
X
X
X
X
X
Stool Sample (Fecal 
Calprotectin)m
X
X
X
X
X
X
X
Stool Sample (Microbiota 
Metagenomic Analysis)m
X
X
X
X
X
Bristol Stool Chart m
X
X
X
X
X
Antinuclear antibody 
(ANA)/ 
Anti-Double-Stranded 
DNA (anti-dsDNA)n
X
Human Antichimeric 
Antibodies (HACA)/ 
Infliximab Concentrations
X


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Table 2.
Study Activities (Continued)
Screening 
Period
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Adalimumab 
Concentrationo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AAA Concentrationo
X
X
X
X
X
X
X
X
Pharmacogenetic 
(optional)p
X
X
Serologic 
Markers/mRNA
X
X
X
X
X
X
Inflammatory Bowel 
Disease Questionnaire 
(IBDQ)
X
X
X
X
X
X
X
X
Partial Mayo Score
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mayo Score
X
X
X
SF-36
X
X
X
Work Productivity and 
Impairment 
Questionnaire (WPAI)
X
X
X


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Table 2.
Study Activities (Continued)
Screening 
Period
8-Week Double-Blind Induction 
Study
44-Week Double-Blind Maintenance Study
Activity
Screening
Baseline (Week 0)a
Week 1
Week 2
Week 4
Week 8 
(Re-Randomization)
Week 10
Week 12
Week 16
Week 22
Week 24
Week 29
Week 35
Week 37
Week 42
Week 48
Week 52/Premature 
Discontinuation
Unscheduled Visitv
70-Day Follow-Upu
Start Corticosteroid 
Taperq
X
Monitor Adverse Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Daily Diarys
X
Daily Diarys
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Trained on 
Self-Administration of 
Injections
X
Study Drug Dispensing/ 
Administrationt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
The 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.


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Table 2.
Study Activities (Continued)
d.
Subjects will undergo an endoscopy (colonoscopy or flexible sigmoidoscopy) with biopsy for histologic assessment during Screening, at Week 8 and at Week 52/PD (for 
subjects who remain in the study through at least Week 24).  A full colonoscopy will be performed at Screening unless the subject underwent a full colonoscopy within 12 
months prior to Screening and appropriate documentation is available (to confirm the diagnosis and extent of disease and no evidence of dysplasia and colon cancer).  In this 
case, the screening endoscopy may be either a full colonoscopy or a flexible sigmoidoscopy.  Appropriate documentation of biopsy results consistent with the diagnosis of UC, 
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 colon must be performed during the Screening endoscopy and evaluated by a qualified local pathologist and the results reviewed 
by the Investigator.  Biopsies to rule out dysplasia and colon cancer may be taken during any study endoscopy per the Investigator's discretion and evaluated by the local 
pathologist.  The Week 8 and Week 52/PD endoscopies may be either full colonoscopies or flexible sigmoidoscopies.  During allendoscopies, 2 biopsies for histologic 
evaluation by a central laboratory will be taken from each observed colonic segment (see Section 5.3.1.1 for details about biopsy sampling).
e.
Physical examinations performed at Screening, Week 8 and Week 52/PD Visits are full physical examinations which must include an assessment of extra-intestinal 
manifestations (EIMs).  Physical exams performed at all other visits are symptom-based.
f.
Subjects with negative latent TB test(s) (In cases where a subject received both a PPD test and IGRA, both must be negative) within 90 days of Screening will not require a 
repeat latent TB 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 will not require a repeat chest x-ray, if 
documentation is available.
h.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.
i.
Laboratory 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 areprovided in the Laboratory Manual.
k.
A serum pregnancy test will be performed on all women of childbearing potential at Screening.  Urine pregnancy test will be performed at Baseline Visit, and at the Week 
52/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 Section 5.3.1.1 in the Hepatitis B testing section 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.


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Table 2.
Study Activities (Continued)
m.
If a sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit (supplieswill be provided at the time-points indicated).  The 
stool from which these samples are prepared should be scored using the Bristol stool chart by the site.  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.  Remaining sample will be stored for potential researchtesting.
n.
Anti-dsDNA performed if ANA result is positive.
o.
Blood samples for the measurement of adalimumab, AAA concentrations, serologic markers and mRNA will be collected prior to dosing.  Note:  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.
p.
Verify subject has signed consent for optional pharmacogenetic sample prior to the sample drawn.  If the sample is not collected at Baseline, preferably it should be collected 
at the next study visit.
q.
Subjects will begin the 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 Serious Adverse Events (SAEs) begins the day the subject signs the informed consent.
s.
Subjects will be dispensed the subject 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, including during hospitalizations whenever possible.  The diary will be reviewed by site personnel 
with the subject at each visit and collected at the Final/PD visit.
t.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.
u.
Subjects will be contacted 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who continue on adalimumab 
therapy after the end of study participation.
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 and assessment of 
ulcerative colitis.


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5.3.2
Drug Concentration Measurements
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 22 samples (not including unscheduled visit sample collections) are 
planned in Japan to be collected per subject for adalimumab (15 samples) and AAA 
(7 samples) assays.  The total number of samples planned (not including unscheduled visit 
sample collections) will not exceed 1,500 (15 samples × 100 subjects) for the adalimumab 
assay and 700 (7 samples × 100 subjects) for the AAA assay for the sub-study.
Collection of Samples for Infliximab and HACA Assays
Blood samples for infliximab and HACA assay will be collected at Week 0 (Baseline) by 
venipuncture into appropriately labeled 4-mL evacuated serum collection tube 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 for Japan will not exceed 200 (2 samples × 
100 subjects) for the sub-study.
5.5.1
Treatments Administered
Double-Blind Induction Study
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction regimens.


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Subjects assigned to the standard induction regimen will receive adalimumab 160 mg 
(4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  At 
Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes).  At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction regimen will receive 160 mg (4 syringes) at 
Weeks 0, 1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Study
At Week 8, subjects will be re-randomized to receive 1 of 2 double-blind adalimumab 
treatment maintenance regimens in a 1:1 ratio.  
Subjects assigned to the adalimumab 40 mg eow regimen will receive 40 mg (1 syringe) 
at Weeks 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 
50.  Matching Placebo (1 syringe) will be administered at Weeks 9, 11, 13, 15, 17, 19, 21, 
23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51.  No dose will be administered at 
Week 52/Premature Discontinuation.
Subjects assigned to the adalimumab 40 mg ew regimen will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No 
dose will be administered at Week 52/Premature Discontinuation.
5.5.3
Method of Assigning Subjects to Treatment Regimens
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 
Week 0 in a 3:2 ratio into the criteria-driven regimens using the IRT, which will assign a 
randomization number according to the randomization scheme, generated by AbbVie 
before the start of the study.  The randomization will be stratified by previous infliximab 


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use and Baseline corticosteroid use.  The criteria-driven regimen assignment will be 
maintained by the IRT.  Subjects will be referred to by the subject number assigned at 
Screening.
Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Study at the conclusion of the Week 8 Visit to one of 
two treatment regimens in a 1:1 ratio.  Subjects will be re-stratified by:  induction 
treatment regimen and response status (per Full Mayo Score) at Week 8.  Among Week 8 
responders, the randomization will be further stratified by remission status (per Full Mayo 
Score) at Week 8.
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 IRT will be 
provided to each site.  Study drug will be dispensed/administered at the study visits 
summarized in Table 2.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any non-serious event of 
malignancy in subjects 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 SAE or non-serious event of 
malignancy in subjects 30 years of age and younger data into the electronic data capture 
(EDC) system.  Serious adverse events and non-serious events of malignancy in subjects 
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.
Email:  
FAX to:  


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For safety concerns, contact the Immunology Safety Management Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician
 MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Contact Information:
Phone:
Mobile:
Fax:
Email:


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Secondary Contact for Japan (Regional Medical Monitor)
 MD, PhD
Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:
In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) or secondary Japan contact 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 Humira Investigator's Brochure.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
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 
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after a subject has been enrolled, the principal investigator is responsible for notifying 
IEC/Independent Review Board (IRB) regulatory authorities (as applicable), and their 
assigned CRO Clinical Monitor or the following AbbVie Clinical Monitor(s):
CRO Contact:
Linical Co., Ltd.
1-6-1, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan
Office:
Fax:
Email:
AbbVie Contact:
AbbVie GK
3-5-27, Mita, Minato-ku, Tokyo 108-6302, Japan
Office:
Fax:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
The Investigator will record all protocol deviations in the appropriate medical records at 
site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objectives of the statistical analyses of the Japan sub-study are to evaluate the 
efficacy and safety of adalimumab for the induction and maintenance of clinical remission 
in subjects with moderately to severely active ulcerative colitis in the Japanese sites and 
all sites from both the main study and the Japan sub-study. Efficacy analysis will be 


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performed in the integrated Intent to Treat (ITT1) set and the Japan ITT1 set. The safety 
analysis will be conducted in the integrated Safety set and the Japan Safety set, using the 
population defined in Section 8.1.1.  A separate detailed statistical analysis plan (SAP) 
will be completed prior to database lock of the main study and the Japan sub-study.
8.1.1
Analysis Population
The integrated ITT1 (I-ITT1) dataset includes all randomized subjects (at both Japanese 
sites and all other sites in the main study).  The Japan ITT1 (J-ITT1) dataset includes all 
subjects who were randomized at Japanese sites only and will be used for efficacy 
analyses of Japanese subjects separately from other subjects in the main study.  The 
integrated Intent to-Treat maintenance (I-ITT2) population includes all subjects (at both 
Japanese sites and all other sites in the main study) who are re randomized to 40 mg eow 
group and 40 mg ew group at Week 8 (subjects who are re-randomized to TDM group 
will not be included).  The I-ITT2 subjects will be analyzed as randomized.  The I-ITT2 is 
the primary population for the efficacy analysis at Week 52 during the maintenance study.
The J-ITT2 dataset includes all subjects who were re-randomized at Week 8 at Japanese 
sites only and will be used for maintenance efficacy analyses of Japanese subjects 
separately from other subjects in the main study.
The integrated Safety set consists of all subjects (from both Japanese sites and those sites 
following the parent protocol) who received at least one dose of study medication.  The 
Japan Safety set consists of all randomized subjects from Japanese sites who received at 
least one dose of study medication.
8.1.3
Demographics and Baseline Characteristics
Demographics and Baseline characteristics of the study subjects will be summarized 
similarly as the main study for each treatment group using descriptive statistics in both the 
I-ITT1 dataset and the J-ITT1 dataset.  The p-value will be provided to assess the 
comparability of the treatment groups assigned by randomization.  Continuous variables 


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will be analyzed using analysis of variance (ANOVA) and discrete variables will be 
analyzed using chi-square test or Fisher's exact test.
8.1.4
Statistical Analysis of Efficacy
8.1.4.1
Primary Efficacy Variables
The primary efficacy endpoint for the Induction Study is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full 
Mayo score of ≥ 3 points and ≥ 30% from Baseline Plus a decrease in the rectal bleeding 
subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full 
Mayo score) at Week 52.
The primary endpoint for the Induction Study will be analyzed similarly as the main study 
using the I-ITT1 and J-ITT1 sets.  The difference between the treatment groups in the 
proportion of subjects achieving clinical remission at Week 8 will be assessed using 
Cochran-Mantel-Haenszel (CMH) test adjusted for previous infliximab use and Baseline 
corticosteroid use at Baseline.  A CMH based two-sided 95% confidence interval for the 
difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 8 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method).  Subjects with missing Mayo score data for Week 8 will also 
be classified as Week 8 non-responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as 
Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline 
will also be performed for the primary endpoint for the Induction Study.


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For primary analysis of the Maintenance Study will compare the Week 8 responders (per 
Full Mayo Score) in the eow regimen versus the subjects in the ew regimen in the I-ITT2 
and J-ITT2 analysis sets.  The difference between the treatment regimen in the proportion 
of subjects achieving clinical remission at Week 52 will be assessed using Cochran-
Mantel-Haenszel (CMH) test adjusted for Induction treatment regimen and the remitter 
status (per Full Mayo Score) at Week 8.  A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated.  Breslow-Day test 
for homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 52 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method) for the Week 52 endpoint.  Subjects with missing Mayo score 
data for Week 52 will also be classified as Week 52 non-responders.
8.1.4.2
Secondary Efficacy Variables
The analysis for secondary efficacy variables will be performed similarly as the main 
study using the I-ITT1 set and the J-ITT1 set for Induction Study endpoints at Week 8, or 
the I-ITT2 set and the J-ITT2 set for Maintenance Study endpoints at Week 52, where 
appropriate.
8.1.5
Statistical Analysis of Safety
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in 
this study and will be analyzed similarly as the main study for the integrated Safety set 
and the Japan Safety set.
8.1.7
Interim Analyses
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
Week 8 only as well as safety data collected from Baseline through double-blind Week 8 
will be performed only if performed for the main study.  


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8.2
Determination of Sample Size of Japan Sub-study
Section 8.2 of the main study outlines the rationale for the sample size of 840 subjects.  
An additional 100 subjects has been determined as the proper sample size for the Japan 
sub-study based on the following rationale.
Using the same assumptions as the main study with the following:
●
Remission rate for induction treatment at 8 weeks:  35% in the high dose group 
and 20% in the standard dose group
●
Remission rate for maintenance treatment at 52 weeks among Week 8 
responders:  48% in the high dose group and 30% in the standard dose group
●
Overall response rate for induction treatment at Week 8:  50%
●
α = 5%, power = 95% for induction study
●
α = 5%, power = 90% for maintenance study
The precisions of point estimations of remission rates in Japanese population are included 
within the 95% CI of remission rates in integrated population will be within 20% with 
100 subjects.  With this sample size, the probability to show consistency between 
Japanese population and integrated population will be greater than 80% using the 
method 2 shown in the "Basic principles on global clinical trials."15
8.3
Randomization Methods
At Baseline, subjects will be randomized 3:2 to one of two double-blinded adalimumab 
induction regimens (higher dose or standard dose).  The randomization will be stratified 
by previous infliximab use and Baseline corticosteroid use.  At the conclusion of the 
8-week Induction Study, all subjects will be re-randomized into the 44-week Maintenance 
Study.  Re-randomization will be stratified by induction treatment regimen, and response 
status (per Full Mayo Score utilizing the Week 8 endoscopy subscore provided by the 
site) at Week 8.  Among Week 8 responders, the randomization will be further stratified 
by remission status (per Full Mayo Score utilizing the Week 8 endoscopy subscore 


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provided by the site) at Week 8.  All subjects will be randomized into one of two blinded 
treatment regimens in a 1:1 ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg ew
The randomization schedules will be prepared separately for the Japan sub-study by the 
Statistics Department of AbbVie.
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.  If the subject is 
< 20 years old, a subject's parent or legal guardian must be explained and willing to give 
written informed consent.  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.
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 be withdrawn.  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 still 
remain as part of the overall research data.
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.


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9.3.1
Informed Consent Form and Explanatory Material
In Japan, the Principal Investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the Principal Investigator will revise without delay the consent form and 
explanatory material based on the information and will obtain the approval of the IRB 
prior to use in the study.  The Investigator will provide the information, without delay, to 
each subject already participating in the study, and will confirm the intention of each 
subject to continue in the study or not.  The Investigator will also provide further 
explanation using the revised consent form and explanatory material and will obtain 
written consent from each subject of their own free will to continue participating in the 
study.  If the subject is < 20 years old, a subject's parent or legal guardian must be 
explained and willing to give written informed consent.
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 Director of the Site and 
the Sponsor.  Continuation of this study beyond this date must be mutually agreed upon in 
writing by both the Director of the Site and the Sponsor.  The investigator will provide a 
final report to the Director of the Site following conclusion of the study, and the Director 
of the Site will inform the summary of the report to IRB and the Sponsor.
The Director of the Site must retain any records related to the study according to local 
requirements.  If the Director of the Site is not able to retain the records, he/she must 
notify the Sponsor to arrange alternative archiving options.


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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 Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
16.0
Clinical Expense and Compensation
16.1
Expenditure of the Clinical Expense
The sponsor will pay the expenses related to this study to the investigative site in 
accordance with "Special Healthcare Expenditure."  The expenses of screening test, etc. 
will be paid based on the contract concluded with each investigative site.  To lighten the 
burden imposed on the subject with participation to the study, transportation expenses, etc. 
will be paid to the subjects via participating investigative site in accordance with the rules 
of the investigative site.
16.2
Compensation for Health Impairment and Insurance
1.
If a subject suffers some sort of health impairment due to this study, the
investigative site will provide treatment and take other necessary measures.  
Among the expenses required for the treatment, the amount not covered by health 
insurance that the patient must pay directly will be borne by the sponsor only when 
the event is associated with the use of the study drug.
2.
When a subject suffers health impairment during this study and a dispute occurs or 
might occur between the investigative site and the subject, the investigative site 
will immediately report this to the sponsor and resolve it.  The sponsor will 
cooperate with the investigative site in resolving any issues or problems.


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3.
When the investigative site must compensate subject for any health impairment 
caused by this study, the compensation paid by the investigative site and the 
expenses related to any dispute will be borne in full by the sponsor, except in cases 
where the responsibility for the problem is attributed to the investigative site.  This 
shall not apply to cases where the health impairment occurred because the 
investigative site performed the study with marked deviation from the GCP or the 
protocol or because of a deliberate action or a major error by the investigative site.
4.
When a subject suffers health impairment during this study and liability for 
compensation arises, the sponsor will compensate in accordance with the SOP 
regarding the compensation prepared in advance.
5.
The sponsor will obtain clinical study insurance and will take other necessary 
measures to cover the claims and compensation required in such cases.
17.0
Storage of Records
The directors of the investigation sites will retain the "Essential documents to be retained 
by study institutions" specified in the Section 4.9.5 of ICH guideline for the period 
specified the following.
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained.


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Appendix L.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency
  Contact:
All Participating Countries
 MD
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Office:
Mobile:
Fax:
Email:
Secondary Japan Contact:
 MD, PhD
 Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:


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Has been changed to read:
Sponsor/Emergency
  Contact:
All Participating Countries
 MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Office:
Mobile:
Fax:
Email:
Secondary Japan Contact:
 MD, PhD
 Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:


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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-033
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  03 December 2015
Protocol Title:  A Double-Blind, Randomized, Multicenter Study of Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Ulcerative Colitis
Objective:  The primary objective is to evaluate safety and efficacy of higher induction and maintenance 
dosing regimens in subjects with moderately to severely active Ulcerative Colitis (UC).
Investigators:  Multicenter Trial (Investigator information on file at AbbVie).
Study Sites:  Approximately 125 sites for the main study and approximately 21 sites for the Japan 
sub-study.
Study Population:  Male and female subjects ≥ 18 and ≤ 75 years of age with a diagnosis of moderately 
to severely active UC (up to 25% infliximab-experienced).
Number of Subjects to be Enrolled:  For the main study, approximately 525 subjects (315 in the higher 
induction dose regimen and 210 in the standard induction dose regimen) will be enrolled at 
approximately 125 sites worldwide.  There also will be 80 Japanese subjects (48 in the higher induction 
dose regimen and 32 in the standard induction dose regimen) in a Japan sub-study to be enrolled at 
21 Japan sites.  In both the main study and Japan sub-study, up to 25% of subjects with previous 
infliximab exposure may be enrolled.
Methodology:
This Phase 3 study design includes a Screening Period, an 8-Week Double-Blind Induction Period and a 
44-Week Double-Blind Maintenance Period.
Subjects will have moderately to severely active UC as defined by a Mayo Score of 6 to 12 points with 
an endoscopy subscore of 2 or 3, confirmed by a central reader.  Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria will be enrolled into the 8-week Induction Period.  For all 
Mayo Score evaluations throughout the study, the stool frequency and the rectal bleeding subscores will 
be calculated based on entries recorded into the subject's diary based on 5 days prior to each study visit.  
During the Induction Period, subjects will be randomized at Baseline to one of 2 double-blinded 
adalimumab induction regimens (higher dose or standard dose) in a 3:2 ratio, as shown in the following 
figure.  Use of the 3:2 randomization scheme allows for collection of additional safety data with the 
higher induction dose regimen.  The randomization will be stratified by previous infliximab use and 
Baseline corticosteroid use.


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Methodology (Continued):
8-Week Double-Blind Induction Period
The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg at Weeks 4 
and 6 leads to a total adalimumab dose over 8 weeks that is approximately twice that of the standard 
induction dose regimen (720 mg versus 320 mg).  The higher induction dose regimen was designed for 
rapid attainment of higher adalimumab serum concentrations in order to rapidly control inflammation.  
Pre-dosing serum samples for infliximab concentration and human antichimeric antibodies (HACAs) 
will be collected at Week 0.  Pre-dosing serum samples for adalimumab drug levels will be collected at 
Weeks 0, 2, 4, and 8.  Pre-dosing serum samples for anti-adalimumab antibodies will be collected at 
Weeks 0, 4, and 8.
At Week 4, all subjects who are on oral steroids will have their steroid dose tapered according to the 
proposed tapering schedule outlined in the 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.
At the conclusion of the 8-Week Induction Period, all subjects will be re-randomized into the 44-week 
Maintenance Period.  Re-randomization will be stratified by induction treatment regimen and response 
status (per Full Mayo Score) at Week 8.  Among the responders at Week 8, the randomization will be 
further stratified by remission status (per Full Mayo score) at Week 8.  All subjects in the main study 
will be randomized into one of three blinded treatment arms in a 2:2:1 ratio:

Adalimumab 40 mg every other week (eow)

Adalimumab 40 mg every week (ew)

Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory arm)*
*
1) All subjects in the TDM arm will receive 40 mg eow at Week 8 and Week 10.  At Weeks 12, 24, 
and 37, the regimen will be adjusted for subjects meeting the dose adjustment criteria (see table 
below) based on blinded serum concentrations at the prior visit (Weeks 10, 22 and 35, respectively) 
and rectal bleeding subscore at the prior and current visits as follows:

Subjects receiving 40 mg eow who meet the dose adjustment criteria will escalate to 40 mg 
weekly.

Subjects receiving 40 mg ew who meet the dose adjustment criteria will receive a one-time dose 
of 160 mg at the visit, and resume 40 mg ew starting the following week.


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Methodology (Continued):
2) Japan sub-study does not have TDM arm.  Subjects will be randomized into Adalimumab 40 mg 
eow arm or Adalimumab 40 mg ew arm in a 1:1 ratio.
During the maintenance period, pre-dosing serum samples for adalimumab drug levels will be collected 
in all subjects at Weeks 10, 12, 16, 22, 24, 29, 35, 37, 42, 48, 52/Premature Discontinuation (PD), and 
unscheduled visits.  Pre-dosing serum samples for anti-adalimumab antibodies will be collected at 
Weeks 12, 24, 37, 52/PD, and unscheduled visits.
The goal of the TDM regimen is to attain serum adalimumab levels within a targeted concentration range 
(selected based on exposure-response analyses from Study M06-827) while avoiding excessively high 
concentrations.  During maintenance therapy in Study M06-827, concentrations ranged from 0 to 
39.3 µg/mL with eow dosing and 0 to 38.0 µg/mL with ew dosing.  The lower bound (10 µg/mL) of the 
targeted concentration range for the TDM regimen is similar to the median concentrations observed over 
time for the subjects in remission at Week 52 of Study M06-827 (11.4, 10.6, and 10.8 µg/mL, for 
Weeks 8, 32, and 52, respectively).  Use of this concentration as the minimum threshold to trigger dose 
escalation will lead to the majority of subjects achieving concentrations greater than 10 µg/mL.  Since 
serum adalimumab concentrations roughly double with a doubling of dose, an upper bound of 20 µg/mL 
is expected to achieve maximal trough concentrations in the range of the highest trough concentrations 
observed in Study M06-827.  It is expected that approximately 60% of subjects in the TDM arm will 
escalate to ew dosing and 15% or fewer will receive reinduction using this concentration range plus the 
Rectal Bleeding Subscore (RBS) criteria outlined in the table below as a guide to adjust adalimumab 
dosing.
TDM Arm Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/ml to 20 µg/mL
< 1
No
10 µg/ml to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for 
the Rectal Bleeding Subscore for each study visit.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose 
of 160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing arms.


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Methodology (Continued)
Study visits for clinical and safety assessments will be performed at Baseline (Week 0), Weeks 1, 2, 4, 8, 
10, 12, 16, 22, 24, 29, 35, 37, 42, 48, and 52/PD.  All subjects will be provided with a Subject Diary 
where they will record ulcerative colitis-related symptoms (daily stool frequency, abdominal discomfort, 
number of bloody stools, fecal urgency, and general well-being), use of anti-diarrheals, use of 
medications for endoscopy preparation, and study drug dosing information throughout the study.  Blood 
samples will be collected for hs-CRP, adalimumab serum concentrations, anti-adalimumab antibody 
(AAA) levels, and other biomarker analyses.  In addition, stool samples for calprotectin and microbiota 
metagenomic analyses will be collected.  The stool samples should be taken before starting bowel 
preparations for endoscopy.  Subjects will undergo an endoscopy (colonoscopy or flexible 
sigmoidoscopy) with biopsy for histologic assessment during Screening, at Week 8 and at Week 52/PD 
(for subjects who remain in the study through at least Week 24) with local investigator assessment for 
Mayo endoscopic subscore confirmed by a central reader.  The central reviewer scoring will be used for 
all efficacy assessments.  The endoscopy subscore result from the central reviewer during the screening 
period will be used to evaluate the eligibility of a subject to enroll in the study.
Subjects who consent to participate in the optional pharmacogenetic (PG) analysis should have an 
additional blood sample drawn at Baseline and at Week 52/PD.
Subjects will be discontinued from the study if they withdraw consent or if they are deemed unsuitable 
to continue for any reason by the Investigator.  Subjects experiencing an active infection or those for 
whom the investigator feels dose escalation is not advisable should contact the Study Designated 
Physician.
Throughout the study, subjects will only be allowed to change the dosage of UC-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 proposed tapering schedule specified in the Protocol.  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.

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 through the end of the study.  
These subjects will continue to be evaluated in the safety population.
Subjects in whom UC-related medications (defined as oral or rectal aminosalicylates, systemic or rectal 
corticosteroids, or systemic medications affecting the immune system, including thiopurines, MTX, and 
agents listed in the study exclusion criteria) 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 
through the end of the study.  These subjects will continue to be evaluated in the safety population.
Immunosuppressant, corticosteroid, and aminosalicylate doses may be decreased or terminated in the 
event of moderate-to-severe treatment-related toxicities.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion criteria are for subjects enrolled in the main study.  Separate 
Inclusion/Exclusion criteria for subjects recruited in Japan will be followed in the Japan sub-study.
Main Inclusion:
1.
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.
2.
Male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3.
Subject with a diagnosis of UC for 90 days or greater prior to Baseline, confirmed by endoscopy 
(colonoscopy or flexible sigmoidoscopy) during the Screening Period, with exclusion of current 
infection, dysplasia and/or malignancy.  Appropriate documentation of biopsy results consistent 
with the diagnosis of UC, in the assessment of the Investigator, must be available.
4.
Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to 3 (confirmed by 
central reader) 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 or immunosuppressants as 
defined below):

Subject taking oral corticosteroids, excluding budesonide or beclomethasone:

Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);

For subject 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 subject 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 subject 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 subject 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.

Subject taking oral beclomethasone:
o
Dose must not exceed 5 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.
or,

At least a consecutive 42-day course of azathioprine, 6-mercaptopurine (6-MP) or injectable 
methotrexate (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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
Note:  If a subject is taking (both an oral corticosteroid and an immunosuppressant listed above) BOTH 
of the drugs need to meet the above dosing and duration of use criteria.  Oral MTX use is allowed during 
the study (at a stable dose for 28 days prior to Baseline), however prior or current 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.
5.
Subject may be included if they have previously experienced a benefit for their UC from infliximab 
and discontinued its use due to a subsequent loss of response (i.e., judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of UC related symptoms) or intolerance (i.e., in the opinion of the investigator therapy 
was discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication).  Confirmed documentation indicating loss of response or lack of tolerability will be 
required.
6.
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 and correctly 
are (see local informed consent for more detail):

Implants, injectables, some, intrauterine devices (IUDs), intrauterine hormone-releasing system 
(IUS);

Sexual abstinence (when in line with preferred and usual lifestyle of the subject);

A vasectomized partner;

Hormonal contraceptives for at least 90 days prior to study drug administration.
Note:  low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 
0.5 mg are not considered adequate.
7.
If female, subject is not breast-feeding throughout the study and for 150 days after last dose.
8.
Subject has a negative tuberculosis (TB) Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a 
full course of TB prophylaxis, prior to Baseline.
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, chest x-ray, 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Subject with diagnosis and/or history of Crohn's disease (CD) or diagnosis of indeterminate colitis 
(IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
4.
Received therapeutic enema or suppository, other than required for endoscopy, within 7 days prior 
to the Screening endoscopy and during the remainder of the Screening Period.
5.
History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Kock pouch, or 
ileostomy or is planning bowel surgery.
6.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
7.
Positive pregnancy test at Screening (serum) or Baseline (urine).
8.
Female who is breast-feeding or considering becoming pregnant during the study.
9.
History of clinically significant drug or alcohol abuse in the last 12 months.
10. Subject on azathioprine, 6-MP, 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.
11. Subject on oral aminosalicylates who:

Has not been on stable doses of these medications for at least 14 days prior to Baseline; or

Has discontinued use of aminosalicylates within 14 days of Baseline.
12. Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on oral budesonide 
> 9 mg/day; or subject on oral beclomethasone > 5 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 of at least 14 days in 
duration 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 oral 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 of at least 14 days in duration 
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 has not been a current steroid course of at least 14 days in duration 
prior to Baseline; or


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):

Subject taking oral beclomethasone:
o
has not been on a stable dose for at least 7 days prior to Baseline; or
o
but has not been on a current steroid course of at least 14 days in duration prior to Baseline; 
or
Has been taking both oral budesonide (or oral becomethasone) and oral prednisone (or equivalent) 
simultaneously
and/or 
Has discontinued use of corticosteroids within 14 days of Baseline.
13. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
14. Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening Period.
15. Currently receiving total parenteral nutrition (TPN).
16. Subject who received any investigational agent or procedure (including previous fecal microbial 
transplantation) within 30 days or 5 half-lives prior to Week 0 (Baseline), whichever is longer.
17. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
18. 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.
19. 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®]) or previous participation in an adalimumab clinical study.  Prior exposure to any 
anti-tumor necrosis factor (TNF) agent other than infliximab (including but not limited to 
adalimumab [Humira®], etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).
20. Subject with known hypersensitivity to the excipients of adalimumab (see Protocol).
21. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
22. 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.  If the Screening endoscopy shows evidence of current 
dysplasia or malignancy, subject may not be enrolled in the study.
23. History of invasive infection (e.g., listeriosis and histoplasmosis), human immunodeficiency virus 
(HIV).
24. Subject with 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):
25. 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 (+)
26. Chronic recurring infections or active TB.
27. History of moderate to severe congestive heart failure (NYHA class III or IV), recent 
cerebrovascular accident and/or any other condition which would put the subject at risk by 
participation in the study.
28. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
29. 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.
Investigational Products:
Adalimumab
Double-Blind Induction 
Doses:
NOTE:  In order to retain 
blinding across regimens, all 
subjects in the Standard 
Induction Dose Regimen will 
receive matching placebo 
injections in addition to the 
adalimumab injection at 
Weeks 1, 2 and 3.
Subjects will be randomized to receive one of 2 double-blind 
adalimumab induction regimens.
Standard Induction Dose Regimen:  160 mg at Week 0 and matching 
placebo at Week 1.  Subjects will receive 80 mg at Week 2 and 
matching placebo at Week 3.  Subjects will receive 40 mg at Week 4 
and Week 6.
Higher Induction Dose Regimen:  160 mg at Weeks 0, 1, 2, and 3.
Subjects will receive 40 mg at Week 4 and Week 6.


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Double-Blind Maintenance 
Doses:
Subjects will be re-randomized to receive one of 3 double-blind 
adalimumab maintenance regimens.
Adalimumab 40 mg eow Regimen:  40 mg every other week, starting at 
Week 8 until Week 50.  Matching Placebo will be administered every 
other week, starting at Week 9 until Week 51.  No dose will be 
administered at Week 52.
Adalimumab 40 mg ew Regimen:  40 mg every week, starting at 
Week 8 until Week 51.  No dose will be administered at Week 52.
Adalimumab TDM Regimen:  40 mg eow at Week 8 and Week 10.  
Matching placebo at Week 9 and Week 11.  At Weeks 12, 24 and 37, 
the regimen will be adjusted for subjects meeting specified criteria.  
Subjects receiving 40 mg eow and meeting the regimen adjustment 
criteria will escalate to 40 mg weekly.  Subjects receiving 40 mg ew and 
meeting the regimen adjustment criteria will receive a one-time dose of 
160 mg at the visit, followed by 40 mg ew starting the following week. 
Subjects receiving 40 mg eow who do not meet the regimen adjustment 
criteria will receive adalimumab 40 mg eow and placebo at alternative 
weeks.  No dose will be administered at Week 52.
NOTE:  In order to retain blinding across regimens, all subjects in the 
40 mg eow and 40 mg ew regimen arms and subjects who do not meet 
the criteria for dose escalation in the TDM regimen arm will receive 
matching placebo injections in addition to the adalimumab injection 
(placebo reinduction) at Weeks 24 and 37.
Mode of Administration:
Subcutaneous injection (SC)
Duration of Treatment:  The treatment period is 52 weeks (8 weeks of induction therapy followed by 
44 weeks of maintenance therapy).  There will be a 70-day follow-up phone call for subjects who 
complete the study or discontinue from the study prematurely.  The 70-day follow-up phone call will not 
be required for any subject who initiates commercial adalimumab.
Criteria for Evaluation:
The following analysis is for subjects recruited in the main study.  A separate statistical analysis will be 
performed for subjects recruited in the Japan sub-study and for all subjects recruited in the main study 
and the Japan sub-study.
Efficacy:
For Week 8 endpoints, this study will compare the subjects in the higher adalimumab induction dose 
regimen versus the standard adalimumab induction dose regimen.  For Week 52 endpoints, this study 
will compare the subjects in the eow regimen versus the ew regimen.  The TDM regimen will be used 
for exploratory analyses.
The primary efficacy endpoint is:

Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with no 
subscore > 1) at Week 8.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) include:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 0 or 1) at 
Week 8.


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Criteria for Evaluation (Continued):
Efficacy (Continued):
2.
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full Mayo score of 
≥ 3 points and ≥ 30% from Baseline Plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) achieving clinical remission (per Full Mayo score) at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
4.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are 
steroid-free for at least 90 days at Week 52.
5.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are 
steroid-free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission (per Full Mayo 
score) at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
8.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are 
steroid-free for at least 90 days at Week 52.
9.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are 
steroid-free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
10. Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.
11. Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) at Week 8.
12. Proportion of Week 8 responders (per Full Mayo score) with IBDQ response (increase of IBDQ 
≥16 from Baseline) at Week 52.
13. Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
14. Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
15. Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
16. Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
17. Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.
18. Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.
Additional pre-specified endpoints include but are not limited to the following:

Evaluation of adalimumab concentrations and immunogenicity at the time of loss of clinical 
remission.

Assessment of the relationship between adalimumab serum concentrations and efficacy during 
induction and maintenance by Week 8 response status.

Analysis of the impact of immunogenicity on safety, pharmacokinetics, and efficacy.

Proportion of subjects who are taking corticosteroids at Baseline and are steroid-free over time.


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Criteria for Evaluation (Continued):
Efficacy (Continued):

Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are 
steroid-free for at least 180 days and in clinical remission (per Full Mayo score) at Week 52.

Proportion of subjects achieving clinical remission per Partial Mayo (defined as a Partial Mayo 
score ≤ 2 with no subscore > 1) score over time.

Proportion of subjects achieving clinical response per Partial Mayo score (defined as a decrease in 
Partial Mayo score of ≥ 2 points and ≥30% from Baseline Plus a decrease in the rectal bleeding 
subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) over time.

Change from Baseline in hs-CRP over time.

Change from Baseline in corticosteroid dose over time.

Change from Baseline in IBDQ score over time.

Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores over time.

Change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, hematocrit, 
albumin, total protein concentration, and weight).

Change from Baseline in subject-reported stool frequency (absolute values).

Change from Baseline in work productivity and impairment questionnaire (WPAI) scores over time.

Change from Baseline in SF-36 score over time.

Proportion of Week 8 responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic improvement at 
Week 52.

All-cause and UC-related hospitalization and surgery rates during Weeks 0 – 8.

All cause and UC-related hospitalization and surgery rates during Weeks 8 – 52.

Change from Baseline in fecal calprotectin over time.

Time to achievement of remission (per Partial Mayo score).

Time to achievement of response (per Partial Mayo score).

Time to loss of response and factors associated with loss of response.

Change from Baseline in histologic score at Week 8.

Change from Baseline in histologic score at Week 52.

Proportion of subjects achieving clinical remission per Full Mayo score (defined as Full Mayo 
score, excluding the PGA subscore, ≤ 2 with no subscore > 1) at Week 8.

Proportion of Week 8 responders (per Full Mayo score) achieving clinical remission (per Full Mayo 
score, excluding the PGA subscore) at Week 52.

Change in presence of extraintestinal manifestations over time.
Additional analyses are outlined in the protocol.


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Criteria for Evaluation (Continued):
Pharmacokinetics:
Blood samples will be collected for the measurement of serum adalimumab concentrations just prior to 
dosing at Baseline and Weeks 2, 4, 8, 10, 12, 16, 22, 24, 29, 35, 37, 42, 48, 52 (or at the PD visit if the 
subject discontinues prior to Week 52), and unscheduled visits.  Pre-dosing serum samples for HACAs 
and infliximab concentrations will be collected at Week 0.
Blood samples will be collected for the measurement of AAA just prior to dosing at Baseline and 
Weeks 4, 8, 12, 24, 37, 52 (or at the PD visit if the subject discontinues prior to Week 52), and 
unscheduled visits.
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:
The following statistical analysis plan is for subjects recruited in the main study.  A separate statistical 
analysis plan will be provided for subjects recruited in the Japan sub-study and for all the subjects 
recruited in the main study and the Japan sub-study (See Appendix K).
Efficacy:
The primary endpoint is the proportion of subjects achieving clinical remission (defined as a Full Mayo 
score ≤2 with no subscore > 1) at Week 8 in the intent-to-treat (ITT) analysis set.  The ITT analysis set 
includes all randomized subjects.  The difference between the higher induction regimen arm versus the 
standard induction regimen arm in the proportion of subjects achieving clinical remission at Week 8 will 
be assessed using Cochran-Mantel-Haenszel (CMH) test adjusted for previous infliximab use, and 
Baseline corticosteroid use.  A CMH based two-sided 95% confidence interval for the difference 
between treatment arms will be calculated.  Breslow-Day test for homogeneity of odds ratios will be 
performed as well.  Subjects with missing primary endpoint data at Week 8 will be classified as "no 
clinical remission" (non-responder imputation [NRI] method) for the Week 8 endpoint.  Subjects with 
missing Mayo score data for Week 8 will also be classified as Week 8 non-responders for the Week 52 
analyses.  As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as IMM use at Baseline, Baseline 
CRP, and disease severity at Baseline will also be performed for the primary endpoint.
For CMH test statistic, if the condition of each stratum to have at least one subject with each treatment 
and at least one subject with each possible outcome is violated for the primary approach to the primary 
efficacy endpoint, the stratification factor Baseline corticosteroid use will be dropped from the CMH 
model in the analysis of all categorical variables.


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Statistical Methods (Continued):
Efficacy (Continued): 
The 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 an alpha level 
of 0.050 (two-sided) in ranked endpoint order until the significant level exceeds 0.05.  No additional 
statistically significant treatment differences could be declared if the preceding ranked endpoint fails to 
achieve 0.05.  The second group includes all other additional secondary variables.  For Week 8 
endpoints, the difference between the higher adalimumab induction arm versus the standard adalimumab 
induction arm will be assessed using ITT analysis set.  For Week 52 endpoints, the difference between 
the eow arm versus the ew arm will be assessed using Intent-to-Treat maintenance (ITT-M) analysis set.  
The ITT-M analysis set includes all subjects who were re-randomized at Week 8.  Categorical data will 
be described by frequency and percentage; continuous data will be described by mean, standard 
deviation, minimum, median, and maximum.  In general, the secondary endpoints at Week 8 that are of 
the binary type will be analyzed using a two-sided CMH test adjusted for previous infliximab use and 
Baseline corticosteroid use in the ITT analysis set, and the secondary endpoints at Week 52 that are of 
the binary type will be analyzed using a two-sided CMH test adjusted for induction treatment regimen, 
and remitter status (per Full Mayo score) at Week 8 (where applicable) in the ITT-M analysis set.  
Additionally, the two-sided 95% confidence interval for the difference in proportions will be provided.  
Continuous secondary efficacy variables will be analyzed using Analysis of Covariance (ANCOVA) 
with factor for treatment arm, stratification variables and Baseline values.  NRI for missing data will be 
used for categorical endpoints.  Procedures for handling missing data for continuous endpoints will be 
described in the Statistical Analysis Plan.
Pharmacokinetic:
Adalimumab trough serum concentrations will be summarized by treatment arm 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 positivity will be 
calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s),
and treatment emergent adverse events may be evaluated.


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Statistical Methods (Continued):
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 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 medication and within 70 days after the last dose of the study medication.  
Treatment-emergent AEs will be summarized separately for the double-blind induction period (Week 0 
to Week 8), double-blind maintenance period (Week 8 to 70 days after the last dose of the study 
medication), and Study M14-033 (Week 0 to 70 days after the last dose of the study medication).  An 
overview of treatment-emergent AEs, including AEs of special interest such as adverse events leading to 
death and adverse events leading to PD (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.  Other safety variables like laboratory data will be described by descriptive statistics.  In 
addition, shift tables and listings will be provided for abnormal values, whereby the normal range of the 
analyzing laboratory will be used.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-033
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  16 June 2016
Protocol Title:  A Double-Blind, Randomized, Multicenter Study of Higher Versus Standard 
Adalimumab Dosing Regimens for Induction and Maintenance Therapy in Subjects with Moderately to 
Severely Active Ulcerative Colitis
Objective:  The objective is to evaluate safety and efficacy of higher induction and maintenance dosing 
regimens in subjects with moderately to severely active Ulcerative Colitis (UC).  
Investigators:  Multicenter Trial (Investigator information on file at AbbVie).
Study Sites:  Approximately 125 sites for the main study and approximately 21 sites for the Japan 
sub-study.
Study Population:  Male and female subjects ≥ 18 and ≤ 75 years of age with a diagnosis of moderately 
to severely active UC (up to 25% infliximab-experienced).
Number of Subjects to be Enrolled:  For the main Induction Study, approximately 840 subjects 
(504 subjects in the higher induction dose regimen and 336 subjects in the standard induction dose 
regimen) will be enrolled at approximately 125 sites worldwide.  All subjects who complete the 
Induction Study (regardless of achievement of response at Week 8) will continue into the Maintenance 
Study.  An additional 100 Japanese subjects (60 in the higher induction dose regimen and 40 in the 
standard induction dose regimen) in a Japan sub-study will be enrolled at 21 Japan sites.  In both the 
main study and Japan sub study, up to 25% of subjects with previous infliximab exposure may be 
enrolled.
Methodology:
This Phase 3 study design includes the Screening Period followed by an 8-Week double blind Induction 
Study and a 44-Week double blind Maintenance Study.   
The Induction Study:  will evaluate the efficacy and safety of a higher induction dosing regimen of 
adalimumab versus standard induction dosing in inducing clinical remission at Week 8 in subjects with 
moderately to severely active UC.  
The Maintenance Study:  will evaluate the safety and efficacy of 44 weeks of three maintenance dosing 
regimens of adalimumab in achieving clinical remission at Week 52 (from the Induction Study Baseline) 
in subjects with moderately to severely active UC who achieved clinical response at Week 8 of the 
Induction Study.


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Methodology (Continued):
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 8 will represent the final assessment in the 
Induction Study.  Week 52 will represent the final assessment in the Maintenance Study (representing 
44 weeks of maintenance treatment in the Maintenance Study).  Subjects will have moderately to 
severely active UC as defined by a Mayo Score of 6 to 12 points with an endoscopy subscore of 2 or 3, 
confirmed by a central reader.  For all Mayo Score evaluations throughout the entire study, the stool 
frequency and the rectal bleeding subscores will be calculated based on entries recorded into the 
subject's diary.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
Induction Study.  During the Induction Study, subjects will be randomized at Baseline to one of 
2 double-blinded adalimumab induction regimens (higher dose or standard dose) in a 3:2 ratio, as shown 
in the following figure.  Use of the 3:2 randomization scheme allows for collection of additional safety 
data with the higher induction dose regimen.  The randomization will be stratified by previous infliximab 
use and Baseline corticosteroid use.
8-Week Double-Blind Induction Study
The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg at Weeks 4 
and 6 leads to a total adalimumab dose over 8 weeks that is approximately twice that of the standard 
induction dose regimen (720 mg versus 320 mg).  The higher induction dose regimen was designed for 
rapid attainment of higher adalimumab serum concentrations in order to rapidly control inflammation.  
Pre dosing serum samples for infliximab concentration and human antichimeric antibodies (HACAs) 
will be collected at Week 0.  Pre-dosing serum samples for adalimumab drug levels will be collected at 
Weeks 0, 2, 4, and 8.  Pre-dosing serum samples for anti-adalimumab antibodies will be collected at 
Weeks 0, 4, and 8.


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Methodology (Continued):
At Week 4, all subjects who are taking oral corticosteroids from Baseline will have their corticosteroid 
therapy tapered according to the proposed tapering schedule specified in the 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.
At the conclusion of the 8-Week Induction Study, all subjects will be re-randomized into the 44-week 
Maintenance Study.  Re-randomization into the Maintenance Study will be stratified by induction 
treatment regimen in the Induction Study and response status (per Full Mayo Score) at Week 8.  Among 
the responders at Week 8, the re-randomization will be further stratified by remission status (per Full 
Mayo score) at Week 8.  All subjects in the main study who complete the Induction Study) will be re-
randomized into one of three blinded treatment groups in a 2:2:1 ratio:

Adalimumab 40 mg every other week (eow)

Adalimumab 40 mg every week (ew)

Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory)*
*
1) All subjects in the TDM dosing regimen will receive 40 mg eow at Week 8 and Week 10.  At 
Weeks 12, 24, and 37, the regimen will be adjusted for subjects meeting the dose adjustment 
criteria (see table below) based on blinded serum concentrations at the prior visit (Weeks 10, 22 and 
35, respectively) and rectal bleeding subscore at the prior and current visits as follows:

Subjects receiving 40 mg eow who meet the dose adjustment criteria will escalate to 40 mg 
weekly.

Subjects receiving 40 mg ew who meet the dose adjustment criteria will receive a one-time dose 
of 160 mg at the visit, and resume 40 mg ew starting the following week.
2) Japan sub-study does not have TDM dosing regimen.  Subjects will be re-randomized into 
Adalimumab 40 mg eow treatment group or Adalimumab 40 mg ew treatment group in a 1:1 ratio.
Pre-dosing serum samples for adalimumab drug levels will be collected in all subjects at Weeks 10, 12, 
16, 22, 24, 29, 35, 37, 42, 48, 52/Premature Discontinuation (PD), and unscheduled visits.  Pre-dosing 
serum samples for anti-adalimumab antibodies will be collected at Weeks 12, 24, 37, 52/PD, and 
unscheduled visits.
The goal of the TDM dosing regimen is to attain serum adalimumab levels within a targeted 
concentration range (selected based on exposure-response analyses from Study M06-827) while 
avoiding excessively high concentrations.  During maintenance therapy in Study M06-827, 
concentrations ranged from 0 to 39.3 µg/mL with eow dosing and 0 to 38.0 µg/mL with ew dosing.  The 
lower bound (10 µg/mL) of the targeted concentration range for the TDM dosing regimen is similar to 
the median concentrations observed over time for the subjects in remission at Week 52 of 
Study M06-827 (11.4, 10.6, and 10.8 µg/mL, for Weeks 8, 32, and 52, respectively).  Use of this 
concentration as the minimum threshold to trigger dose escalation will lead to the majority of subjects 
achieving concentrations greater than 10 µg/mL.  Since serum adalimumab concentrations roughly 
double with a doubling of dose, an upper bound of 20 µg/mL is expected to achieve maximal trough 
concentrations in the range of the highest trough concentrations observed in Study M06-827.  It is 
expected that approximately 60% of subjects in the TDM dosing regimen will escalate to ew dosing and 
15% or fewer will receive reinduction using this concentration range plus the Rectal Bleeding Subscore 
(RBS) criteria outlined in the table below as a guide to adjust adalimumab dosing.


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Methodology (Continued):
TDM Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/ml to 20 µg/mL
< 1
No
10 µg/ml to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for 
the Rectal Bleeding Subscore for each study visit.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose 
of 160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing regimens.
  
Study visits for clinical and safety assessments will be performed at Baseline (Week 0), Weeks 1, 2, 4, 8, 
10, 12, 16, 22, 24, 29, 35, 37, 42, 48, and 52/PD.  All subjects will be provided with a Subject Diary 
where they will record ulcerative colitis-related symptoms (daily stool frequency, abdominal discomfort, 
number of bloody stools, fecal urgency, and general well-being), use of anti-diarrheals, use of 
medications for endoscopy preparation, and study drug dosing information throughout the study.  Blood 
samples will be collected for hs-CRP, adalimumab serum concentrations, anti-adalimumab antibody 
(AAA) levels, and other biomarker analyses.  In addition, stool samples for calprotectin and microbiota 
metagenomic analyses will be collected.  The stool samples should be taken before starting bowel 
preparations for endoscopy.  Subjects will undergo an endoscopy (colonoscopy or flexible 
sigmoidoscopy) with biopsy for histologic assessment during Screening, at Week 8 and at Week 52/PD 
(for subjects who remain in the study through at least Week 24) with local investigator assessment for 
Mayo endoscopic subscore confirmed by a central reader.  The central reviewer scoring will be used for 
all efficacy assessments.  The endoscopy subscore result from the central reviewer during the screening 
period will be used to evaluate the eligibility of a subject to enroll in the study.
Subjects who consent to participate in the optional pharmacogenetic (PG) analysis should have an 
additional blood sample drawn at Baseline and at Week 52/PD.  If the sample is not collected at 
Baseline, preferably it should be collected at the next study visit.
Subjects will be discontinued if they withdraw consent or if they are deemed unsuitable to continue for 
any reason by the Investigator.  Subjects experiencing an active infection or those for whom the 
investigator feels dose escalation is not advisable should contact the Study Designated Physician.


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Methodology (Continued):
Subjects will only be allowed to change the dosage of UC-specific concomitant medications as specified 
below:

At Week 4, all subjects who are taking oral corticosteroids from Baseline will have their 
corticosteroid therapy tapered according to the proposed tapering schedule specified in the 
Protocol.  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.

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.
Subjects in whom UC-related medications (defined as oral or rectal aminosalicylates, systemic or rectal 
corticosteroids, or systemic medications affecting the immune system, including thiopurines, MTX, and 
agents listed in the study exclusion criteria) 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.
Immunosuppressant, corticosteroid, and aminosalicylate doses may be decreased or terminated in the 
event of moderate-to-severe treatment-related toxicities.
Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion criteria are for subjects enrolled in the main study.  Separate 
Inclusion/Exclusion criteria for subjects recruited in Japan will be followed in the Japan sub-study.
Main Inclusion:
1.
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.
2.
Male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3.
Subject with a diagnosis of UC for 90 days or greater prior to Baseline, confirmed by endoscopy 
(colonoscopy or flexible sigmoidoscopy) during the Screening Period, with exclusion of current 
infection, dysplasia and/or malignancy.  Appropriate documentation of biopsy results consistent with 
the diagnosis of UC, in the assessment of the Investigator, must be available.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
4.
Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to 3 (confirmed by 
central reader) 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 or immunosuppressants as 
defined below):

Subject taking oral corticosteroids, excluding budesonide or beclomethasone:
o
Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);

For subject 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 subject 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 subject 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 subject 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.

Subject taking oral beclomethasone:
o
Dose must not exceed 5 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.
or,

At least a consecutive 42-day course of azathioprine, 6-mercaptopurine (6-MP) or injectable 
methotrexate (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 dosing and duration of use criteria.  Oral MTX use is allowed during 
the study (at a stable dose for 28 days prior to Baseline), however prior or current 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.


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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 for their UC from infliximab 
and discontinued its use due to a subsequent loss of response (i.e., judged by the Investigator to have 
responded to infliximab in the past and subsequently experienced an overall lack of improvement or 
worsening of UC related symptoms) or intolerance (i.e., in the opinion of the investigator therapy 
was discontinued as a result of a significant acute or delayed infusion/administration reaction to the 
medication).  Confirmed documentation indicating loss of response or lack of tolerability will be 
required.
6.
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 and correctly 
are (see local informed consent for more detail):

Implants, injectables, some, intrauterine devices (IUDs), intrauterine hormone-releasing system 
(IUS);

Sexual abstinence (when in line with preferred and usual lifestyle of the subject);

A vasectomized partner;

Hormonal contraceptives for at least 90 days prior to study drug administration.
Note:  low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 
0.5 mg are not considered adequate.
7.
If female, subject is not breast-feeding throughout the study and for 150 days after last dose.
8.
Subject has a negative tuberculosis (TB) Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a 
full course of TB prophylaxis, prior to Baseline.
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, chest x-ray, 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 diagnosis and/or history of Crohn's disease (CD) or diagnosis of indeterminate colitis 
(IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
4.
Received therapeutic enema or suppository, other than required for endoscopy, within 7 days prior 
to the Screening endoscopy and during the remainder of the Screening Period.
5.
History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Kock pouch, or 
ileostomy or is planning bowel surgery.
6.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
7.
Positive pregnancy test at Screening (serum) or Baseline (urine).
8.
Female who is breast-feeding or considering becoming pregnant during the study.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
9.
History of clinically significant drug or alcohol abuse in the last 12 months.
10. Subject on azathioprine, 6-MP, 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.
11. Subject on oral aminosalicylates who:

Has not been on stable doses of these medications for at least 14 days prior to Baseline; or

Has discontinued use of aminosalicylates within 14 days of Baseline.
12. Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on oral budesonide 
> 9 mg/day; or subject on oral beclomethasone > 5 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 of at least 14 days in 
duration 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 oral 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 of at least 14 days in duration 
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 has not been a current steroid course of at least 14 days in duration 
prior to Baseline; or

Subject taking oral beclomethasone:
o
has not been on a stable dose for at least 7 days prior to Baseline; or
o
but has not been on a current steroid course of at least 14 days in duration prior to Baseline; 
or
Has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) 
simultaneously
and/or 
Has discontinued use of corticosteroids within 14 days of Baseline.
13. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
14. Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening Period.
15. Currently receiving total parenteral nutrition (TPN).


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
16. Subject who received any investigational agent or procedure (including previous fecal microbial 
transplantation) within 30 days or 5 half-lives prior to Week 0 (Baseline), whichever is longer.
17. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
18. 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.
19. 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®]) or previous participation in an adalimumab clinical study.  Prior exposure to any 
anti-tumor necrosis factor (TNF) agent other than infliximab (including but not limited to 
adalimumab [Humira®], etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol 
[Cimzia®]).  Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab 
(Entyvio®).
20. Subject with known hypersensitivity to the excipients of adalimumab (see Protocol).
21. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
22. 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.  If the Screening endoscopy shows evidence of current 
dysplasia or malignancy, subject may not be enrolled in the study.
23. History of invasive infection (e.g., listeriosis and histoplasmosis), human immunodeficiency virus 
(HIV).
24. Subject with any active viral infection that based on the investigator's clinical assessment makes the 
subject an unsuitable candidate for the study.
25. 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.
26. Chronic recurring infections or active TB.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
27. History of moderate to severe congestive heart failure (NYHA class III or IV), recent 
cerebrovascular accident and/or any other condition which would put the subject at risk by 
participation in the study.
28. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
29. 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.
Investigational Products:
Adalimumab
Induction Study: 
Double-Blind Induction 
Doses:
NOTE:  In order to retain 
blinding, all subjects in the 
Standard Induction Dose 
Regimen will receive 
matching placebo injections 
in addition to the adalimumab 
injection at Weeks 1, 2 and 3.
Subjects will be randomized to receive one of 2 double-blind 
adalimumab induction dosing regimens.
Standard Induction Dose Regimen:  160 mg at Week 0 and matching 
placebo at Week 1.  Subjects will receive 80 mg at Week 2 and 
matching placebo at Week 3.  Subjects will receive 40 mg at Week 4 
and Week 6.
Higher Induction Dose Regimen:  160 mg at Weeks 0, 1, 2, and 3.
Subjects will receive 40 mg at Week 4 and Week 6.


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Maintenance Study:
Double-Blind Maintenance 
Doses:
Subjects will be re-randomized to receive one of 3 double-blind 
adalimumab maintenance dosing regimens.
Adalimumab 40 mg eow Regimen:  40 mg every other week, starting at 
Week 8 until Week 50.  Matching Placebo will be administered every 
other week, starting at Week 9 until Week 51.  No dose will be 
administered at Week 52.
Adalimumab 40 mg ew Regimen:  40 mg every week, starting at 
Week 8 until Week 51.  No dose will be administered at Week 52.
Adalimumab TDM Regimen:  40 mg eow at Week 8 and Week 10.  
Matching placebo at Week 9 and Week 11.  At Weeks 12, 24 and 37, 
the regimen will be adjusted for subjects meeting specified criteria.  
Subjects receiving 40 mg eow and meeting the regimen adjustment 
criteria will escalate to 40 mg weekly.  Subjects receiving 40 mg ew and 
meeting the regimen adjustment criteria will receive a one-time dose of 
160 mg at the visit, followed by 40 mg ew starting the following week.  
Subjects receiving 40 mg eow who do not meet the regimen adjustment 
criteria will receive adalimumab 40 mg eow and placebo at alternative 
weeks.  No dose will be administered at Week 52.
NOTE:  In order to retain blinding, all subjects in the 40 mg eow and 
40 mg ew regimen groups and subjects who do not meet the criteria for 
dose escalation in the TDM regimen group will receive matching 
placebo injections in addition to the adalimumab injection (placebo 
reinduction) at Weeks 24 and 37.
Mode of Administration:
Subcutaneous injection (SC)
Duration of Treatment:  The overall study treatment duration is 52 weeks (8 weeks of induction 
therapy during the Induction Study followed by 44 weeks of maintenance therapy during the 
Maintenance Study).  There will be a 70-day follow-up phone call for subjects who complete the study 
or discontinue from the study prematurely.  The 70-day follow-up phone call will not be required for any 
subject who initiates commercial adalimumab.
Criteria for Evaluation:
The following analysis is for subjects recruited in the main study.  A separate statistical analysis will be 
performed for subjects recruited in the Japan sub-study and for all subjects recruited in the main study 
and the Japan sub-study.
Efficacy:
For the Induction Study endpoints, the subjects receiving the higher adalimumab induction dose regimen 
will be compared to subjects receiving the standard adalimumab induction dose regimen.  For the 
Maintenance Study endpoints, the subjects receiving the eow regimen will be compared to subjects 
receiving the ew regimen.  The TDM regimen will be used for exploratory analyses.  For the primary 
endpoints, clinical remission or response will be evaluated using Full Mayo Score.  Exploratory analysis 
will also be performed using Full Mayo Score excluding PGA (Adapted Mayo Score) and Full Mayo 
Score excluding Endoscopy Subscore (Partial Mayo Score).


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Criteria for Evaluation (Continued):
Efficacy (Continued):
The primary efficacy endpoint for the Induction Study is:

Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with no 
subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:

Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full Mayo 
score of ≥ 3 points and ≥ 30% from Baseline Plus a decrease in the rectal bleeding subscore 
[RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full Mayo score) at 
Week 52.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the Induction Study 
are:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 0 or 1) at 
Week 8.
2.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.
3.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) at Week 8.
4.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
5.
Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
Additional pre-specified endpoints in the Induction Study include but are not limited to the following:

Assessment of the relationship between adalimumab serum concentrations and efficacy during 
the Induction Study

All-cause and UC-related hospitalization and surgery rates during Weeks 0 – 8.

Change from Baseline in histologic score at Week 8.

Proportion of subjects achieving clinical remission per Adapted Mayo Score (defined as stool 
frequency subscore ≤ 1, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1) at Week 8.

Proportion of subjects achieving Full Mayo score, excluding the PGA subscore, ≤ 2 with no 
subscore > 1 at Week 8.

Relationship between histologic scores and endoscopic improvement (endoscopy subscore of 0 
or 1) at Week 8.

Relationship between histologic scores and endoscopic subscore of 0 at Week 8.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the Maintenance 
Study are:
1.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
2.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are steroid 
free for at least 90 days at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are steroid 
free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
4.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission (per Full Mayo 
score) at Week 52.


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Criteria for Evaluation (Continued):
Efficacy (Continued):
5.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic improvement 
(endoscopic subscore of 0 or 1) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are steroid-
free for at least 90 days at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline who are steroid-
free for at least 90 days and in clinical remission (per Full Mayo score) at Week 52.
8.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response (increase of IBDQ ≥ 16 
from Baseline) at Week 52.
9.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
10. Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission (per Full Mayo 
score) at Week 52.
11. Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.
12. Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic subscore of 0 at 
Week 52.  
Additional pre-specified endpoints in the Maintenance Study include but are not limited to the following:  

Assessment of the relationship between adalimumab serum concentrations and efficacy during 
the Maintenance Study by Week 8 response status.

Proportion of Week 8 responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with clinical response at Week 52.

Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic improvement at 
Week 52.

All cause and UC-related hospitalization and surgery rates during Weeks 8 – 52.

Change from Baseline in histologic score at Week 52.

Proportion of Week 8 responders per Adapted Mayo Score (defined as decrease from Baseline 
in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal 
bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1) achieving clinical remission per Adapted 
Mayo Scores at Week 52.

Proportion of Week 8 responders (per Full Mayo score) achieving Full Mayo score, excluding 
the PGA subscore, ≤ 2 with no subscore > 1 at Week 52.

Relationship between histologic scores and endoscopic improvement (endoscopy subscore of 0 
or 1) at Week 52.

Relationship between histologic scores and endoscopic subscore of 0 at Week 52.

Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline who are 
steroid free for at least 180 days and in clinical remission (per Full Mayo score) at Week 52.


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Criteria for Evaluation (Continued):
Efficacy (Continued):
The following additional pre-specified endpoints will also be analyzed in both the Induction Study and 
the Maintenance Study.

Analysis of the impact of immunogenicity on safety, pharmacokinetics, and efficacy.

Proportion of subjects who are taking corticosteroids at Baseline and are steroid-free over time.

Evaluation of adalimumab concentrations and immunogenicity at the time of loss of clinical 
remission.

Proportion of subjects achieving clinical remission per Partial Mayo (defined as a Partial Mayo 
score ≤ 2 with no subscore > 1) score over time.

Proportion of subjects achieving clinical response per Partial Mayo score (defined as a decrease 
in Partial Mayo score of ≥ 2 points and ≥ 30% from Baseline Plus a decrease in the rectal 
bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) over time.

Change from Baseline in hs-CRP over time.

Change from Baseline in corticosteroid dose over time.

Change from Baseline in IBDQ score over time.

Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores over time.

Change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, hematocrit, 
albumin, total protein concentration, and weight).

Change from Baseline in subject-reported stool frequency (absolute values).

Change from Baseline in work productivity and impairment questionnaire (WPAI) scores over 
time.

Change from Baseline in SF-36 score over time.

Change from Baseline in fecal calprotectin over time.

Time to achievement of remission (per Partial Mayo score).

Time to achievement of response (per Partial Mayo score).

Time to loss of response and factors associated with loss of response.

Change in presence of extraintestinal manifestations over time.
Pharmacokinetics:  
Blood samples will be collected for the measurement of serum adalimumab concentrations just prior to 
dosing at Baseline and Weeks 2, 4, 8, 10, 12, 16, 22, 24, 29, 35, 37, 42, 48, 52 (or at the PD visit if the 
subject discontinues prior to Week 52), and unscheduled visits.  Pre-dosing serum samples for HACAs 
and infliximab concentrations will be collected at Week 0.
Blood samples will be collected for the measurement of AAA just prior to dosing at Baseline and 
Weeks 4, 8, 12, 24, 37, 52 (or at the PD visit if the subject discontinues prior to Week 52), and 
unscheduled visits.
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.


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Statistical Methods:
The following statistical analysis plan is for subjects recruited in the main study.  A separate statistical 
analysis plan will be provided for subjects recruited in the Japan sub-study and for all the subjects 
recruited in the main study and the Japan sub-study (See Appendix K).
Efficacy:
For the Induction Study, a total of 840 subjects will be allocated to the adalimumab higher induction 
dosing regimen and the adalimumab standard induction dosing regimen in a 3:2 ratio (504 and 
336 subjects in each regimen, respectively).  The sample size for the Induction Study is based on the 
expected proportions of subjects who achieve clinical remission at Week 8.  Assuming the clinical 
remission rate of 35% in the adalimumab higher induction dosing regimen and 20% in the adalimumab 
standard induction dosing regimen at Week 8, this sample size will provide > 95% power to detect a 
difference of 15% between the two treatment groups for the primary endpoint of the Induction Study 
using two-sided Fisher's Exact test at a 0.05 significance level.  The efficacy analysis will be based on 
intent-to-treat analysis set.  The intent-to-treat analysis set includes all randomized subjects who receive 
at least one dose of study drug in the Induction Study 1 (ITT1).  The difference between the higher 
induction dosing regimen group versus the standard induction dosing regimen group in the proportion of 
subjects achieving clinical remission at Week 8 will be assessed using Cochran-Mantel-Haenszel (CMH) 
test adjusted for previous infliximab use and Baseline corticosteroid use.  A CMH based two-sided 95% 
confidence interval for the difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary endpoint data at 
Week 8 will be classified as "no clinical remission" (non-responder imputation [NRI] method) for the 
Week 8 endpoint.  Subjects with missing Mayo score data at Week 8 will be classified as Week 8 non-
responders for the Week 52 Maintenance Study analyses.  As sensitivity analyses, logistic regression 
including treatment, the randomization stratification factors and additional clinically important factors 
such as Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline will also 
be performed for the primary endpoint.  
For the Maintenance Study, the sample size is based on the expected proportions of subjects who 
achieve clinical remission at Week 52.  Assuming the average response rate at Week 8 in the Induction 
Study is 50%, a total of 420 Week 8 responders will be re-randomized to adalimumab 40 mg eow, 
adalimumab 40 mg ew, and TDM regimen in a ratio of 2:2:1; i.e., 168 subjects each in the eow and ew 
groups and 84 subjects in the TDM regimen.  Assuming the Week 52 clinical remission rate of 48% in 
the ew group and 30% in the eow group among Week 8 responders, this sample size will provide 90% 
power to detect a treatment difference of 18% between the two groups using two-sided Fisher's Exact 
test at a 0.05 significance level.  The efficacy analysis will be based on intent-to-treat analysis set.  The 
intent-to-treat analysis set includes all re-randomized subjects who receive at least one dose of study 
drug in the Maintenance Study (ITT2).  The difference between the adalimumab eow regimen versus the 
adalimumab ew regimen in the proportion of subjects achieving clinical remission at Week 52 among 
Week 8 responders will be assessed using Cochran-Mantel-Haenszel (CMH) test adjusted for the 
induction treatment regimen dosing and remitter status at Week 8 (per Full Mayo score utilizing the 
Week 8 endoscopy subscore provided by the site).  A CMH based two-sided 95% confidence interval for 
the difference between treatment groups will be calculated.  Breslow-Day test for homogeneity of odds 
ratios will be performed as well.  Subjects with missing primary endpoint data at Week 52 will be 
classified as "no clinical remission" (non-responder imputation [NRI] method) for the Week 52 
endpoint.


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Statistical Methods (Continued):
Efficacy (Continued): 
As sensitivity analyses, logistic regression including treatment, the randomization stratification factors 
and additional clinically important factors such as Immunosuppressant use at Baseline, Baseline hs-CRP, 
and disease severity at Baseline will also be performed for the primary endpoint.
The secondary efficacy variables of the Induction Study and the Maintenance Study are divided into 
two groups.  The first group includes ranked secondary endpoints, which are ranked by clinical 
importance.  Statistical significance is assessed at an alpha level of 0.050 (two-sided) in ranked endpoint 
order until the significant level exceeds 0.05.  No additional statistically significant treatment differences 
could be declared if the preceding ranked endpoint fails to achieve 0.05.  The second group includes all 
other additional secondary variables.  For the Induction Study Week 8 endpoints, the difference between 
the higher adalimumab induction dosing regimen versus the standard adalimumab induction dosing 
regimen will be assessed using ITT1 analysis set.  For the Maintenance Study Week 52 endpoints, the 
difference between the eow group versus the ew group will be assessed using ITT2 analysis set.  
Categorical data will be described by frequency and percentage; continuous data will be described by 
mean, standard deviation, minimum, median, and maximum.  In general, the secondary endpoints at 
Week 8 for the Induction Study that are of the binary type will be analyzed using a two-sided CMH test 
adjusted for previous infliximab use and Baseline corticosteroid use using the ITT1 analysis set, and the 
secondary endpoints at Week 52 for the Maintenance Study that are of the binary type will be analyzed 
using a two-sided CMH test adjusted for induction treatment regimen and remitter status (per Full Mayo 
score) at Week 8 (where applicable) using the ITT2 analysis set.  Additionally, the two-sided 95% 
confidence interval for the difference in proportions will be provided.  Continuous secondary efficacy 
variables will be analyzed using Analysis of Covariance (ANCOVA) with factor for treatment group, 
stratification variables and Baseline values.  NRI for missing data will be used for categorical endpoints.  
Procedures for handling missing data for continuous endpoints will be described in the Statistical 
Analysis Plan.
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 positivity 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 for both Induction and Maintenance Studies using the safety 
analysis set, which includes all subjects who receive at least one dose of study medication in each Study, 
respectively.  Treatment-emergent adverse events will be tabulated by system organ class and by 
MedDRA preferred term by treatment group for the Induction Study and the Maintenance Study, and for 
any adalimumab over the entire study.  Mean changes in vital signs, physical examination results, ECGs, 
and clinical laboratory values will be analyzed.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
"I-TT," "ITT-M," "ITT," "ITT-M," "J-ITT" and "J-ITT-M" previously read:
I-ITT
Integrated Intent-To-Treat
I-ITT-M
Integrated Intent-To Treat Maintenance
ITT
Intent-To-Treat
ITT-M
Intent-to-Treat Maintenance
J-ITT
Japan Integrated Intent-To-Treat
J-ITT-M
Japan Integrated Intent-To-Treat Maintenance
Has been changed to read:
I-ITT1
Integrated Intent-To-Treat Induction Study
I-ITT2
Integrated Intent-To Treat Maintenance Study
ITT1
Intent-To-Treat Induction Study
ITT2
Intent-to-Treat Maintenance Study
J-ITT1
Japan Integrated Intent-To-Treat Induction Study
J-ITT2
Japan Integrated Intent-To-Treat Maintenance Study
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "PGA, "PMS" and "SFS"
PGA
Physician's Global Assessment
PMS
Partial Mayo Score
SFS
Stool Frequency Subscore


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Definition of Terms
Add:  "Adapted Mayo Score," "Remission per Adapted Mayo Score" and 
"Response per Adapted Mayo Score"
Adapted Mayo Score
Full Mayo Score minus the Physician's Global Assessment (PGA)
Remission per Adapted Mayo Score
An Adapted Mayo Score ≤ 2, with stool frequency subscore ≤ 1, 
rectal bleeding subscore of 0, and endoscopic subscore ≤ 1
Response per Adapted Mayo Score
A decrease in the Adapted Mayo Score ≥ 2 points and ≥ 30% 
from baseline, PLUS a decrease in rectal bleeding subscore 
(RBS) ≥ 1 or an absolute RBS ≤ 1
Section 3.0  Introduction
Seventh paragraph, first sentence previously read:
The purpose of this study is to evaluate a higher induction and maintenance regimen, 
including an exploratory arm evaluating a therapeutic drug monitoring strategy, than the 
standard approved adalimumab induction regimen (160 mg at Week 0 and 80 mg at 
Week 2, followed by 40 mg every other week [eow] beginning at Week 4) for induction 
and maintenance therapy in adult patients with moderately to severely active ulcerative
colitis.
Has been changed to read:
The purpose of this study is to evaluate a higher induction and maintenance regimen, 
including an exploratory dosing regimen evaluating a therapeutic drug monitoring 
strategy, than the standard approved adalimumab induction regimen (160 mg at Week 0 
and 80 mg at Week 2, followed by 40 mg every other week [eow] beginning at Week 4) 
for induction and maintenance therapy in adult patients with moderately to severely active 
ulcerative colitis.  


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Section 3.0  Introduction
Last paragraph
Add:  new second sentence
Both the main study and Japan sub-study include an Induction Study and a Maintenance 
Study.  
Section 3.1  Differences Statement
First paragraph previously read:
The differences between Study M14-033 and the other UC studies (Study M06-826 and 
Study M06-827), are the inclusion of a higher induction dose, a higher maintenance dose 
(weekly dosing) and an adjustable dosing arm based on therapeutic drug monitoring 
during the maintenance phase, which will allow for a greater range of exposure and 
ultimately provide greater precision around adalimumab dosing/exposure and 
efficacy/safety relationships in subjects with moderately to severely active ulcerative 
colitis.  The pharmacokinetic profile of adalimumab during induction and maintenance 
phases and its relationship to efficacy in adult subjects with moderately to severely active 
ulcerative colitis will be characterized.
Has been changed to read:
The differences between Study M14-033 and the other UC studies (Study M06-826 and
Study M06-827), are the inclusion of a higher induction dose, a higher maintenance dose 
(weekly dosing) and an adjustable dosing regimen based on therapeutic drug monitoring 
during the Maintenance Study, which will allow for a greater range of exposure and 
ultimately provide greater precision around adalimumab dosing/exposure and 
efficacy/safety relationships in subjects with moderately to severely active ulcerative 
colitis.  The pharmacokinetic profile of adalimumab during Induction and Maintenance 
Studies and its relationship to efficacy in adult subjects with moderately to severely active 
ulcerative colitis will be characterized.


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Section 4.0  Study Objective
Previously read:
The primary study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis.
Has been changed to read:
The study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis.
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, first and second sentence previously read:
The study was designed to enroll 525 subjects in the main study (315 in the higher 
induction dose regimen and 210 in the standard induction dose regimen) at approximately 
125 sites worldwide to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  There also will be 
80 Japanese subjects (48 in the higher induction dose regimen and 32 in the standard 
induction dose regimen) in a Japan sub-study to be enrolled at 21 Japan sites.  
Has been changed to read:
The study was designed to enroll 840 subjects in the main study (504 subjects in the 
higher induction dose regimen and 336 subjects in the standard induction dose regimen) at 
approximately 125 sites worldwide to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  There 
also will be 100 Japanese subjects (60 subjects in the higher induction dose regimen and 
40 subjects in the standard induction dose regimen) in a Japan sub-study to be enrolled at 
21 Japan sites.  


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Section 5.1  Overall Study Design and Plan:  Description
Third paragraph, second and third bullet previously read:
●
An 8-Week Double-Blind Induction Period
●
A 44-Week Double-Blind Maintenance Period
Has been changed to read:
●
An 8-Week Double-Blind Induction Study 
●
A 44-Week Double-Blind Maintenance Study
Section 5.1  Overall Study Design and Plan:  Description
Fourth paragraph
Add:  new first, second, third and fourth sentence
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 8 will represent the final 
assessment in the Induction Study and the beginning of the Maintenance Study.  Week 52 
will represent the final assessment in the Maintenance Study (representing 44 weeks of 
maintenance treatment in the Maintenance Study).  
Section 5.1  Overall Study Design and Plan:  Description
Fifth paragraph
Add:  new last sentence
If the sample is not collected at Baseline, it should be collected at the next study visit.


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Figure 1.  Study Schematic
Previously read:
Has been changed to read:


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Second paragraph, first and second sentence previously read:
Subjects who meet all eligibility criteria during the Screening Period (refer to 
Section 5.2.1) will enter the 8-Week Double-Blind Induction Period.  The length of time 
between screening and the 8-Week Double-Blind Induction Period Baseline Visit must 
allow time for endoscopy central reading and lab results.  
Has been changed to read:
Subjects who meet all eligibility criteria during the Screening Period (refer to 
Section 5.2.1) will enter the 8-Week Double-Blind Induction Study.  The length of time 
between screening and the 8-Week Double-Blind Induction Study Baseline Visit must 
allow time for endoscopy central reading and lab results.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection 8-Week Double-Blind Induction Period
Subsection title previously read:
8-Week Double-Blind Induction Period
Has been changed to read:
8-Week Double-Blind Induction Study
Section 5.1  Overall Study Design and Plan:  Description
Subsection 8-Week Double-Blind Induction Period
First paragraph, first sentence previously read:
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the 8-Week Induction Period. 
Has been changed to read:
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the 8-Week Induction Study.


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Figure 2.  8-Week Double-Blind Induction Period
Figure title previously read:
8-Week Double-Blind Induction Period
Has been changed to read:
8-Week Double-Blind Induction Study
Section 5.1  Overall Study Design and Plan:  Description
Subsection 8-Week Double-Blind Induction Period
Last paragraph, first sentence previously read:
At Week 4, all subjects who are on oral steroids will have their steroid dose tapered 
according to the proposed tapering schedule outlined in the protocol.  
Has been changed to read:
At Week 4, all subjects who are on oral corticosteroids from Baseline will have their 
corticosteroid dose tapered according to the proposed tapering schedule outlined in the 
protocol.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection 44-Week Double-Blind Maintenance Period
Subsection title and text previously read:
44-Week Double-Blind Maintenance Period
At the conclusion of the 8-Week Double-Blind Induction Period, subjects will return to 
the study site and will be re-randomized via IRT into the 44-Week Double-Blind 
Maintenance Period to one of three treatment arms in a 2:2:1 ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
●
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory arm).  
See Figure 3.  (The Japan sub-study does not have a TDM arm.  Subjects will 


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be randomized into Adalimumab 40 mg eow arm or Adalimumab 40 mg ew in 
a 1:1 ratio.)
At Week 8, subjects will be re-stratified by:
●
Induction treatment regimen
and
●
Response status (per Full Mayo score utilizing the Week 8 endoscopy subscore 
provided by the site) at Week 8.  Among the responders at Week 8, the 
randomization will be further stratified by remission status (per Full Mayo 
score utilizing the Week 8 endoscopy subscore provided by the site) 
determined at Week 8.
Figure 3.
Drug Monitoring (TDM) Regimen


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Subjects in the adalimumab 40 mg eow arm will continue to receive 40 mg eow until the 
end of the study.  Subjects in the adalimumab 40 mg ew arm will start 40 mg ew at 
Week 8 until the end of the study.
All subjects in the TDM arm will receive 40 mg eow at Week 8 and Week 10, and may 
have their adalimumab dose adjusted at Weeks 12, 24, and 37 based on criteria assessing 
blinded serum concentration at the prior visit (Weeks 10, 22, and 35, respectively, 
Table 1) and rectal bleeding subscore (RBS) at the prior and current visits as follows:
●
Subjects receiving 40 mg eow and meeting the regimen adjustment criteria will 
escalate to 40 mg weekly.
●
Subjects receiving 40 mg ew and meeting the regimen adjustment criteria will 
receive a one-time dose of 160 mg at the visit, followed by 40 mg ew starting 
the following week.
Table 1.
TDM Arm Dose Adjustment Criteria
TDM Arm Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/mL to 20 µg/mL
< 1
No
10 µg/mL to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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 SDP.
b.
Measured from the serum concentration taken at the prior study visit.
c.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for the 
Rectal Bleeding subscore for each study visit, Appendix C.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose of 
160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing arms.


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Throughout the study, subjects will only be allowed to change the dosage of UC-specific 
concomitant medications as specified in Section 5.2.3.2.
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit as outlined in Section 5.3.1.1.  Site staff to ensure all data needed to complete 
Weeks 12, 24 and 37 is available prior to the subject arriving at the site.  Notify the 
Clinical Research Associate (CRA) should any needed reports be missing.  No study drug 
will be administered or injected at the final visit.
Has been changed to read:
44-Week Double-Blind Maintenance Study
At the conclusion of the 8-Week Double-Blind Induction Study, subjects will return to the 
study site and will be re-randomized via IRT into the 44-Week Double-Blind 
Maintenance Study to one of three treatment groups in a 2:2:1 ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
●
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory).  See 
Figure 3.  (The Japan sub-study does not have a TDM regimen.  Subjects will 
be randomized into Adalimumab 40 mg eow treatment group or Adalimumab 
40 mg ew treatment group in a 1:1 ratio.)
At Week 8, subjects will be re-stratified by:
●
Treatment regimen in the Induction Study
and
●
Response status (per Full Mayo score utilizing the Week 8 endoscopy subscore 
provided by the site) at Week 8.  Among the responders at Week 8, the re-
randomization will be further stratified by remission status (per Full Mayo 
score utilizing the Week 8 endoscopy subscore provided by the site) 
determined at Week 8.


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Figure 3.
Drug Monitoring (TDM) Regimen
Subjects in the adalimumab 40 mg eow treatment group will continue to receive 40 mg 
eow until the end of the study.  Subjects in the adalimumab 40 mg ew treatment group 
will start 40 mg ew at Week 8 until the end of the study.
All subjects in the TDM regimen will receive 40 mg eow at Week 8 and Week 10, and 
may have their adalimumab dose adjusted at Weeks 12, 24, and 37 based on criteria 
assessing blinded adalimumab serum concentration at the prior visit (Weeks 10, 22, and 
35, respectively, Table 1) and rectal bleeding subscore (RBS) at the prior and current 
visits as follows:
●
Subjects receiving 40 mg eow and meeting the regimen adjustment criteria will 
escalate to 40 mg weekly.


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●
Subjects receiving 40 mg ew and meeting the regimen adjustment criteria will 
receive a one-time dose of 160 mg at the visit, followed by 40 mg ew starting 
the following week.
Table 1.
TDM Dose Adjustment Criteria
TDM Dose Adjustment Criteriaa
Adalimumab Serum Concentrationb
Rectal Bleeding Subscorec
Dose Escalate?d
< 10 µg/mL
Any
Yes
10 µg/mL to 20 µg/mL
< 1
No
10 µg/mL to 20 µg/mL
≥ 1
Yes
> 20 µg/mL
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 SDP.
b.
Measured from the adalimumab serum concentration taken at the prior study visit.
c.
The score entries into the subject's diary based on 5 days prior to each study visit will be averaged and used for the 
Rectal Bleeding subscore for each study visit, Appendix C.
d.
For subjects on 40 mg eow, escalate to 40 mg ew.  Subjects on 40 mg ew will receive "reinduction" with a dose of 
160 mg at the visit and resume 40 mg ew 1 week later.
Note:
There will be no allowance for dose adjustment in the adalimumab eow or ew dosing groups.
Throughout the study, subjects will only be allowed to change the dosage of UC-specific 
concomitant medications as specified in Section 5.2.3.2.
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit as outlined in Section 5.3.1.1.  Site staff to ensure all data needed to complete 
Weeks 12, 24 and 37 is available prior to the subject arriving at the site.  Notify the 
Clinical Research Associate (CRA) should any needed reports be missing.  No study drug 
will be administered or injected at the final visit.
Section 5.2  Selection of Study Population
First and second paragraph previously read:
Five hundred and twenty-five subjects will be enrolled at up to 125 non-Japan sites.


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An additional 80 subjects will be enrolled at approximately 21 sites in Japan as part of a 
separate Japan sub-study outlined in Appendix K.
Has been changed to read:
Eight hundred and forty (840) subjects will be enrolled at up to 125 sites in the Main 
Study.
An additional 100 subjects will be enrolled at approximately 21 sites in Japan as part of a 
separate Japan sub-study outlined in Appendix K.
Section 5.2.2  Exclusion Criteria
Criterion 25 previously read:
25. Subjects with a positive result for 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 (+)
Has been changed to read:
25. Subjects with a positive result for 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.  


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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.
Section 5.2.3.2  Concomitant Therapy
Third 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 
categorical endpoints and will have Baseline values carried forward for non-categorical 
assessments) from that point through the end of the study. 
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 Baseline values carried forward for non-categorical 
assessments) from that point forward.  
Section 5.2.3.2  Concomitant Therapy
Fourth paragraph, first sentence previously read:
Subjects in whom the following UC-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 


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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 
through the end of the study.
Has been changed to read:
Subjects in whom the following UC-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.
Table 2.  Study Activities
Header row, column "8-Week Double-Blind Induction Period" and "44-Week 
Double-Blind Maintenance Period" previously read:
"8-Week Double-Blind Induction Period" and "44-Week Double-Blind Maintenance 
Period"
Has been changed to read:
"8-Week Double-Blind Induction Study" and "44-Week Double-Blind Maintenance 
Study"
Table 2.  Study Activities
Table note "j."
Add:  new last sentence
Further explanations of these tests are provided in the Laboratory Manual.


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Table 2.  Study Activities
Table note "m."
Add:  new last sentence
Remaining sample will be stored for potential research testing.
Section 5.3.1.1  Study Procedures
Subsection For the PPD Test:
Ninth paragraph previously read: 
Newly initiated prophylactic treatment should be captured on the concomitant 
medications page in the eCRF and in the source documents.  Prior therapy should be 
captured in medical history.
Has been changed to read:
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 in medical history eCRF page.
Section 5.3.1.1  Study Procedures
Subsection Hepatitis B Testing
Previously read:
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 (+)


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●
HBc Ab Total (+) and HBs Ab (+)
Has been changed to read:
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.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Collection of Samples for Adalimumab and AAA Assays
Last paragraph, last sentence previously read:
The total number of samples planned (not including unscheduled visit sample collections) 
will not exceed 7,875 (15 samples × 525 subjects) for the adalimumab assay and 3,675 
(7 samples × 525 subjects) for the AAA assay for the main study.
Has been changed to read:
The total number of samples planned (not including unscheduled visit sample collections) 
will not exceed 12,600 (15 samples × 840 subjects) for the adalimumab assay and 5,880 
(7 samples × 840 subjects) for the AAA assay for the main study.


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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 1050 (2 samples × 525 subjects) for 
the main study.
Has been changed to read:
The total number of samples planned will not exceed 1,680 (2 samples × 840 subjects) for 
the main study.
5.3.2.3  Disposition of Samples
Second sentence previously read:
Samples will be shipped pursuant to instructions from the onsite CRA.  
Has been changed to read:
Samples will be shipped pursuant to instructions from the CRA.  
Section 5.3.3.1  Primary Variable
Section title and text previously read:
5.3.3.1
Primary Variable
The primary efficacy variable is the proportion of subjects achieving clinical remission 
(defined as a Full Mayo score ≤ 2 with no subscore > 1) at Week 8.
Has been changed to read:
5.3.3.1
Primary Variables
The primary efficacy variable for the Induction Study is the proportion of subjects 
achieving clinical remission (defined as a Full Mayo score ≤ 2 with no subscore > 1) at 
Week 8.


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The primary efficacy variable for the Maintenance Study is the proportion of Week 8 
responders (per Full Mayo score, defined as a decrease in Full Mayo score of ≥ 3 points
and ≥ 30% from Baseline plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) achieving clinical remission (per Full Mayo score) at Week 52.
Section 5.3.3.2  Secondary Variables
First paragraph and item list previously read:
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) include:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 
0 or 1) at Week 8.
2.
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in 
Full Mayo score of ≥ 3 points and ≥ 30% from Baseline Plus a decrease in the 
rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical 
remission (per Full Mayo score) at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
4.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
5.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission 
(per Full Mayo score) at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
8.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.


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9.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
10.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.
11.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) 
at Week 8.
12.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response 
(increase of IBDQ ≥ 16 from Baseline) at Week 52.
13.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
14.
Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
15.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
16.
Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
17.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
18.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
Has been changed to read:
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Induction Study are:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic subscore of 
0 or 1) at Week 8.
2.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.


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3.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) 
at Week 8.
4.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.
5.
Proportion of subjects achieving endoscopic subscore of 0 at Week 8.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Maintenance Study are:
1.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
2.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
3.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
4.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission
(per Full Mayo score) at Week 52.
5.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
8.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response 
(increase of IBDQ ≥ 16 from Baseline) at Week 52.


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9.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
10.
Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
11.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
12.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
Section 5.3.3.3  Additional Variables
Previously read:
Additional pre-specified endpoints include but are not limited to the following:
●
Evaluation of adalimumab concentrations and immunogenicity at the time of 
loss of clinical remission.
●
Assessment of the relationship between adalimumab serum concentrations and 
efficacy during induction and maintenance by Week 8 response status.
●
Analysis of the impact of immunogenicity on safety, pharmacokinetics, and 
efficacy.
●
Proportion of subjects who are taking corticosteroids at Baseline and are 
steroid free over time.
●
Proportion of Week 8 responders (per Full Mayo score) taking steroids at 
Baseline who are steroid-free for at least 180 days and in clinical remission 
(per Full Mayo score) at Week 52.
●
Proportion of subjects achieving clinical remission per Partial Mayo (defined 
as a Partial Mayo score ≤ 2 with no subscore > 1) score over time.
●
Proportion of subjects achieving clinical response per Partial Mayo score 
(defined as a decrease in Partial Mayo score of ≥ 2 points and ≥30% from 
Baseline Plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) over time.


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●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in corticosteroid dose over time.
●
Change from Baseline in IBDQ score over time.
●
Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores 
over time.
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight).
●
Change from Baseline in subject-reported stool frequency (absolute values).
●
Change from Baseline in work productivity and impairment questionnaire 
(WPAI) scores over time.
●
Change from Baseline in SF-36 score over time.
●
Proportion of Week 8 responders (per Full Mayo score) with clinical response 
at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with clinical 
response at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic 
improvement at Week 52.
●
All-cause and UC-related hospitalization and surgery rates during 
Weeks 0 – 8.
●
All cause and UC-related hospitalization and surgery rates during 
Weeks 8 – 52.
●
Change from Baseline in fecal calprotectin over time.
●
Time to achievement of remission (per Partial Mayo score)
●
Time to achievement of response (per Partial Mayo score)
●
Time to loss of response and factors associated with loss of response.
●
Change from Baseline in histologic score at Week 8.
●
Change from Baseline in histologic score at Week 52.
●
Proportion of subjects achieving clinical remission per Full Mayo score, 
excluding the PGA subscore (defined as  Full Mayo Score, excluding the PGA 
subscore, ≤ 2 with no subscore > 1) at Week 8.


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●
Proportion of Week 8 responders (per Full Mayo score) achieving clinical
remission (per Full Mayo score, excluding the PGA subscore) at Week 52.
●
Change in presence of extraintestinal manifestations over time.
Has been changed to read:
Additional pre-specified endpoints in the Induction Study include but are not limited to 
the following:
●
Assessment of the relationship between adalimumab serum concentrations and 
efficacy during the Induction Study.
●
All-cause and UC-related hospitalization and surgery rates during Weeks 0 – 8.
●
Change from Baseline in histologic score at Week 8.
●
Proportion of subjects achieving clinical remission per Adapted Mayo Score 
(defined as stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and 
endoscopic subscore ≤ 1) at Week 8.
●
Proportion of subjects achieving Full Mayo score excluding the PGA subscore, 
≤ 2 with no subscore > 1 at Week 8.
●
Relationship between histologic subscores and endoscopic improvement 
(endoscopy subscore of 0 or 1) at Week 8.
●
Relationship between histologic scores and endoscopic subscore of 0 as 
Week 8.
Additional pre-specified endpoints in the Maintenance Study include but are not limited to 
the following:
●
Assessment of the relationship between adalimumab serum concentrations and 
efficacy during the Maintenance Study by Week 8 response status.
●
Proportion of Week 8 responders (per Full Mayo score) with clinical response 
at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with clinical 
response at Week 52.


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●
Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic 
improvement at Week 52.
●
All cause and UC-related hospitalization and surgery rates during Weeks 8 –
52.
●
Change from Baseline in histologic score at Week 52.
●
Proportion of Week 8 responders per Adapted Mayo score (defined as decrease 
from Baseline in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, 
PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS 
≤1) achieving clinical remission per Adapted Mayo scores at Week 52.
●
Proportion of Week 8 responders (per Full Mayo score) achieving Full Mayo 
Score, excluding the PGA subscore ≤ 2 with no subscore > 1 at Week 52.
●
Relationship between histologic scores and endoscopic improvement 
(endoscopy subscore of 0 or 1) at Week 52.
●
Relationship between histologic scores and endoscopic subscore of 0 at 
Week 52.
●
Proportion of Week 8 responders (per Full Mayo score) taking steroids at 
Baseline who are steroid-free for at least 180 days and in clinical remission 
(per Full Mayo score) at Week 52.
The following additional pre-specified endpoints will also be analyzed in both the 
Induction Study and the Maintenance Study.
●
Analysis of the impact of immunogenicity on safety, pharmacokinetics, and 
efficacy.
●
Proportion of subjects who are taking corticosteroids at Baseline and are 
steroid free over time.
●
Evaluation of adalimumab concentrations and immunogenicity at the time of 
loss of clinical remission.
●
Proportion of subjects achieving clinical remission per Partial Mayo (defined 
as a Partial Mayo score ≤ 2 with no subscore > 1) score over time.
●
Proportion of subjects achieving clinical response per Partial Mayo score 
(defined as a decrease in Partial Mayo score of ≥ 2 points and ≥ 30% from 


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Baseline Plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) over time.
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in corticosteroid dose over time.
●
Change from Baseline in IBDQ score over time.
●
Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores 
over time.
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight).
●
Change from Baseline in subject-reported stool frequency (absolute values).
●
Change from Baseline in work productivity and impairment questionnaire 
(WPAI) scores over time.
●
Change from Baseline in SF-36 score over time.
●
Change from Baseline in fecal calprotectin over time.
●
Time to achievement of remission (per Partial Mayo score)
●
Time to achievement of response (per Partial Mayo score)
●
Time to loss of response and factors associated with loss of response.
●
Change in presence of extraintestinal manifestations over time.
Section 5.3.4  Pharmacokenetic Variables
First sentence previously read:
Serum concentrations of adalimumab at each scheduled sampling time will be 
summarized and stratified by treatment arm.  
Has been changed to read:
Serum concentrations of adalimumab at each scheduled sampling time will be 
summarized and stratified by treatment regimen.


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Section 5.5.1  Treatments Administered
Previously read:
Double-Blind Induction Period
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction doses.
Subjects assigned to the standard induction arm will receive adalimumab 160 mg 
(4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  At 
Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes) At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction arm will receive 160 mg (4 syringes) at Weeks 0, 
1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Doses
At Week 8, subjects will be re-randomized to receive 1 of 3 double-blind adalimumab 
treatment maintenance regimens in a 2:2:1 ratio.
Subjects assigned to the adalimumab 40 mg eow arm will receive 40 mg (1 syringe) at 
Weeks 8, 10, 12, 14, 16, 18, 20, 22, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 50.  
Subjects will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24.  At Week 37, 
subjects will receive matching placebo (4 syringes).  Matching Placebo (1 syringe) will be 
administered at Weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 39, 41, 43, 45, 
47, 49, 51.  No dose will be administered at Week 52.
Subjects assigned to the adalimumab 40 mg ew arm will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 
32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  Subjects will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Weeks 24 and 37.  No dose will be 
administered at Week 52.


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Subjects assigned to the TDM arm will receive adalimumab 40 mg eow (1 syringe) at 
Week 8 and Week 10.  Matching placebo (1 syringe) will be administered at Weeks 9 and 
11.  At Weeks 12, 24 and 37, the regimen will be adjusted for subjects meeting specified 
criteria in Table 1.
Subjects who don't dose escalate at Week 12 will receive 40 mg eow (1 syringe) at 
Weeks 12, 14, 16, 18, 20, and 22 and placebo (1 syringe) at Weeks 13, 15, 17, 19, 21 and 
23.  Subjects who escalate at Week 12 will receive 40 mg ew (1 syringe) at Weeks 12, 13, 
14, 15, 16, 17, 18, 19, 20, 21, 22 and 23. 
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg eow 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 
eow (1 syringe) at Weeks 26, 28, 30, 32, 34, and 36 and placebo (1 syringe) at Weeks 25, 
27, 29, 31, 33 and 35.  Subjects who escalate at Week 24 and were receiving adalimumab 
40 mg eow will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed 
by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 
ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.  Subjects who 
escalate at Week 24 and were receiving adalimumab 40 mg ew will receive 160 mg 
(4 syringes) at Week 24, followed by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 
30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg eow 
will receive placebo (4 syringes) at Week 37, followed by 40 mg eow (1 syringe) at 
Weeks 38, 40, 42, 44, 46, 48, and 50 and placebo (1 syringe) at Weeks 39, 41, 43, 45, 47, 
49, 51.  No dose will be administered at Week 52. 
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg eow will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg ew 


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(1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52.  
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg 
ew (1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52.  
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg ew will receive 
160 mg (4 syringes) at Week 37, followed by 40 mg ew (1 syringe) at Weeks 38, 39, 40, 
41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose will be administered at Week 52.  
Has been changed to read:
Double-Blind Induction Study
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction dosing regimens.
Subjects assigned to the standard induction dosing regimen will receive adalimumab 
160 mg (4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  
At Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes) At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction dosing regimen will receive 160 mg (4 syringes) 
at Weeks 0, 1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Study
At Week 8, subjects will be re-randomized to receive 1 of 3 double-blind adalimumab 
treatment maintenance regimens in a 2:2:1 ratio.
Subjects assigned to the adalimumab 40 mg eow regimen will receive 40 mg (1 syringe) 
at Weeks 8, 10, 12, 14, 16, 18, 20, 22, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 50.  


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Subjects will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24.  At Week 37, 
subjects will receive matching placebo (4 syringes).  Matching Placebo (1 syringe) will be 
administered at Weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 39, 41, 43, 45, 
47, 49, 51.  No dose will be administered at Week 52/Premature Discontinuation.
Subjects assigned to the adalimumab 40 mg ew regimen will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 
32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  Subjects will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Weeks 24 and 37.  No dose will be 
administered at Week 52/Premature Discontinuation.
Subjects assigned to the TDM regimen will receive adalimumab 40 mg eow (1 syringe) at 
Week 8 and Week 10.  Matching placebo (1 syringe) will be administered at Weeks 9 and 
11.  At Weeks 12, 24 and 37, the regimen will be adjusted for subjects meeting specified 
criteria in Table 1.
Subjects who don't dose escalate at Week 12 will receive 40 mg eow (1 syringe) at 
Weeks 12, 14, 16, 18, 20, and 22 and placebo (1 syringe) at Weeks 13, 15, 17, 19, 21 and 
23.  Subjects who escalate at Week 12 will receive 40 mg ew (1 syringe) at Weeks 12, 13, 
14, 15, 16, 17, 18, 19, 20, 21, 22 and 23. 
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg eow 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 
eow (1 syringe) at Weeks 26, 28, 30, 32, 34, and 36 and placebo (1 syringe) at Weeks 25, 
27, 29, 31, 33 and 35.  Subjects who escalate at Week 24 and were receiving adalimumab 
40 mg eow will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed 
by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 24 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 24, followed by 40 mg 
ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.  Subjects who 
escalate at Week 24 and were receiving adalimumab 40 mg ew will receive 160 mg 


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(4 syringes) at Week 24, followed by 40 mg ew (1 syringe) at Weeks 25, 26, 27, 28, 29, 
30, 31, 32, 33, 34, 35 and 36.
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg eow 
will receive placebo (4 syringes) at Week 37, followed by 40 mg eow (1 syringe) at 
Weeks 38, 40, 42, 44, 46, 48, and 50 and placebo (1 syringe) at Weeks 39, 41, 43, 45, 47, 
49, 51.  No dose will be administered at Week 52/Premature Discontinuation.
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg eow will 
receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg ew 
(1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52/Premature Discontinuation.
Subjects who don't dose escalate at Week 37 and were receiving adalimumab 40 mg ew 
will receive 40 mg (1 syringe) and placebo (3 syringes) at Week 37, followed by 40 mg 
ew (1 syringe) at Weeks 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose 
will be administered at Week 52/Premature Discontinuation.
Subjects who escalate at Week 37 and were receiving adalimumab 40 mg ew will receive 
160 mg (4 syringes) at Week 37, followed by 40 mg ew (1 syringe) at Weeks 38, 39, 40, 
41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No dose will be administered at 
Week 52/Premature Discontinuation.
Section 5.5.3  Method of Assigning Subjects to Treatment Arms
Section title previously read:
Method of Assigning Subjects to Treatment Arms
Has been changed to read:
Method of Assigning Subjects to Treatment Regimens


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Section 5.5.3  Method of Assigning Subjects to Treatment Arms
First and second paragraph previously read:
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 
Week 0 in a 3:2 ratio into the criteria-driven arms using the IRT, which will assign a 
randomization number according to the randomization scheme, generated by AbbVie 
before the start of the study.  The randomization will be stratified by previous infliximab 
use and Baseline corticosteroid use.  The criteria-driven arm assignment will be 
maintained by the IRT.  Subjects will be referred to by the subject number assigned at 
Screening.
Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Period at the conclusion of the Week 8 Visit to one of 
three treatment arms in a 2:2:1 ratio.  Subjects will be re-stratified by:  induction treatment 
regimen and response status (per Full Mayo Score) at Week 8.  Among Week 8 
responders, the randomization will be further stratified by remission status (per Full Mayo 
Score) at Week 8.
Has been changed to read:
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 Induction Study.  Subjects who enter the Induction Study 
will be randomized at Week 0 in a 3:2 ratio into the criteria-driven regimens using the 
IRT, which will assign a randomization number according to the randomization scheme, 
generated by AbbVie before the start of the study.  The randomization will be stratified by 
previous infliximab use and Baseline corticosteroid use.  The criteria-driven regimen 
assignment will be maintained by the IRT.  Subjects will be referred to by the subject 
number assigned at Screening.


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Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Study at the conclusion of the Week 8 Visit to one of three 
treatment regimens in a 2:2:1 ratio.  Subjects will be re-stratified by:  induction treatment 
regimen and response status (per Full Mayo Score) at Week 8.  Among Week 8 
responders, the randomization will be further stratified by remission status (per Full Mayo 
Score) at Week 8.
Section 5.5.4  Selection and Timing of Dose for Each Subject 
Second paragraph, last sentence previously read:
The subject must record all dosing information in the subject diary.
Has been changed to read:
The subject must record all home dosing information in the subject diary.
Section 5.5.6  Treatment Compliance
Second paragraph, third sentence previously read:
In order to document compliance with the treatment regimen, the subject will be given a 
diary to record all injection dates and times.
Has been changed to read:
In order to document compliance with the treatment regimen, the subject will be given a 
diary to record all injection dates and times administered at home.  
Section 5.6.1  Discussion of Study Design and Choice of Control Arms
Section title previously read:
Discussion of Study Design and Choice of Control Arms
Has been changed to read:
Discussion of Study Design and Choice of Control Regimens


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Section 5.6.1  Discussion of Study Design and Choice of Control Arms
First paragraph, second sentence previously read:
No placebo arm is planned due to documented efficacy of adalimumab in UC and the 
purpose of this study is to investigate whether greater efficacy is achieved with the higher 
dose than with the standard dose, and to compare safety outcomes.  
Has been changed to read:
No placebo regimen is planned due to documented efficacy of adalimumab in UC and the 
purpose of this study is to investigate whether greater efficacy is achieved with the higher 
dose than with the standard dose, and to compare safety outcomes.  
Section 5.6.1  Discussion of Study Design and Choice of Control Arms
Last paragraph previously read:
The primary study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active UC.
Has been changed to read:
The study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active UC.
Section 5.6.4  Selection of Doses in the Study
Subsection Maintenance Dose Selection
First paragraph, third and fourth sentence previously read:
An exploratory arm evaluating a TDM strategy will also be evaluated.  The goal of the 
TDM maintenance dosing arm is to analyze the feasibility, efficacy, and safety of aiming 
for serum adalimumab levels within a targeted concentration range for making decisions 
regarding dosing.
Has been changed to read:
An exploratory regimen evaluating a TDM strategy will also be evaluated.  The goal of 
the TDM maintenance dosing regimen is to analyze the feasibility, efficacy, and safety of 


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aiming for serum adalimumab levels within a targeted concentration range for making 
decisions regarding dosing.
Section 5.6.4  Selection of Doses in the Study
Subsection Maintenance Dose Selection
Second paragraph, first sentence previously read:
The targeted concentration range selected for the TDM arm was based on serum 
concentrations observed during Study M06-827 and the mean serum concentrations 
observed in subjects who achieved remission during this study.  
Has been changed to read:
The targeted concentration range selected for the TDM dosing regimen was based on 
serum concentrations observed during Study M06-827 and the mean serum concentrations
observed in subjects who achieved remission during this study.  
Section 5.6.4  Selection of Doses in the Study
Subsection Maintenance Dose Selection
Last paragraph, last sentence previously read:
Based on observed adalimumab pharmacokinetics in Study M06-827, it is expected that 
approximately 60% of subjects in the TDM arm will escalate to 40 mg weekly dosing, and 
approximately 15% will receive re-induction thereafter using this concentration range and 
the RBS criteria described in Table 1 as a guide to adjust dosing.
Has been changed to read:
Based on observed adalimumab pharmacokinetics in Study M06-827, it is expected that 
approximately 60% of subjects in the TDM dosing regimen will escalate to 40 mg weekly 
dosing, and approximately 15% will receive re-induction thereafter using this 
concentration range and the RBS criteria described in Table 1 as a guide to adjust dosing.


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Section 6.1.4  Adverse Event Collection Period
Third paragraph, second sentence previously read:
Thus, all SAEs and non-serious AEs, as defined by AbbVie, reported during the 70-day 
follow-up phone call must be captured in the clinical database (Appendix J.
Has been changed to read:
Thus, all SAEs and non-serious AEs, as defined by AbbVie, as well as the medication for 
AEs/SAEs, reported during the 70-day follow-up phone call must be captured in the 
clinical database via the eCRF and also recorded in source documentation (Appendix J).  
Section 6.1.5  Adverse Event Reporting
Second paragraph, "Dept." previously read:
Has been changed to read:
Section 6.1.5  Adverse Event Reporting
Fourth paragraph, "address" previously read:
Primary Study Designated Physician
 MD
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany


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Has been changed to read:
Primary Study Designated Physician
 MD
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Section 7.0  Protocol Deviations
"Alternate Contact:" previously read:
Alternate Contact:
MD
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Telephone Contact Information:
Office:
Mobile:
Email:


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Has been changed to read:
Alternate Contact:
 MD
Immunology Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Telephone Contact Information:
Office:
Mobile:
Email:
Section 8.1  Statistical and Analytical Plans
First paragraph previously read:
The objectives of the statistical analyses are to evaluate the efficacy and safety of 
adalimumab for the induction and maintenance of clinical remission in subjects with 
moderately to severely active ulcerative colitis.  The statistical analyses described in this 
section are for the main study (i.e., will be restricted to subjects recruited in the non-Japan 
sites).
Has been changed to read:
The objectives of the statistical analyses are to evaluate the efficacy and safety of 
adalimumab for the induction and maintenance of clinical remission in subjects with 
moderately to severely active ulcerative colitis.  The following statistical analysis plan is 
for subjects recruited in the main study.  A separate statistical analysis plan will be 
provided for subjects recruited in the Japan sub-study and for all the subjects recruited in 
the main study and the Japan sub-study (See Appendix K).


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Section 8.1.1  Analysis Population
Second and third paragraph previously read:
Intent-to-Treat (ITT) population includes all subjects who were randomized.  ITT subjects 
will be analyzed as randomized.  ITT is the primary population for the efficacy analysis at 
Week 8 during the induction period.
Intent-to-Treat maintenance (ITT-M) population includes all subjects who are 
re-randomized at Week 8.  ITT-M subjects will be analyzed as randomized.  ITT-M is the 
primary population for the efficacy analysis at Week 52 during the maintenance period.
Has been changed to read:
Intent-to-Treat (ITT1) population includes all subjects who were randomized at Baseline.  
ITT1 subjects will be analyzed as randomized.  ITT1 is the primary population for the 
efficacy analysis at Week 8 during the Induction Study.
Intent-to-Treat maintenance (ITT2) population includes all subjects who are re-
randomized at Week 8 to the Maintenance Study.  ITT2 subjects will be analyzed as 
randomized.  ITT2 is the primary population for the efficacy analysis at Week 52 during 
the Maintenance Study.
Section 8.1.1  Analysis Population
Last paragraph, first sentence previously read:
The Safety set consists of all randomized subjects who received at least one injection of 
study drug.  
Has been changed to read:
The Safety set consists of all subjects who received at least one injection of study drug.  


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Section 8.1.3  Demographics and Baseline Characteristics
Second sentence previously read:
The p-value will be provided to assess the comparability of the treatment arms assigned 
by randomization.  
Has been changed to read:
The p-value will be provided to assess the comparability of the treatment groups assigned 
by randomization.  
Section 8.1.4.1  Primary Efficacy Variable
Section title and text previously read:
8.1.4.1
Primary Efficacy Variable
The primary efficacy endpoint is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary analysis will compare the subjects in the higher adalimumab induction arm 
versus the standard adalimumab induction arm in the ITT analysis set.  The difference 
between the treatment arms in the proportion of subjects achieving clinical remission at 
Week 8 will be assessed using Cochran-Mantel-Haenszel (CMH) test adjusted for 
previous infliximab use and Baseline corticosteroid use at Baseline.  A CMH based 
two-sided 95% confidence interval for the difference between treatment arms will be 
calculated.  Breslow-Day test for homogeneity of odds ratios will be performed as well.  
Subjects with missing primary endpoint data at Week 8 will be classified as "no clinical 
remission" (non-responder imputation [NRI] method) for the Week 8 endpoint.  Subjects 
with missing Mayo score data for Week 8 will also be classified as Week 8 
non-responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as IMM use at 


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Baseline, Baseline CRP, and disease severity at Baseline will also be performed for the 
primary endpoint.
For CMH test statistic, if the condition of each stratum to have at least one subject with 
each treatment and at least one subject with each possible outcome is violated for the 
primary approach to the primary efficacy endpoint, the stratification factor Baseline 
corticosteroid use will be dropped from the CMH model in the analysis of all categorical 
variables.
Has been changed to read:
8.1.4.1
Primary Efficacy Variables
The primary efficacy endpoint for the Induction Study is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full 
Mayo score of ≥ 3 points and ≥ 30% from Baseline plus a decrease in the rectal bleeding 
subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full 
Mayo score) at Week 52.
The primary analysis of the Induction Study will compare the subjects in the higher 
adalimumab induction regimen versus the standard adalimumab induction regimen in the 
ITT1 analysis set.  The difference between the treatment regimens in the proportion of 
subjects achieving clinical remission at Week 8 will be assessed using Cochran-Mantel-
Haenszel (CMH) test adjusted for previous infliximab use and Baseline corticosteroid use 
at Baseline.  A CMH based two sided 95% confidence interval for the difference between 
treatment groups will be calculated.  Breslow-Day test for homogeneity of odds ratios will 
be performed as well.  Subjects with missing primary endpoint data at Week 8 will be 
classified as "no clinical remission" (non-responder imputation [NRI] method) for the 


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Week 8 endpoint.  Subjects with missing Mayo score data for Week 8 will also be 
classified as Week 8 non responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as 
Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline 
will also be performed for the primary endpoint for the Induction Study.
The primary analysis of the Maintenance Study will compare the Week 8 responders (per 
Full Mayo Score) in the eow regimen versus the subjects in the ew regimen in the ITT2 
analysis set.  The difference between the treatment regimens in the proportion of subjects 
achieving clinical remission at Week 52 will be assessed using Cochran-Mantel-Haenszel 
(CMH) test adjusted for Induction treatment regimen and the remitter status (per Full 
Mayo Score) at Week 8.  A CMH based two-sided 95% confidence interval for the 
difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 52 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method) for the Week 52 endpoint.  Subjects with missing Mayo score 
data for Week 52 will also be classified as Week 52 non-responders.
The TDM regimen will be used for exploratory analyses.
Section 8.1.4.2  Secondary Efficacy Variables
Previously read:
The 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 an alpha level of 0.050 (two-sided) in ranked endpoint order 
until the significant level exceeds 0.05.  No additional statistically significant treatment 
differences could be declared if the preceding ranked endpoint fails to achieve 0.05.  The 
second group includes all other additional secondary variables.  For Week 8 endpoints, the 
difference between the higher adalimumab induction arm versus the standard adalimumab 
induction arm will be assessed using ITT analysis set.  For Week 52 endpoints, the 


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difference between the eow arm versus the ew arm will be assessed using Intent-to-Treat 
maintenance (ITT-M) analysis set where Week 8 responder/remitter status will be 
determined based on the Full Mayo score using endoscopy subscore from the central 
reader.  Categorical data will be described by frequency and percentage; continuous data 
will be described by mean, standard deviation, minimum, median, and maximum.  In 
general, the secondary endpoints at Week 8 that are of the binary type will be analyzed 
using a two-sided CMH test adjusted for previous infliximab use and Baseline 
corticosteroid use in the ITT analysis set, and the secondary endpoints at Week 52 that are 
of the binary type will be analyzed using a two-sided CMH test adjusted for induction 
treatment regimen, and remitter status (per Full Mayo score) at Week 8 (where applicable) 
in the ITT-M analysis set.  Additionally, the two-sided 95% confidence interval for the 
difference in proportions will be provided.  Continuous secondary efficacy variables will 
be analyzed using Analysis of Covariance (ANCOVA) with factor for treatment arm, 
stratification variables and Baseline values.  NRI for missing data will be used for 
categorical endpoints.  Procedures for handling missing data for continuous endpoints will 
be described in the Statistical Analysis Plan.
Has been changed to read:
The 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 an alpha level of 0.050 (two-sided) in ranked endpoint order 
until the significant level exceeds 0.05.  No additional statistically significant treatment 
differences could be declared if the preceding ranked endpoint fails to achieve 0.05.  The 
second group includes all other additional secondary variables.  For the Induction Study 
endpoints, the difference between the higher adalimumab induction regimen versus the 
standard adalimumab induction regimen will be assessed using ITT1 analysis set.  For the 
Maintenance Study endpoints, the difference between the eow dosing regimen versus the 
ew doing regimen will be assessed using Intent-to-Treat maintenance (ITT2) analysis set 
where Week 8 responder/remitter status will be determined based on the Full Mayo score 
using endoscopy subscore from the central reader.  Categorical data will be described by 


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frequency and percentage; continuous data will be described by mean, standard deviation, 
minimum, median, and maximum.  In general, the secondary endpoints at Week 8 that are 
of the binary type will be analyzed using a two-sided CMH test adjusted for previous 
infliximab use and Baseline corticosteroid use in the ITT1 analysis set, and the secondary 
endpoints at Week 52 that are of the binary type will be analyzed using a two-sided CMH 
test adjusted for induction treatment regimen, and remitter status (per Full Mayo score) at 
Week 8 (where applicable) in the ITT2 analysis set.  Additionally, the two-sided 95% 
confidence interval for the difference in proportions will be provided.  Continuous 
secondary efficacy variables will be analyzed using Analysis of Covariance (ANCOVA) 
with factor for treatment regimen, stratification variables and Baseline values.  NRI for 
missing data will be used for categorical endpoints.  Procedures for handling missing data 
for continuous endpoints will be described in the Statistical Analysis Plan.
Section 8.1.5  Statistical Analyses of Safety
Previously read:
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 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 medication and within 70 days after 
the last dose of the study medication.  Treatment-emergent AEs will be summarized 
separately for the double-blind induction period (Week 0 to Week 8), double-blind 
maintenance period (Week 8 to 70 days after the last dose of the study medication), and 
Study M14-033 (Week 0 to 70 days after the last dose of the study medication).  An 
overview of treatment-emergent AEs, including AEs of special interest such as adverse 
events leading to death and adverse events leading to PD (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.  Other safety 
variables like laboratory data will be described by descriptive statistics.  In addition, shift 
tables and listings will be provided for abnormal values, whereby the normal range of the 
analyzing laboratory will be used.


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Has been changed to read:
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 
Studies using the safety analysis set which includes all subjects who receive at least 
one dose of study medication in each Study respectively.  Treatment-emergent AEs, will 
be tabulated by MedDRA preferred term by treatment group for the Induction Study and 
the Maintenance Study, and for any adalimumab over the entire study.  Mean changes in 
vital signs, physical examination results, ECGs, and clinical laboratory data values will be 
analyzed.
Section 8.1.6  Other Statistical Analyses of Efficacy
First paragraph previously read:
The subgroups listed below will be used in subgroup analyses of the primary endpoint.
Has been changed to read:
The subgroups listed below will be used in subgroup analyses of the primary endpoints.
Section 8.1.7  Interim Analysis
Previously read:
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
Week 8 only as well as safety data collected from Baseline through double-blind Week 8 
will be performed after the last subject in ITT population completes the 8-week 
double-blind period of the main study.  A database lock 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 primary efficacy endpoint of the main study, no adjustment of 
alpha-level is necessary.
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-


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blind Week 8 may be performed after the last subject in ITT1 population completes the 
8-week double-blind Induction Study of the main 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 primary efficacy endpoint of the Induction Study, no 
adjustment of alpha-level is necessary.
Section 8.1.8  Pharmacokinetic Analysis
First paragraph, first sentence previously read:
Adalimumab trough serum concentrations will be summarized by treatment arm at each 
time point using descriptive statistics.  
Has been changed to read:
Adalimumab trough serum concentrations will be summarized by treatment regimen at 
each time point using descriptive statistics.  
Section 8.2  Determination of Sample Size
Previously read:
Subjects will be randomized to the adalimumab higher induction arm and the adalimumab 
standard induction arm in a 3:2 ratio.  The sample size calculations for the main study are 
based on a two-sided Fisher's exact test at a significance level of 0.05.  Assuming an 
expected Week 8 endoscopic improvement rate of 60% in the adalimumab higher 
induction dose arm and 45% in the adalimumab standard induction dose arm, 525 subjects 
(315 in the higher induction dose arm and 210 in the standard induction dose arm) will 
provide 90% statistical power to detect the difference between the two induction treatment 
arms.  This sample size of 525 subjects in the main study will provide at least 95% power 
to detect a treatment difference of 15% for the primary endpoint of clinical remission, 
assuming an expected Week 8 clinical remission rate of 35% in the adalimumab higher 
induction arm and 20% in the adalimumab standard induction arm.
Assuming the average response rate at Week 8 in the adalimumab induction dose arms in 
the main study is 60%, there will be 315 responders for the analysis of Week 52 clinical 


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remission among the Week 8 responders (126 in the higher maintenance dose arm, 126 in 
the standard maintenance dose arm, and 63 in the TDM regimen arm).  This sample size 
will provide 80% power to detect a treatment difference of 18%, assuming an expected 
Week 52 clinical remission rate of 48% in the adalimumab higher maintenance arm and 
30% in the adalimumab standard maintenance arm. 
The sample size calculations for the Japan sub-study are described in Appendix K.
Has been changed to read:
When Protocol M14-033 was initially designed, AbbVie used an assumption regarding 
induction response rate in order to calculate the expected number of Week 8 responders 
that would comprise the analysis set used to compare the Week 52 remission rates in the 
adalimumab 40 mg every other week and 40 mg weekly groups.  AbbVie assumed that 
the overall response rate (per Full Mayo Score) at Week 8 would be 60%, which would 
provide 315 Week 8 responders for the analysis of Week 52 remission (126 in the every 
other week dosing group, 126 in the every week dosing group, and 63 in the exploratory 
TDM group, based upon a 2:2:1 randomization scheme) from the 525 randomized 
induction subjects.  This sample size would provide 80% power to detect a treatment 
difference of 18%, assuming an expected Week 52 remission rate of 48% in the 
adalimumab weekly dosing group and 30% in the adalimumab every other week dosing 
group.
Considering the uncertainty in the Week 8 response rate may be caused by the impact of 
central reading on the endoscopic subscore, based on the ozanimod Phase 2 
TOUCHSTONE trial data presented in early 2015, AbbVie re-estimated the Week 8 
response rate to be 50% instead of 60%.  Under this assumption, if the sample remains 
525, a smaller size of the Week 52 analysis set than was original predicted, and thus an 
insufficient power (72%) for the analysis of the Week 52 remission endpoint is expected.  
Furthermore, Week 52 remission rate will be the primary endpoint of the Maintenance 
Study.  AbbVie proposes to increase the power for this endpoint from 80% as originally 
designed to 90% retaining the currently assumed treatment difference.  The combined 


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impact of these changes (i.e., increased power plus higher uncertainty in Week 8 response 
rate) results in an increase in the overall Study M14-033 sample size from 525 subjects to 
a total of 840 subjects.
Subjects will be randomized to the adalimumab higher induction regimen and the 
adalimumab standard induction regimen in a 3:2 ratio.  The sample size calculations for 
the main study are based on a two sided Fisher's exact test at a significance level of 0.05.  
Assuming an expected Week 8 endoscopic improvement rate of 60% in the adalimumab 
higher induction dosing regimen and 45% in the adalimumab standard induction dosing 
regimen, 804 subjects (504 subjects in the higher induction dosing regimen and 
336 subjects in the standard induction dosing regimen) will provide 90% statistical power 
to detect the difference between the two induction treatment regimens.  This sample size 
of 804 subjects in the main study will provide at least 95% power to detect a treatment 
difference of 15% for the primary endpoint of clinical remission, assuming an expected 
Week 8 clinical remission rate of 35% in the adalimumab higher induction regimen and 
20% in the adalimumab standard induction regimen.
Assuming the average response rate at Week 8 in the adalimumab induction dosing 
regimens in the main study is 50%, there will be 420 responders for the analysis of 
Week 52 clinical remission among the Week 8 responders (168 in the higher maintenance 
dosing regimen, 168 in the standard maintenance dosing regimen, and 84 in the TDM 
regimen).  This sample size will provide 90% power to detect a treatment difference of 
18%, assuming an expected Week 52 clinical remission rate of 48% in the adalimumab 
higher maintenance dosing regimen and 30% in the adalimumab standard maintenance 
dosing regimen. 
The sample size calculations for the Japan sub-study are described in Appendix K.
Section 8.3  Randomization Methods
Second paragraph, first sentence previously read:
At the conclusion of the 8-week Induction Period, all subjects will be re-randomized into 
the 44-week Maintenance Period.


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Has been changed to read:
At the conclusion of the 8-week Induction Study, all subjects will be re-randomized into 
the 44-week Maintenance Study.
Section 8.3  Randomization Methods
Second paragraph, last sentence previously read:
All subjects will be randomized into one of three blinded treatment arms in a 2:2:1 ratio:
Has been changed to read:
All subjects will be randomized into one of three blinded treatment regimens in a 
2:2:1 ratio:
Section 8.3  Randomization Methods
Last bullet previously read:
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory arm).  (The 
Japan sub-study does not have a TDM arm.  Subjects will be randomized into 
Adalimumab 40 mg eow arm or Adalimumab 40 mg ew arm in a 1:1 ratio.)
Has been changed to read:
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory).  (The Japan 
sub-study does not have a TDM regimen.  Subjects will be randomized into Adalimumab 
40 mg eow or Adalimumab 40 mg ew treatment regimens in a 1:1 ratio.)
Section 11.0  Data Quality Assurance
Previously read:
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.


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Has been changed to read:
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.
Data from the central laboratory and the imaging vendor will be electronically transferred 
to the study database.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Data and Statistical Sciences
Clinical Pharmacokinetics and Pharmacodynamics
Clinical
Clinical
Clinical


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Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Data and Statistical Sciences
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical
Bioanalysis
Appendix J.  70-Day Follow-Up Phone Call – Sample
Previously read:
Site Name/Number:  ____________________________
Subject Number:  __________________
Please contact subjects who discontinue adalimumab 70 days following study drug 
discontinuation.
Date of Call:  _____________________
Lost to Follow-up (Please check this box if subject was not willing to provide 
any follow-up information or you were unable to speak to the subject following 
at least one attempt.)
No Events Reported
N/A subject continued adalimumab therapy after the end of their study 
participation
List any Adverse Events (AE) and/or Serious Adverse Events (SAE) that occurred since the 
subject was last seen in clinic for this study.  If needed, provide AE/SAE details on the AE 
worksheet attached.  (Please report all SAEs to AbbVie within 24 hours of being made aware of 
the event.)


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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
Has been changed to read:
Site Name/Site Number:  ____________________________
Subject Number:  __________________
Date of last study drug administration (DD/MMM/YY): __________________
Please contact subjects who discontinue adalimumab 70 days following study drug 
discontinuation.
Note:  Subjects who continue commercial adalimumab do not require a 70-day follow-up call.
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
AEs/SAEs Reported
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.)  Any medications taken as a result of the events should also be entered on the eCRF.


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If events are listed above, your monitor will review and retrieve the appropriate eCRF pages during their 
next visit.
If 70-day follow-up call was not performed:
Subject continued adalimumab therapy after the end of their study participation
Other, describe below:
Please fax all completed forms to:
Fax:   
Email:  
Subject line:  PI NAME_Subject number_70 day followup
Appendix K.  Japan Sub-Study
Section 4.0  Study Objective
Previously read:
The primary study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis.
Has been changed to read:
The study objective is to evaluate the safety and efficacy of higher induction and 
maintenance dosing regimens in subjects with moderately to severely active ulcerative 
colitis.


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Appendix K.  Japan Sub-Study
Section 5.1  Overall Study Design and Plan:  Description
Previously read:
The primary analysis for the Japan sub-study will be an analysis of subjects achieving 
clinical remission (per Full Mayo Score) at Week 8.  The analysis will include 
approximately 80 subjects (48 in the higher induction dose regimen and 32 in the standard 
induction dose regimen) from 21 Japanese sites and approximately 525 subjects from all 
other sites in the main study.
Has been changed to read:
The primary analysis for the Japan sub-study during the Induction Study will be an 
analysis of subjects achieving clinical remission (per Full Mayo Score) at Week 8.  The 
primary analysis for the Japan sub-study during the Maintenance Study will be an analysis 
of subjects is the proportion of Week 8 responders achieving clinical remission (per Full 
Mayo score) at Week 52.
The analysis will include approximately 100 subjects (60 in the higher induction dose 
regimen and 40 in the standard induction dose regimen) from 21 Japanese sites and 
approximately 840 subjects from all other sites in the main study.
Appendix K.  Japan Sub-Study
Section 5.1  Overall Study Design and Plan:  Description
Subsection 44-Week Double-Blind Maintenance Period
Subsection title and text previously read:
44-Week Double-Blind Maintenance Period
The TDM arm in the maintenance period will not be applied to the Japan sub-study 
because of logistical challenges in obtaining adalimumab serum concentration results 
within the time period specified in the main study.  At the conclusion of the 8-Week 
Double-Blind Induction Period, subjects will return to the study site and will be 
re-randomized using the same stratification variables as the main study via IRT into the 


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44-Week Double-Blind Maintenance Period to one of two treatment arms in a 1:1 ratio 
with the same stratification from the main study:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
Subjects in the adalimumab 40 mg eow arm will continue to receive 40 mg eow until the 
end of the study.  Subjects in the adalimumab 40 mg ew arm will start 40 mg ew at 
Week 8 until the end of the study.
Has been changed to read:
44-Week Double-Blind Maintenance Study
The TDM regimen in the maintenance period will not be applied to the Japan sub-study 
because of logistical challenges in obtaining adalimumab serum concentration results 
within the time period specified in the main study.  At the conclusion of the 8-Week 
Double-Blind Induction Study, subjects will return to the study site and will be 
re-randomized using the same stratification variables as the main study via IRT into the 


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44-Week Double-Blind Maintenance Study to one of two treatment groups in a 1:1 ratio 
with the same stratification from the main study:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg every week (ew)
Screening 
Period
Up to 21 days
Double-Blind 
Induction
Study
8 weeks
Double-Blind Maintenance Study
44 weeks
Follow-up
0*  1   2      4             8     10    12            16                     22   24              29                     35    37            42                      48                    52
Week
RR
RR
ADA 40 eow
ADA 40 ew
Std (N=40)
High 
(N=60)
Re-Randomization of all 
subjects
* Randomization
Subjects in the adalimumab 40 mg eow treatment group will continue to receive 40 mg 
eow until the end of the study.  Subjects in the adalimumab 40 mg ew treatment group 
will start 40 mg ew at Week 8 until the end of the study.
Appendix K.  Japan Sub-Study
Section 5.2.2  Exclusion Criteria
Criterion 25 previously read:
25. Subjects with a positive result for 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.


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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 (+)
Has been changed to read:
25. Subjects with a positive result for 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.
Appendix K.  Japan Sub-Study
Table 2.  Study Activities
Header row, column "8-Week Double-Blind Induction Period" and "44-Week 
Double-Blind Maintenance Period" previously read:
"8-Week Double-Blind Induction Period" and "44-Week Double-Blind Maintenance 
Period"


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Has been changed to read:
"8-Week Double-Blind Induction Study" and "44-Week Double-Blind Maintenance 
Study"
Appendix K.  Japan Sub-Study
Table 2.  Study Activities
Table note "j."
Add:  new last sentence
Further explanations of these tests are provided in the Laboratory Manual.
Appendix K.  Japan Sub-Study
Table 2.  Study Activities
Table note "m."
Add:  new last sentence
Remaining sample will be stored for potential research testing.
Appendix K.  Japan Sub-Study
Section 5.3.2  Drug Concentration Measurements
Subsection Collection of Samples for Adalimumab and AAA Assays
Last paragraph, last sentence previously read:
The total number of samples planned (not including unscheduled visit sample collections) 
will not exceed 1,200 (15 samples × 80 subjects) for the adalimumab assay and 560 
(7 samples × 80 subjects) for the AAA assay for the sub-study.
Has been changed to read:
The total number of samples planned (not including unscheduled visit sample collections) 
will not exceed 1,500 (15 samples × 100 subjects) for the adalimumab assay and 700 
(7 samples × 100 subjects) for the AAA assay for the sub-study.


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Appendix K.  Japan Sub-Study
Section 5.3.2  Drug Concentration Measurements
Subsection Collection of Samples for Infliximab and HACA Assays
Last paragraph previously read:
The total number of samples planned for Japan will not exceed 160 (2 samples × 
80 subjects) for the sub-study.
Has been changed to read:
The total number of samples planned for Japan will not exceed 200 (2 samples × 
100 subjects) for the sub-study.
Appendix K.  Japan Sub-Study
Section 5.5.1 Treatments Administered 
Previously read:
Double-Blind Induction Period
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction doses.
Subjects assigned to the standard induction arm will receive adalimumab 160 mg 
(4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  At 
Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes).  At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction arm will receive 160 mg (4 syringes) at Weeks 0, 
1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Doses
At Week 8, subjects will be re-randomized to receive 1 of 2 double-blind adalimumab 
treatment maintenance regimens in a 1:1 ratio.  


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Subjects assigned to the adalimumab 40 mg eow arm will receive 40 mg (1 syringe) at 
Weeks 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 
50.  Matching Placebo (1 syringe) will be administered at Weeks 9, 11, 13, 15, 17, 19, 21, 
23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51.  No dose will be administered at 
Week 52.
Subjects assigned to the adalimumab 40 mg ew arm will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51. No 
dose will be administered at Week 52.
Has been changed to read:
Double-Blind Induction Study
At Baseline (Week 0), subjects will be randomized 3:2 to one of two double-blind 
adalimumab induction regimens.
Subjects assigned to the standard induction regimen will receive adalimumab 160 mg 
(4 syringes) at Baseline (Week 0) and matching placebo (4 syringes) at Week 1.  At 
Week 2, subjects will receive 80 mg (2 syringes) and matching placebo (2 syringes).  At 
Week 3, subjects will receive matching placebo (4 syringes) and at Weeks 4 and 6, 
subjects will receive a dosing regimen of 40 mg (1 syringe).
Subjects assigned to the higher induction regimen will receive 160 mg (4 syringes) at 
Weeks 0, 1, 2, and 3 followed by 40 mg (1 syringe) at Weeks 4 and 6.
Double-Blind Maintenance Study
At Week 8, subjects will be re-randomized to receive 1 of 2 double-blind adalimumab 
treatment maintenance regimens in a 1:1 ratio.  
Subjects assigned to the adalimumab 40 mg eow regimen will receive 40 mg (1 syringe) 
at Weeks 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 and 


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50.  Matching Placebo (1 syringe) will be administered at Weeks 9, 11, 13, 15, 17, 19, 21, 
23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51.  No dose will be administered at 
Week 52/Premature Discontinuation.
Subjects assigned to the adalimumab 40 mg ew regimen will receive 40 mg (1 syringe) at 
Weeks 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 and 51.  No 
dose will be administered at Week 52/Premature Discontinuation.
Appendix K.  Japan Sub-Study
Section 5.5.3  Method of Assigning Subjects to Treatment Arms
Section title previously read:
Method of Assigning Subjects to Treatment Arms
Has been changed to read:
Method of Assigning Subjects to Treatment Regimens
Appendix K.  Japan Sub-Study
Section 5.5.3  Method of Assigning Subjects to Treatment Arms
First paragraph, third sentence previously read:
Subjects who enter the study will be randomized at Week 0 in a 3:2 ratio into the criteria-
driven arms using the IRT, which will assign a randomization number according to the 
randomization scheme, generated by AbbVie before the start of the study.
Has been changed to read:
Subjects who enter the study will be randomized at Week 0 in a 3:2 ratio into the criteria-
driven regimens using the IRT, which will assign a randomization number according to 
the randomization scheme, generated by AbbVie before the start of the study.


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Appendix K.  Japan Sub-Study
Section 5.5.3  Method of Assigning Subjects to Treatment Arms
First paragraph, last sentence previously read:
The criteria-driven arm assignment will be maintained by the IRT.
Has been changed to read:
The criteria-driven regimen assignment will be maintained by the IRT. 
Appendix K.  Japan Sub-Study
Section 5.5.3  Method of Assigning Subjects to Treatment Arms
Second paragraph, first sentence previously read:
Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Period at the conclusion of the Week 8 Visit to one of 
two treatment arms in a 1:1 ratio.  
Has been changed to read:
Subjects will return to the study site and will be re-randomized via IRT into the 44-Week 
Double-Blind Maintenance Study at the conclusion of the Week 8 Visit to one of 
two treatment regimens in a 1:1 ratio.
Appendix K.  Japan Sub-Study
Section 6.1.5  Adverse Event Reporting 
Second paragraph, "Dept." previously read:
Has been changed to read:


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Appendix K.  Japan Sub-Study
Section 6.1.5  Adverse Event Reporting 
Fourth paragraph, "address" previously read:
Primary Study Designated Physician
 MD
Pharmaceutical Development
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany
Has been changed to read:
Primary Study Designated Physician
MD
AbbVie Deutschland GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen, Germany


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Appendix K.  Japan Sub-Study
Section 6.1.5  Adverse Event Reporting 
Fifth paragraph previously read:
Secondary Contact for Japan (Regional Medical Monitor)
MD, PhD
 Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:
Has been changed to read:
Secondary Contact for Japan (Regional Medical Monitor)
MD, PhD
 Japan Development
AbbVie GK
3-5-27 Mita, Minato
Tokyo, 108-6302
Japan
Office:
Mobile:
Fax:
Email:


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Appendix K.  Japan Sub-Study
Section 8.1  Statistical and Analysis Plans
Second sentence previously read:
Efficacy analysis will be performed in the integrated Intent to Treat (ITT) set and the 
Japan ITT set. 
Has been changed to read:
Efficacy analysis will be performed in the integrated Intent to Treat (ITT1) set and the 
Japan ITT1 set.
Appendix K.  Japan Sub-Study
Section 8.1.1  Analysis Population
Previously read:
The integrated ITT (I-ITT) dataset includes all randomized subjects (at both Japanese sites 
and all other sites in the main study).  The Japan ITT (J-ITT) dataset includes all subjects 
who were randomized at Japanese sites only and will be used for efficacy analyses of 
Japanese subjects separately from other subjects in the main study.  The integrated 
Intent-to-Treat maintenance (I-ITT-M) population includes all subjects (at both Japanese 
sites and all other sites in the main study) who are re-randomized to 40 mg eow group and 
40 mg ew group at Week 8 (subjects who are re-randomized to TDM group will not be 
included).  The I-ITT-M subjects will be analyzed as randomized.  The I-ITT-M is the 
primary population for the efficacy analysis at Week 52 during the maintenance period.
The J-ITT-M dataset includes all subjects who were re-randomized at Week 8 at Japanese 
sites only and will be used for maintenance efficacy analyses of Japanese subjects 
separately from other subjects in the main study.
The integrated Safety set consists of all randomized subjects (from both Japanese sites and 
those sites following the parent protocol) who received at least one dose of study 
medication.  The Japan Safety set consists of all randomized subjects from Japanese sites 
who received at least one dose of study medication.


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Has been changed to read:
The integrated ITT1 (I-ITT1) dataset includes all randomized subjects (at both Japanese 
sites and all other sites in the main study).  The Japan ITT1 (J-ITT1) dataset includes all 
subjects who were randomized at Japanese sites only and will be used for efficacy 
analyses of Japanese subjects separately from other subjects in the main study.  The 
integrated Intent to-Treat maintenance (I-ITT2) population includes all subjects (at both 
Japanese sites and all other sites in the main study) who are re randomized to 40 mg eow 
group and 40 mg ew group at Week 8 (subjects who are re-randomized to TDM group 
will not be included).  The I-ITT2 subjects will be analyzed as randomized.  The I-ITT2 is 
the primary population for the efficacy analysis at Week 52 during the maintenance study.
The J-ITT2 dataset includes all subjects who were re-randomized at Week 8 at Japanese 
sites only and will be used for maintenance efficacy analyses of Japanese subjects 
separately from other subjects in the main study.
The integrated Safety set consists of all subjects (from both Japanese sites and those sites 
following the parent protocol) who received at least one dose of study medication.  The 
Japan Safety set consists of all randomized subjects from Japanese sites who received at 
least one dose of study medication.
Appendix K.  Japan Sub-Study
Section 8.1.2  Planned Methods of Statistical Analysis
Delete:  section title and text 
8.1.2
Planned Methods of Statistical Analysis
All statistical tests will be two-sided at a significance level of 0.05.  Descriptive statistics 
will be provided.  These include the number of observations, means, standard deviation,
minimum, median, and maximum for continuous variables; and counts and percentages 
for discrete variables.  The analyses will be performed using SAS® (SAS Institute Inc., 
Cary, NC, USA).


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Appendix K.  Japan Sub-Study
Section 8.1.3  Demographics and Baseline Characteristics
First and second sentence previously read:
Demographics and Baseline characteristics of the study subjects will be summarized 
similarly as the main study for each treatment group using descriptive statistics in both the 
I-ITT dataset and the J-ITT dataset.  The p-value will be provided to assess the 
comparability of the treatment arms assigned by randomization.  
Has been changed to read:
Demographics and Baseline characteristics of the study subjects will be summarized 
similarly as the main study for each treatment group using descriptive statistics in both the 
I-ITT1 dataset and the J-ITT1 dataset.  The p-value will be provided to assess the 
comparability of the treatment groups assigned by randomization.  
Appendix K.  Japan Sub-Study
Section 8.1.4.1  Primary Efficacy Variable
Section title and text previously read:
8.1.4.1
Primary Efficacy Variable
The primary efficacy endpoint is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary analysis will be analyzed similarly as the main study using the integrated ITT 
set (I-ITT) and the Japan ITT (J-ITT) set.  The difference between the treatment arms in 
the proportion of subjects achieving clinical remission at Week 8 will be assessed using 
Cochran-Mantel-Haenszel (CMH) test adjusted for previous infliximab use and Baseline 
corticosteroid use at Baseline.  A CMH based two-sided 95% confidence interval for the 
difference between treatment arms will be calculated.  Breslow-Day test for homogeneity 
of odds ratios will be performed as well.  Subjects with missing primary endpoint data at 
Week 8 will be classified as "no clinical remission" (non-responder imputation [NRI] 


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method).  Subjects with missing Mayo score data for Week 8 will also be classified as 
Week 8 non-responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as IMM use at 
Baseline, Baseline CRP, and disease severity at Baseline will also be performed for the 
primary endpoint.
For CMH test statistic, if the condition of each stratum to have at least one subject with 
each treatment and at least one subject with each possible outcome is violated for the 
primary approach to the primary efficacy endpoint, the stratification factor Baseline 
corticosteroid use will be dropped from the CMH model in the analysis of all categorical 
variables.
Has been changed to read:
8.1.4.1
Primary Efficacy Variables
The primary efficacy endpoint for the Induction Study is:
Proportion of subjects achieving clinical remission (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 8.
The primary efficacy endpoint for the Maintenance Study is:
Proportion of Week 8 responders (per Full Mayo score, defined as a decrease in Full 
Mayo score of ≥ 3 points and ≥ 30% from Baseline Plus a decrease in the rectal bleeding 
subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1) achieving clinical remission (per Full 
Mayo score) at Week 52.
The primary endpoint for the Induction Study will be analyzed similarly as the main study 
using the I-ITT1 and J-ITT1 sets.  The difference between the treatment groups in the 
proportion of subjects achieving clinical remission at Week 8 will be assessed using 
Cochran-Mantel-Haenszel (CMH) test adjusted for previous infliximab use and Baseline 


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corticosteroid use at Baseline.  A CMH based two-sided 95% confidence interval for the 
difference between treatment groups will be calculated.  Breslow-Day test for 
homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 8 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method).  Subjects with missing Mayo score data for Week 8 will also 
be classified as Week 8 non-responders.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors and additional clinically important factors such as 
Immunosuppressant use at Baseline, Baseline hs-CRP, and disease severity at Baseline 
will also be performed for the primary endpoint for the Induction Study.
For primary analysis of the Maintenance Study will compare the Week 8 responders (per 
Full Mayo Score) in the eow regimen versus the subjects in the ew regimen in the I-ITT2 
and J-ITT2 analysis sets.  The difference between the treatment regimen in the proportion 
of subjects achieving clinical remission at Week 52 will be assessed using Cochran-
Mantel-Haenszel (CMH) test adjusted for Induction treatment regimen and the remitter 
status (per Full Mayo Score) at Week 8.  A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated.  Breslow-Day test 
for homogeneity of odds ratios will be performed as well.  Subjects with missing primary 
endpoint data at Week 52 will be classified as "no clinical remission" (non-responder 
imputation [NRI] method) for the Week 52 endpoint.  Subjects with missing Mayo score 
data for Week 52 will also be classified as Week 52 non-responders.
Appendix K.  Japan Sub-Study
Section 8.1.4.2  Secondary Efficacy Variables
Previously read:
The analysis for secondary efficacy variables will be performed similarly as the main 
study using the I-ITT set and the J-ITT set for endpoints at Week 8, or the I-ITT-M set 
and the J-ITT-M set for endpoints at Week 52, where appropriate.


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Has been changed to read:
The analysis for secondary efficacy variables will be performed similarly as the main 
study using the I-ITT1 set and the J-ITT1 set for Induction Study endpoints at Week 8, or 
the I-ITT2 set and the J-ITT2 set for Maintenance Study endpoints at Week 52, where 
appropriate.
Appendix K.  Japan Sub-Study
Section 8.1.7  Interim Analysis
Previously read:
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
Week 8 only as well as safety data collected from Baseline through double-blind Week 8 
will be performed after the last subject enrolled in both main (ITT) and Japan sub-study 
ITT (J-ITT) population completes the 8-week double-blind period of the study.  The 
analyses will be applied to integrated ITT (I-ITT) population and Japan ITT (J-ITT) 
population.  A database lock will be performed and any discrepant data will be clarified 
before the lock.
Has been changed to read:
An interim analysis of the primary endpoint and ranked secondary efficacy variables for 
Week 8 only as well as safety data collected from Baseline through double-blind Week 8 
will be performed only if performed for the main study.  
Appendix K.  Japan Sub-Study
Section 8.2  Determination of Sample Size of Japan Sub-study 
First paragraph previously read:
Section 8.2 of the main study outlines the rationale for the sample size of 525 subjects.  
An additional 80 subjects has been determined as the proper sample size for the Japan 
sub-study based on the following rationale.


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Has been changed to read:
Section 8.2 of the main study outlines the rationale for the sample size of 840 subjects.  
An additional 100 subjects has been determined as the proper sample size for the Japan 
sub-study based on the following rationale.
Appendix K.  Japan Sub-Study
Section 8.2  Determination of Sample Size of Japan Sub-study 
Third, fourth and fifth bullet previously read:
●
Overall response rate for induction treatment at Week 8:  60%
●
α = 5%, power = 95% for induction phase
●
α = 5%, power = 80% for maintenance phase
Has been changed to read:
●
Overall response rate for induction treatment at Week 8:  50%
●
α = 5%, power = 95% for induction study
●
α = 5%, power = 90% for maintenance study
Appendix K.  Japan Sub-Study
Section 8.2  Determination of Sample Size of Japan Sub-study 
Last paragraph, first sentence previously read:
The precisions of point estimations of remission rates in Japanese population are included 
within the 95% CI of remission rates in integrated population will be within 20% with 
80 subjects.
Has been changed to read:
The precisions of point estimations of remission rates in Japanese population are included 
within the 95% CI of remission rates in integrated population will be within 20% with 
100 subjects.


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Appendix K.  Japan Sub-Study
Section 8.3  Randomization Methods 
First paragraph, third sentence previously read:
At the conclusion of the 8-week Induction Period, all subjects will be re-randomized into 
the 44-week Maintenance Period.
Has been changed to read:
At the conclusion of the 8-week Induction Study, all subjects will be re-randomized into 
the 44-week Maintenance Study.
Appendix K.  Japan Sub-Study
Section 8.3  Randomization Methods 
First paragraph, last sentence previously read:
All subjects will be randomized into one of two blinded treatment arms in a 1:1 ratio:
Has been changed to read:
All subjects will be randomized into one of two blinded treatment regimens in a 1:1 ratio:

SAP_001.pdf: 
Adalimumab
M14-033 – Statistical Analysis Plan for Maintenance Japan Sub-Study
Version 1.0 – 13 September 2019
1
1.0
Title Page
Statistical Analysis Plan for Maintenance Study
Study M14-033
A Double-Blind, Randomized, Multicenter Study of 
Higher Versus Standard Adalimumab Dosing 
Regimens for Induction and Maintenance Therapy in 
Subjects with Moderately to Severely Active 
Ulcerative Colitis
Japan Sub-Study
Date:  13 September 2019
Version 1.0
NCT02065622


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M14-033 – Statistical Analysis Plan for Maintenance Japan Sub-Study
Version 1.0 – 13 September 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
Design Diagram .........................................................................................5
4.3
Sample Size................................................................................................8
4.4
Final Analysis of Maintenance Study........................................................9
4.5
Derived, Defined and Transformed Variables ...........................................9
5.0
Analysis Populations .............................................................11
5.1
Definition for Analysis Populations.........................................................11
5.2
Variables Used for Stratification of Randomization................................12
6.0
Analysis Conventions ............................................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............20
7.1
Demographic and Baseline Characteristics .............................................20
7.2
Medical History .......................................................................................22
7.3
Previous Treatment and Concomitant Medications.................................23
8.0
Patient Disposition.................................................................24
9.0
Study Drug Exposure and Compliance...............................24
10.0
Efficacy Analysis....................................................................25
10.1
General Considerations............................................................................25
10.2
Primary Efficacy Analysis .......................................................................25
10.3
Secondary Efficacy Analyses...................................................................26
10.4
Additional Efficacy Analyses ..................................................................28
10.5
Handling of Multiplicity ..........................................................................31
10.6
Efficacy Subgroup Analysis ....................................................................31
11.0
Safety Analysis.......................................................................32
11.1
General Considerations............................................................................32
11.2
Analysis of Adverse Events.....................................................................33
11.2.1
Treatment-Emergent Adverse Events ......................................................33


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11.2.2
Adverse Events of Special Interest ..........................................................35
11.3
Analysis of Laboratory Data....................................................................37
11.3.1
Assessment of Shifts from Baseline in Liver-Specific Laboratory 
Variables ..................................................................................................37
11.3.2
Hy's Law Cases........................................................................................38
11.4
Analysis of Vital Signs and Weight.........................................................39
12.0
Summary of Changes ............................................................40
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP .......................................................................................40
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .....................................................................41
13.0
Appendix.................................................................................41
14.0
References...............................................................................41
List of Tables
Table 1.
Visit Windows for Analysis of Efficacy Variables, Laboratory 
Parameters and Vital Signs (Maintenance Study)....................................15
Table 2.
Visit Windows for Analysis of hs-CRP (Maintenance Study) ................15
Table 3.
Visit Windows for Analysis of Fecal Calprotectin (Maintenance 
Study).......................................................................................................16
Table 4.
Visit Windows for Analysis of Endoscopy Variables 
(Maintenance Study)................................................................................16
Table 5.
Visit Windows for Analysis of IBDQ (Maintenance Study) ...................16
Table 6.
Visit Windows for Analysis of EIM, SF36 and WPAI 
(Maintenance Study)................................................................................17
Table 7.
Equivalent Steroid Dose ..........................................................................19
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Findings..........40
List of Figures
Figure 1.
Study Schematic (Japan Sub-Study)..........................................................6
Figure 2.
8-Week Double-Blind Induction Study .....................................................7


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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 M14-033 Amendment 3 
dated 16 June 2016.  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 SAP for the 44-Week Double-Blind Maintenance Japan Sub-
Study of Protocol M14-033.
Study M14-033 consists of a Main Study and a Japan Sub-Study.  This SAP version is 
developed solely for the Maintenance Japan Sub-Study, which is conducted in 
approximately 21 Japanese sites following the Protocol Amendment 3.  All data from 
subjects enrolled under the Main Study will be excluded from the analyses described in 
this SAP.  A separate SAP will be developed for the Main Study.
This analysis plan describes the primary and secondary efficacy analyses as well as the 
safety analysis for the Maintenance Study under the Protocol Amendment 3. A separate 
SAP was developed for the Induction Japan Sub-Study.
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 Japan Sub-Study objective is to evaluate the safety and efficacy of higher induction 
and maintenance dosing regimens in subjects with moderately to severely active 
ulcerative colitis and to show the consistency of efficacy between Japanese population 
and integrated population of Japanese and Western subjects from the Main Study.


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4.2
Design Diagram
This is a Phase 3, double-blind, randomized, multicenter study of higher versus standard 
adalimumab dosing regimens for induction and maintenance therapy in subjects with 
moderately to severely active UC (Mayo Score of 6 to 12 points with an endoscopy 
subscore of 2 or 3, confirmed by a central reader).  For all Mayo Score evaluations 
throughout the study, the stool frequency and the rectal bleeding subscores will be 
calculated based on entries recorded in daily electronic patient diaries.
The Japan Sub-Study was designed to enroll 100 Japanese subjects (60 subjects in the 
higher induction dose regimen and 40 subjects in the standard induction dose regimen) at 
approximately 21 sites in Japan to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  There are 
also 840 subjects in a Main Study to be enrolled at 125 sites worldwide outside Japan. 
This study will include:
●
An up to 21 days Screening Period
●
An 8-Week Double-Blind Induction Study
●
A 44-Week Double-Blind Maintenance Study
●
A 70-Day Follow-Up Period
During both the Induction Study and the Maintenance Study, visit week designations will 
represent weeks since first adalimumab dose in the Induction Study.  Week 0 (Baseline) 
will reflect the date of first adalimumab dosing in the Induction Study.  Week 8 will 
represent the final assessment in the Induction Study and the beginning of the 
Maintenance Study.  Week 52 will represent the final assessment in the Maintenance 
Study (representing 44 weeks of maintenance treatment in the Maintenance Study).  A 
subject's participation in the study is anticipated to be up to 65 weeks.  There is a ± 3 day 
window for all study visits.  An effort will be made to bring subjects back to their original 
scheduled visit (calculated from Baseline) if they are out of the visit window.


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A schematic of the study design is presented in Figure 1.
Figure 1.
Study Schematic (Japan Sub-Study)
8-Week Double-Blind Induction Study
Subjects who met all of the inclusion criteria and none of the exclusion criteria were to be 
enrolled into the 8-Week Induction Study.  The Main Study and the Japan Sub-Study 
would each allow enrollment of up to 25% of subjects with previous infliximab exposure.
Subjects were to be randomized via interactive response system (IRT) at Baseline 
(Week 0) to one of 2 double-blinded adalimumab induction regimens (higher dose or 
standard dose) in a 3:2 ratio.  Use of the 3:2 randomization scheme allows for collection 
of additional safety data with the higher induction dose regimen.  The randomization was 
to be stratified by:
●
Previous infliximab use, and
●
Baseline corticosteroid use.


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The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg 
at Weeks 4 and 6 leads to a total adalimumab dose over 8 weeks that is approximately 
twice that of the standard induction regimen (720 mg versus 320 mg) as shown in 
Figure 2 below.
Figure 2.
8-Week Double-Blind Induction Study
Subjects would return to the study site at scheduled visits and complete study procedures 
for each visit.
At Week 4, all subjects who were on oral corticosteroids at Baseline would have their 
corticosteroid dose tapered according to the proposed tapering schedule outlined in the 
protocol.  If the Investigator felt that the steroid taper was not advisable for a particular 
subject at Week 4, the SDP should have been consulted for evaluation and approval.
44-Week Double-Blind Maintenance Study
The TDM regimen in the maintenance period will not be applied to the Japan Sub-Study 
because of logistical challenges in obtaining adalimumab serum concentration results 


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within the time period specified in the Main Study. At the conclusion of the 8-Week 
Double-Blind Induction Japan Sub-Study, subjects will return to the study site and will be 
re-randomized via IRT into the 44-Week Double-Blind Maintenance Japan Sub-Study to 
one of two treatment groups in a 1:1 ratio:  
●
Adalimumab 40 mg eow.
●
Adalimumab 40 mg every week (ew).
Subjects in the adalimumab 40 mg eow treatment group will continue to receive 40 mg 
eow until the end of the study.  Subjects in the adalimumab 40 mg ew treatment group 
will start 40 mg ew at Week 8 until the end of the study.
70-Day Follow-Up/Premature Discontinuation
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects who end study participation early will have a premature discontinuation (PD) 
Visit.  Subjects 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 AEs.  The 
70 day follow-up phone call will not be required for any subject who initiates commercial 
adalimumab. 
4.3
Sample Size
One hundred Japanese subjects have been determined as the proper sample size for the 
Japan Sub-Study based on the following rationale. Using the same assumptions as the 
Main Study with the following:
!
Remission rate for induction treatment at 8 weeks: 35% in the high dose group and 
20% in the standard dose group
!
Remission rate for maintenance treatment at 52 weeks among Week 8 responders: 
48% in the high dose group and 30% in the standard dose group
!
Overall response rate for induction treatment at Week 8: 50%
!
α = 5%, power = 95% for induction study
!
α = 5%, power = 90% for maintenance study


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The precisions of point estimations of remission rates in Japanese population are included
within the 95% CI of remission rates in integrated population will be within 20% with 100 
subjects. With this sample size, the probability to show consistency between Japanese 
population and integrated population will be greater than 80% using the method 2 shown 
in the "Basic principles on global clinical trials."
4.4
Final Analysis of Maintenance Study
The final analysis of the primary endpoint, ranked secondary efficacy variables and 
additional efficacy variables as well as safety data will be performed after the last subject 
in the I-ITT (Section 5.1 for definition) population completes the 44-week double-blind 
Maintenance Study.  A database lock will be performed and any discrepant data will be 
clarified before the lock.  The statistical methods for the analysis of the primary endpoint 
are outlined in Section 10.2.  The statistical methods for the analyses of the ranked 
secondary efficacy endpoints are outlined in Section 10.3.
4.5
Derived, Defined and Transformed Variables
The following defined variables will be used:
●
Full Mayo Score
○
Full Mayo Score is defined as the composite score of UC disease activity 
based on the subscores of stool frequency (0 – 3), rectal bleeding (0 – 3), 
physician's global assessment (0 – 3) and endoscopy (0 – 3).  This score 
ranges from 0 – 12 points with higher scores representing more severe 
disease (also see Section 6.0 for the rules for calculation of rectal bleeding 
and stool frequency subscores).
○
Clinical Response is defined as a decrease in Full Mayo Score of ≥ 3 points 
and ≥ 30% from Baseline, PLUS a decrease in the rectal bleeding subscore 
[RBS] ≥ 1 or an absolute RBS ≤ 1.
○
Clinical Remission is defined as Full Mayo Score ≤ 2 with no subscore 
> 1.
●
Partial Mayo Score


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○
Partial Mayo Score is defined as the composite score of UC disease 
activity based on the subscores of stool frequency, rectal bleeding, and 
physician's global assessment and DOES NOT include the endoscopy 
subscore.  This score ranges from 0 – 9 points also see Section 6.0 for the
rules for calculation of rectal bleeding and stool frequency subscores.
○
Clinical Response per Partial Mayo Score is defined as a decrease in 
Partial Mayo Score ≥ 2 points and ≥ 30% from Baseline, PLUS a decrease 
in RBS ≥ 1 or an absolute RBS ≤ 1.
○
Clinical Remission per Partial Mayo Score is defined as Partial Mayo 
Score ≤ 2, with no subscore > 1.
●
Adapted Mayo Score
○
Adapted Mayo Score is defined as Full Mayo Score minus the Physician's 
Global Assessment (PGA) subscore.
○
Clinical Remission per Adapted Mayo Score is defined as an Adapted 
Mayo Score ≤ 2, with stool frequency subscore ≤ 1, RBS of 0, and 
endoscopic subscore ≤ 1.
○
Clinical Response per Adapted Mayo Score is defined as a decrease in the 
Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, PLUS a 
decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
●
IBDQ Response
○
IBDQ Response is defined as at least a 16-point increase from Baseline in 
total Inflammatory Bowel Disease Questionnaire (IBDQ) score.
●
Endoscopic Improvement: endoscopy subscore of 0 or 1.
●
Endoscopic Remission: endoscopy subscore of 0.
●
Histologic Improvement: decrease in Geboes score from Baseline
●
Histologic Remission: Geboes score < 2.0


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
The Japanese population is defined as all Japanese subjects who were randomized at sites
in Japan.  The following populations will be used for analyses in Japan Sub-Study:
Integrated Intent-to-Treat maintenance (I-ITT) population includes all subjects who are 
re-randomized at both Japanese sites and all other sites in the Main Study at Week 8 into 
the Maintenance Study. The Japan ITT (J-ITT) dataset includes all Japanese subjects who 
are re-randomized at Japanese sites at Week 8 into the Maintenance Study. I-ITT and J-
ITT subjects will be analyzed as randomized.  
Integrated ITT-Responder (I-ITT-RP) population includes all subjects in I-ITT who 
achieve Week 8 response based on the Full Mayo Score utilizing the endoscopy subscore 
provided by the central reader. Japan ITT-Responder (J-ITT-RP) population includes all 
subjects in J-ITT who achieve Week 8 response based on the Full Mayo Score utilizing 
the endoscopy subscore provided by the central reader. I-ITT-RP and J- ITT-RP are the 
populations for the efficacy analysis of Week 8 responders during the Maintenance Study.
Integrated ITT-Non-Responder (I-ITT-NRP) population includes all subjects in I-ITT who 
do not achieve Week 8 response based on the Full Mayo Score utilizing the endoscopy 
subscore provided by the central reader. Japan ITT-Non-Responder (J-ITT-NRP) 
population includes all subjects in J-ITT who do not achieve Week 8 response based on 
the Full Mayo Score utilizing the endoscopy subscore provided by the central reader.  
ITT-NRP is the population for the efficacy analysis of Week 8 non-responders during the 
Maintenance Study.
Integrated ITT-Remitter (I-ITT-RM) population includes all subjects in I-ITT who 
achieve Week 8 remission based on the Full Mayo Score utilizing the endoscopy subscore 
provided by the central reader. Japan ITT-Remitter (J-ITT-RM) population includes all 
subjects in J-ITT who achieve Week 8 remission based on the Full Mayo Score utilizing 


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the endoscopy subscore provided by the central reader. I-ITT-RM and J- ITT-RM is the 
population for the efficacy analysis of Week 8 remitters during the Maintenance Study.
Integrated ITT-Non-Remitter (I-ITT-NRM) population includes all subjects in I-ITT who 
do not achieve Week 8 remission based on the Full Mayo Score utilizing the endoscopy 
subscore provided by the central reader.  Japan ITT-Non-Remitter (J-ITT-NRM) 
population includes all subjects in J-ITT who do not achieve Week 8 remission based on 
the Full Mayo Score utilizing the endoscopy subscore provided by the central reader. I-
ITT-NRM and J- ITT-NRM are the populations for the efficacy analysis of Week 8 non-
remitters during the Maintenance Study.
The integrated safety set for Maintenance Study consists of all subjects (from both 
Japanese sites and sites in the Main Study) who received at least one dose of study drug in 
the Maintenance Study.  The Japan safety set for Maintenance Study consists of all 
Japanese subjects from Japanese sites who received at least one dose of study drug in the 
Maintenance Study. The integrated safety set and Japan safety set for Maintenance Study 
will be analyzed as treated, according to treatment the subject actually received.  
5.2
Variables Used for Stratification of Randomization
At Baseline, subjects will be randomized 3:2 to one of two double-blinded adalimumab 
induction dosing regimens (higher dose or standard dose) for the Induction Japan Sub-
Study.  The randomization will be stratified by previous infliximab use and baseline 
corticosteroid use.
At the conclusion of the 8-week Induction Japan Sub-Study, all subjects will be re-
randomized into the 44-week Maintenance Japan Sub-Study.  Re-randomization will be 
stratified by induction treatment regimen and response status (per Full Mayo Score 
utilizing the Week 8 endoscopy subscore provided by the site) at Week 8.  Among the 
responders at Week 8, the randomization will be further stratified by remission status (per 
Full Mayo Score utilizing the Week 8 endoscopy subscore provided by the site) at Week 


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8.  All subjects will be randomized into one of three blinded treatment groups in a 1:1 
ratio:
●
Adalimumab 40 mg eow
●
Adalimumab 40 mg ew
6.0
Analysis Conventions
Definition of Induction Baseline
The induction baseline (thereafter referred to as Baseline) visit date is the date when the 
first dose of study drug is received during Induction Study and referred to as Day 1 or 
Week 0.  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 during Induction Study.
Definition of Maintenance Baseline
The maintenance baseline visit date is the date when the first dose of study drug is 
received during Maintenance Study.  The maintenance 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 
during Maintenance Study.
Definition of Final Observation
Final Observation in Maintenance Study is defined as the last non-missing observation 
collected within 70 days following the last dose of study drug for subjects who are 
re-randomized.  The 70-day follow-up phone call will not be required for any subject who 
initiates commercial adalimumab.
Definition of Rx Days (Days Relative to the First Dose of Maintenance Study Drug)
Rx Day during the Maintenance Study is calculated as the event date minus the date of 
first dose of the Maintenance Study drug plus 1. The Rx Day will be a negative value 


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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 the first dose date.  Rx 
days are used to map actual study visits to the protocol specified study visits during 
Maintenance Study, as defined below. If a subject has not taken any study drug during 
Maintenance Study, Rx Day during the Maintenance Study will be calculated as the event 
date minus the date of re-randomization date plus 1.
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 along with 
a window around the target day will be selected to represent the corresponding visit.  
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 target 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 1.
Visit Windows for Analysis of Efficacy Variables, Laboratory 
Parameters and Vital Signs (Maintenance Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of the Maintenance Study 
(Maintenance Baseline)
1
≤ 1
Week 10 (Week 2 of Maintenance Study)
15
2 – 22
Week 12 (Week 4 of Maintenance Study)
29
23 – 43
Week 16 (Week 8 of Maintenance Study)
57
44 – 78
Week 22 (Week 14 of Maintenance Study)
99
79 – 106
Week 24 (Week 16 of Maintenance Study)
113
107 – 130
Week 29 (Week 21 of Maintenance Study)
148
131 – 169
Week 35 (Week 27 of Maintenance Study)
190
170 – 197
Week 37 (Week 29 of Maintenance Study)
204
198 – 221
Week 42 (Week 34 of Maintenance Study)
239
222 – 260
Week 48 (Week 40 of Maintenance Study)
281
261 – 295
Week 52 (Week 44 of Maintenance Study)
309
296 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.
Table 2.
Visit Windows for Analysis of hs-CRP (Maintenance Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of the Maintenance Study 
(Maintenance Baseline)
1
≤ 1
Week 12 (Week 4 of Maintenance Study)
29
2 – 43
Week 16 (Week 8 of Maintenance Study)
57
44 – 85
Week 24 (Week 16 of Maintenance Study)
113
86 – 130
Week 29 (Week 21 of Maintenance Study)
148
131 – 176
Week 37 (Week 29 of Maintenance Study)
204
177 – 221
Week 42 (Week 34 of Maintenance Study)
239
222 – 274
Week 52 (Week 44 of Maintenance Study)
309
275 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.


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Table 3.
Visit Windows for Analysis of Fecal Calprotectin (Maintenance 
Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of the Maintenance Study 
(Maintenance Baseline)
1
≤ 1
Week 12 (Week 4 of Maintenance Study)
29
2 – 43
Week 16 (Week 8 of Maintenance Study)
57
44 – 85
Week 24 (Week 16 of Maintenance Study)
113
86 – 159
Week 37 (Week 29 of Maintenance Study)
204
160 – 257
Week 52 (Week 44 of Maintenance Study)
309
258 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.
Table 4.
Visit Windows for Analysis of Endoscopy Variables (Maintenance 
Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of maintenance period (Maintenance 
Baseline)
1
≤ 1
Week 52 (Week 44 of Maintenance Study)
309
113 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.
Table 5.
Visit Windows for Analysis of IBDQ (Maintenance Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of the Maintenance Study 
(Maintenance Baseline)
1
≤ 1
Week 12 (Week 4 of Maintenance Study)
29
2 – 71
Week 24 (Week 16 of Maintenance Study)
113
72 – 159
Week 37 (Week 29 of Maintenance Study)
204
160 – 257
Week 52 (Week 44 of Maintenance Study)
309
258 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.


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Table 6.
Visit Windows for Analysis of EIM, SF36 and WPAI (Maintenance 
Study)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Entry of maintenance period (Maintenance 
Baseline)
1
≤ 1
Week 52 (Week 44 of Maintenance Study)
309
113 – 379
Rx Day = date of visit – date of first study drug injection in the Maintenance Study + 1.
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 value 
will be considered as 'Not Achieved.'  In addition, subjects who prematurely discontinue 
from the study drug will be considered as 'Not Achieved' for all subsequent visits after 
discontinuation.
Observed Case (OC)
The OC analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the OC analysis 
for that visit.  In addition, the OC analysis will not use values after premature 
discontinuation of study drug.
Mixed-Effect Model Repeated Measure (MMRM)
The repeated measure analysis will be conducted using mixed model including observed 
measurements at all visits.  Data collected after premature discontinuation of study drug 
will be excluded from the analysis.  The mixed model includes the categorical fixed 


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effects of treatment, visit and treatment-by-visit interaction, stratification factors at 
randomization, and the continuous fixed covariates of baseline measurement.  An 
unstructured variance covariance matrix will be used.
Last Observation Carried Forward (LOCF)
The LOCF rule will be used to impute for missing continuous and categorical efficacy 
data. Values on or prior Maintenance Baseline will not be used to impute the missing 
values post Maintenance Baseline.  Missing values after Maintenance Baseline will be 
imputed using the latest non-missing value after Maintenance Baseline and prior to the 
missing value.  If there are no non-missing values after Maintenance Baseline, then the 
LOCF value will be missing.  If a subject has missing values for a specific visit, the data 
will be imputed using LOCF only for the period which the subject started. 
Rules for Calculation of Stool Frequency Subscore and Rectal Bleeding Subscore
The diary entries on the days the subjects take endoscopy preparation medications, the 
day of endoscopy procedure, and the 2 days after endoscopy procedure will be excluded.  
For the calculation of the stool frequency subscore and the rectal bleeding subscore at 
each visit, the most recent 5 available diary days from up to 14 days preceding the visit 
will be used.
To calculate these subscores when fewer than 5 days of diary data are available in the 
previous 14 days, the average will be based on the most recent 4 days will be used if only 
4 days are available, or the average will be based on the most recent 3 days will be used if 
only 3 days are available.
If the subject has fewer than 3 days of diary entries, the score for that subject at the visit 
will be considered missing, and the subject will be categorized as a non-responder (NRI) 
for any categorical endpoints relating to data for this visit.
Rounding to one decimal place will be applied to the calculation above for the subscores, 
Partial Mayo Score and Full Mayo Score.


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The last day of the 5 days will be used to decide the actual visits that should be assigned 
to the Mayo Score and Partial Mayo Score data.
Rules for Efficacy Assessment Based on Concomitant Treatment
Subjects in whom the UC-related systemic or rectal corticosteroids 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 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 
integrated safety and Japan safety populations.
The equivalent steroid dose will be determined based on Table :
Table 7.
Equivalent Steroid Dose
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
Definition of Medication Use at Baseline
Medications are considered to be used at Baseline if the medication start date is on or 
before the first study drug dose date and the medication end date is on or after the 


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first dose date.  All medications with a start date after the first dose date or an end date 
before the first dose date are excluded.
Treatment Interruption
If the study drug treatment interruption is longer than 60 days and treatment re-
introduction is evaluated as not feasible, the subject will be considered as premature 
discontinuation from the study in all efficacy assessment after the last dose and all the 
aforementioned imputation rules apply.
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
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in I-ITT-RP, J-ITT-RP, integrated safety and Japan safety analysis sets 
for Maintenance Study, demographic information and baseline values will be summarized 
by descriptive statistics.  Categorical data will be summarized by frequency and 
percentage; and quantitative data will be presented by n, mean, standard deviation, 
minimum, median, and maximum values.
The following demographic and baseline values will be summarized.


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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
●
Full Mayo score and its components (stool frequency, rectal bleeding, PGA, 
and endoscopy subscores)
●
Partial Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (mcg/g)
●
Short Form 36 Health Survey (SF-36) and its components
●
WPAI and its components
●
Albumin (g/L)
●
Disease duration
Categorical Variables:
●
Sex [male/female]
●
Race [White, Black, Asian, American Indian/Alaska Native, Other, Multirace]
●
Ethnicity 
●
Tobacco use [user, ex-user, never used, unknown]
●
Alcohol use [drinker, ex-drinker, non-drinker, unknown]
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L) 
●
Disease extent (ulcerative proctitis, left-sided, extensive/pancolitis)


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●
Prior infliximab use (yes, no)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Region (US versus non-US)
7.2
Medical History
Medical and Surgical History:  A complete medical and surgical history (which includes 
UC-onset date) and 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 
condition/diagnosis for -ITT-RP, J-ITT-RP, integrated safety and Japan safety analysis 
sets for Maintenance Study 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.  If PPD skin test is performed, induration will be summarized 
descriptively using n, mean, standard deviation, minimum values, median, and maximum 
values.  The frequency distribution of induration ≥ 5 mm and < 5 mm 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 include all medications taken prior to the first dose of study drug of 
Induction study.  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 for Maintenance Study include medications with a start date 
prior to the Maintenance Baseline date which are continuing after Maintenance Baseline 
and all medications with a start date between the Maintenance Baseline date and last study 
drug administration + 14 days.  All medications with an end date prior to the first dose 
date for Maintenance are excluded. If the start date is completely missing for a 
medication and if the stop date is before the Maintenance Baseline date, it is considered 
previous medication for the Maintenance and not further evaluated.  In addition to start 
date being completely missing, if the stop date is also completely missing or the stop date 
is on or after the Maintenance baseline date, it will also be considered as a concomitant 
medication.
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by counts and percentages for I-ITT-RP, 
J-ITT-RP, integrated safety and Japan safety analysis sets for Maintenance Study by 
treatment group.  No statistical tests will be performed.
The number and percentage of subjects using immunosuppressants (defined as 
azathioprine, mercaptopurine, or methotrexate), and anti-TNF therapies at any time prior 
to baseline will be tabulated.  Similarly, the use of oral corticosteroids, 
immunosuppressants, oral aminosalicylates, and anti-TNF therapies at baseline will be 
tabulated.


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8.0
Patient Disposition
Subject disposition will be present for subjects in the I-ITT-RP, J-ITT-RP, integrated 
safety and Japan safety analysis sets for Maintenance Study using the following 
information by treatment group:
●
Number and percentages of subjects in various analysis sets by treatment 
group and by investigator and/or site number
●
Number and percentages of subjects completing Week 52 visit and 
discontinuing on or before Week 52 visit
●
Number and percent of subjects who prematurely discontinued the study (on or 
before Week 52) by primary reason and by any reason
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 for the Maintenance Study.
The number of injections received at each schedule time point will be summarized with 
frequencies and percentages for each treatment group for the Maintenance Study.
Study Drug Exposure (in Days) during the Maintenance Study
Study drug exposure is calculated as:
●
Date of last dose of Maintenance Study drug – Date of first dose of 
Maintenance Study drug + 14 days


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Study Drug Compliance:
Treatment compliance will be summarized for each treatment group in the I-ITT and J-
ITT populations.  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 counts and 
percentages for discrete variables.  The analysis will be performed using SAS® (SAS 
Institute Inc., Cary, NC, USA). All efficacy analysis will be performed using I-ITT-RP
and J-ITT-RP analysis set for the Maintenance Study, unless otherwise specified.
10.2
Primary Efficacy Analysis
This section provides the details of the primary efficacy analysis for the Maintenance 
Study.
Primary Efficacy Variable:
The primary efficacy variable for the Maintenance Study is the proportion of Week 8 
responders (per Full Mayo score) achieving clinical remission (per Full Mayo score) at 
Week 52.
Analysis Data Set for the Primary Efficacy Analysis:
The primary efficacy analysis will use the I-ITT-RP analysis set for the Maintenance 
Study.


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Imputation Method used for the Primary Efficacy Analysis:
The primary efficacy analysis will use the NRI method to impute the missing values at 
Week 52 for the Maintenance Study.  Subjects with missing primary endpoint data at 
Week 52 will be classified as "no clinical remission."
Statistical Method of the Primary Efficacy Analysis:
The primary analysis of the Maintenance Japan Sub-Study will compare the Week 8 
responders (per Full Mayo Score) in the eow regimen versus the subjects in the ew 
regimen in the I-ITT-RP analysis set.  The difference between the treatment regimens in 
the proportion of subjects achieving clinical remission at Week 52 will be assessed using 
Cochran-Mantel-Haenszel (CMH) test adjusted for Induction treatment regimen and 
remitter status at Week 8, where Week 8 remitter status will be determined based on the 
Full Mayo Score using the endoscopy subscore from the central reader.  A CMH based 
two-sided 95% confidence interval for the difference between treatment groups will be 
calculated.  Breslow-Day test for homogeneity of odds ratios will be performed as well.
10.3
Secondary Efficacy Analyses
For the analysis purpose, the secondary efficacy endpoints are divided into two groups:  
(1) ranked secondary endpoints and (2) additional, non-ranked endpoints.
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Maintenance Study are:
1.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
2.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.


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3.
Proportion of Week 8 responders (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
4.
Proportion of Week 8 remitters (per Full Mayo score) achieving clinical remission 
(per Full Mayo score) at Week 52.
5.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
improvement (endoscopic subscore of 0 or 1) at Week 52.
6.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days at Week 52.
7.
Proportion of Week 8 remitters (per Full Mayo score) taking steroids at Baseline 
who are steroid-free for at least 90 days and in clinical remission (per Full Mayo 
score) at Week 52.
8.
Proportion of Week 8 responders (per Full Mayo score) with IBDQ response 
(increase of IBDQ ≥ 16 from Baseline) at Week 52.
9.
Proportion of Week 8 non-responders (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
10.
Proportion of Week 8 non-remitters (per Full Mayo score) with clinical remission 
(per Full Mayo score) at Week 52.
11.
Proportion of Week 8 responders (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
12.
Proportion of Week 8 remitters (per Full Mayo score) achieving endoscopic 
subscore of 0 at Week 52.
13.
Proportion of Week 8 responders (per Full Mayo score) with response in IBDQ 
Bowel Symptom domain (increase of IBDQ bowel symptom domain score ≥ 6 
from Baseline) at Week 52.
14.
Proportion of Week 8 responders (per Full Mayo score) with response in IBDQ 
fatigue item (increase of IBDQ fatigue item score ≥ 1 from Baseline) at Week 52.


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As all these endpoints are categorical variables, NRI method of imputation, as described 
for the primary efficacy analysis, will be used for the missing values. 
For the Maintenance Study endpoints, the difference between the adalimumab 40 mg eow 
treatment group versus the adalimumab 40 mg ew treatment will be assessed.  The 
secondary endpoints at Week 52 that are of the categorical type will be analyzed using a 
two-sided CMH test adjusted for induction treatment regimen, and responder/remitter 
status at Week 8.  Additionally, the CMH based two-sided 95% confidence interval (CI) 
for the difference in the proportions between the treatment groups will be calculated.
10.4
Additional Efficacy Analyses
Additional pre-specified endpoints in the Maintenance Study are as follows:
●
Proportion of Week 8 responders (per Full Mayo score) with clinical response 
at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with clinical 
response at Week 52.
●
Proportion of Week 8 non-responders (per Full Mayo score) with endoscopic 
improvement at Week 52.
●
All cause and UC-related hospitalization and surgery rates during
Weeks 8 – 52.
●
Proportion of Week 8 responders per Adapted Mayo score (defined as decrease 
from Baseline in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, 
PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute 
RBS ≤1) achieving clinical remission per Adapted Mayo scores at Week 52.
●
Proportion of Week 8 responders (per Full Mayo score) achieving Full Mayo 
Score, excluding the PGA subscore, ≤ 2 with no subscore > 1 at Week 52.
●
Relationship between histologic scores and endoscopic improvement 
(endoscopy subscore of 0 or 1) at Week 52.
●
Relationship between histologic scores and endoscopic subscore of 0 at 
Week 52.


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●
Proportion of Week 8 responders (per Full Mayo score) taking steroids at 
Baseline who are steroid-free for at least 180 days and in clinical remission 
(per Full Mayo score) at Week 52.
●
Proportion of subjects who are taking corticosteroids at Baseline and are 
steroid free over time.
●
Proportion of subjects achieving clinical remission per Partial Mayo (defined 
as a Partial Mayo score ≤ 2 with no subscore > 1) score over time.
●
Proportion of subjects achieving clinical response per Partial Mayo score 
(defined as a decrease in Partial Mayo score of ≥ 2 points and ≥ 30% from 
Baseline Plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an 
absolute RBS of 0 or 1) over time.
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in corticosteroid dose over time.
●
Change from Baseline in IBDQ score over time.
●
Proportion of subjects with IBDQ total score ≥ 170 over time.
●
Change from Baseline in Mayo score, Partial Mayo score and Mayo subscores 
over time.
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight).
●
Change from Baseline in subject-reported stool frequency (absolute values).
●
Change from Baseline in work productivity and impairment questionnaire 
(WPAI) scores.
●
Change from Baseline in SF-36 score.
●
Change from Baseline in fecal calprotectin over time.
●
Proportion of subjects with fecal calprotectin below 150 mg/kg over time.
●
Time to achievement of remission (per Partial Mayo score).
●
Time to achievement of response (per Partial Mayo score).
●
Time to loss of response and factors associated with loss of response.
●
Change in presence of extraintestinal manifestations.


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The difference in proportions of subjects between treatment groups will be analyzed 
similarly as the ranked secondary endpoints and 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 baseline between treatment groups will be analyzed using 
an ANCOVA model including factors of treatment, stratification variables and Baseline 
values.  Parameter estimates with 95% confidence interval and P value will be provided.
NRI for missing data will be used for categorical endpoints.  Mixed-Effect Model 
Repeated Measure (MMRM) model will be applied as the main analysis for the 
continuous endpoints.  
Events of hospitalization and surgery will be identified by blinded adjudication of the 
serious adverse events (SAEs).  Subjects in the integrated safety and Japan safety analysis
sets for the Maintenance Study will be included in the all-cause and UC-related 
hospitalization and surgery rates analyses during the Maintenance Study.  
All-cause hospitalization is defined as SAEs resulting in admission to the hospital or 
prolongation of an existing hospitalization for any reason.  UC-related hospitalizations are 
defined as hospital admissions or prolongation of an existing hospitalization due to AEs 
or complications that are related to UC and included the following categories:  UC-related 
surgery, hospitalizations for nonsurgical UC-related events, such as UC-related flares, and 
hospitalizations related to the complications/extra-intestinal manifestations of UC.  
For all-cause and UC-related hospitalization and surgery rates during Weeks 8 – 52, 
adjusted incidence rates will be used to compare the risk between the treatment groups.  
Adjusted rates will be calculated as the number of subjects with the respective event 
divided by the time at risk.  For subjects with an event during the study period, time at 
risk is the patient-years (PYs) from Week 8 to the first event.  For subjects without an 
event during the study period, time at risk is PYs from Week 8 to the end of study follow 
up period.  Relative risk ratios of the incidence rates and confidence intervals will be 


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calculated to evaluate the statistical significance of the difference between treatment 
groups using z-score normal approximations.  Additionally, because subjects could have 
more than one hospitalization during the follow-up period, an event-based approach will 
be taken.  The total number of hospitalizations during the Weeks 8 – 52 will be compared 
between the treatment groups using Poisson regression with the length of follow-up as the 
offset variable.  Multiple events will be counted in this model.
10.5
Handling of Multiplicity
The overall type I error rate of the primary and the ranked secondary endpoints will be 
strongly controlled using the approach of fixed-sequence multiple testing procedure.1  
Specifically, the testing will utilize the endpoint sequence of the primary and ranked 
secondary endpoints in the order as specified in Section 10.2 and Section 10.3 at the pre-
specified alpha level. That is, only if success has been demonstrated for the primary 
endpoint of clinical remission will the testing continue to the first ranked secondary 
endpoint of endoscopic improvement.  If success has been demonstrated for the 
first ranked secondary endpoint, then testing will continue to the next ranked secondary 
endpoint. Similarly, testing will continue through the other ranked secondary endpoints 
only if success was met for the preceding endpoint; otherwise, statistical testing will stop.
No multiplicity adjustment will be applied to the additional efficacy endpoints listed in 
Section 10.4.  The analysis for additional efficacy endpoints will be performed at the 
nominal α level of 0.05 (two-sided).
10.6
Efficacy Subgroup Analysis
The subgroups listed below will be used in subgroup analyses of the primary endpoint of 
the Maintenance Study.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline corticosteroid use (yes, no)


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●
Baseline immunosuppressant use (yes, no)
●
Baseline Mayo Score (≤ 9, > 9)
●
Baseline Mayo Score (≤ median, > median)
●
Prior exposure to anti-TNF (yes, no)
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Baseline hs-CRP (≤ median, > median)
●
Baseline albumin (≤ median, > median)
●
Region (US versus non-US)
11.0
Safety Analysis
11.1
General Considerations
All safety analyses will be performed on the integrated safety analysis set and the Japan 
safety analysis set for the Maintenance Study.  The safety variables will be summarized 
by treatment regimen according to the treatment a subject actually received.  Treatment 
group differences between the adalimumab 40 mg eow treatment group and the 
adalimumab 40 mg ew treatment group in safety parameters will be evaluated using two-
sided tests at the significance level of 0.05.  
Unless otherwise specified, the treatment group differences in continuous safety variables 
(e.g., change from baseline to final observation on laboratory tests) will be assessed using 
an ANOVA model with the term of treatment, and the treatment group differences in 
categorical safety variables will be evaluated using a Fisher's exact test.


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11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs during the Maintenance Study are defined as events that begin 
or worsen either on or after the first dose of the study drug in the Maintenance Study and 
within 70 days after the last dose of the study drug.
An overview of treatment-emergent AEs, including AEs of special interest such as 
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 percentage. In 
addition, an overview of treatment-emergent AEs will be summarized by onset of adverse 
events in 3-month interval for the integrated safety analysis set. 
The number and percentage 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 with reasonable 
possibility of relationship 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:


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●
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, Preferred Term and onset of adverse events 
in 3-month interval (for the integrated safety analysis set).
●
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).
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 drug, 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.


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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.
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 special interest will be summarized 
and presented using primary MedDRA system organ classes (SOCs) and preferred terms 
(PTs) for the following AE categories:  
●
Any Infections AE
●
Any Serious Infection AE
●
Any Legionella Infection AE
●
Any Diverticulitis AE
●
Any Opportunistic Infection AE (Excluding Oral Candidiasis and TB)
●
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)


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●
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 AE
●
Any Myocardial Infarction Related AE
●
Any Cerebrovascular Accident Related AE
●
Any Congestive Heart Failure Related AE
●
Any Pulmonary Embolism Related AE
●
Any Interstitial Lung Disease AE
●
Any Intestinal Perforation AE
●
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 AE Leading to Death
●
Any AE Leading to Discontinuation of Study Drug
●
Any Deaths


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Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
11.3
Analysis of Laboratory Data
Changes from Baseline and Maintenance Baseline in continuous laboratory parameters 
will be summarized by n, mean, standard deviation, minimum value, median, and 
maximum value for each treatment group in the Maintenance Study.  Treatment group 
differences for changes from Baseline will be analyzed using a one-way Analysis of 
Variance (ANOVA) and 95% CI for treatment difference will be presented for selected 
laboratory parameters.
Shift tables from Baseline to the final value (the last assessment during each treatment 
period) according to the normal range will be provided for each hematology, clinical 
chemistry parameter and urinalysis parameter.  The laboratory data will be categorized as 
low, normal, or high based on the normal ranges of the laboratory used in this study.  The 
shift tables will tabulate the number and percentage of subjects with Baseline values 
within/above the normal range versus final and post-baseline values below the normal 
range and with Baseline values below/within the normal range versus final and post-
baseline values above the normal range.
For selected laboratory parameter with Common Toxicity Criteria (CTC), the number and 
percentage of subjects with any laboratory determinations meeting CTC Version 3.0 (or 
later) of Grade ≥ 3, as well as being a higher grade than the Baseline grade, will be 
summarized.  For each of these subjects, the whole course of the laboratory parameters 
with CTC Grade ≥ 3 will be listed.
11.3.1
Assessment of Shifts from Baseline in Liver-Specific 
Laboratory Variables
Baseline and post-baseline liver-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;


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●
≥ 3 to < 5 the upper limit of the reference range;
●
≥ 5 to 8 and the upper limit of the reference range;
●
≥ 8 the limit of the reference range.
For each variable, shift tables will be generated that cross tabulate the subjects' as deemed 
appropriate:
●
Category of the baseline value versus category of the final value,
●
Category of the baseline value versus maximum category
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.
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 treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN


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●
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
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
Alkaline Phosphatase ≥ 2.5 × ULN, or
●
Total Bilirubin ≥ 1.5 × ULN.
11.4
Analysis of Vital Signs and Weight
The following vital signs are measured at every visit during the Maintenance 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.  
Treatment group differences for changes from Baseline will be analyzed using a one-way 
Analysis of Variance (ANOVA) and 95% CI for treatment difference will be presented.


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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 .
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
This is the first version of the SAP for 44-Week Double-Blind Maintenance Japan Sub-
Study.
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The statistical changes between current SAP and the latest version of protocol are listed 
below:
●
Added two endpoints in the additional efficacy analysis (Section 10.4): 
○
proportion of subjects with IBDQ total score ≥ 170 over time.
○
proportion of subjects with fecal calprotectin below 150 mg/kg over time.
●
Updated the rules for efficacy assessment based on concomitant medication 
per latest analysis conventions for immunology clinical studies.  Only UC-
related systemic or rectal corticosteroids will be used for censoring purpose 


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and will have last non-missing value prior to censoring carried forward for 
non-categorical assessments from that point forward.
●
The following two IBDQ-related endpoints have been added as ranked #13 and 
#14 secondary endpoints (Section 10.3) for the Maintenance Study. The 
addition of these two ranked secondary endpoints is based on recent FDA's 
feedback from Upadacitinib UC program to consider specific questions or 
domains within IBDQ that are most relevant to IBD patients.
○
Proportion of Week 8 responders (per Full Mayo score) with response in 
IBDQ Bowel Symptom domain (increase of IBDQ bowel symptom 
domain score ≥ 6 from Baseline) at Week 52.
○
Proportion of Week 8 responders (per Full Mayo score) with response in 
IBDQ fatigue item (increase of IBDQ fatigue item score ≥ 1 from 
Baseline) at Week 52.
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
This is the first version of the SAP for the 44-Week Double-Blind Maintenance Japan 
Sub-Study.
13.0
Appendix
None.
14.0
References
1.
Westfall PH, Krishen A.  Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures.  J Stat Plan Inference.  2001;99:25-40.


Adalimumab
M14-033 – Statistical Analysis Plan for Induction Study
Version 1.0 – 12 Nov 2018
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1.0
Title Page
Statistical Analysis Plan for Induction Japan Sub-
Study
Study M14-033
A Double-Blind, Randomized, Multicenter Study of 
Higher Versus Standard Adalimumab Dosing 
Regimens for Induction and Maintenance Therapy in 
Subjects with Moderately to Severely Active 
Ulcerative Colitis
Japan sub-study
Date:  12 Nov 2018
Version 1.0


Adalimumab
M14-033 – Statistical Analysis Plan for Induction Study
Version 1.0 – 12 Nov 2018
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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 for Japan Sub-Study.............................................................. 4
4.2
Design Diagram ..................................................................................... 4
4.3
Sample Size............................................................................................ 9
4.4
Final Analysis of Induction Japan Sub-Study........................................ 10
4.5
Derived, Defined and Transformed Variables ....................................... 10
5.0
Analysis Populations ...........................................................11
5.1
Definition for Analysis Populations ...................................................... 11
5.2
Variables Used for Stratification of Randomization .............................. 12
6.0
Analysis Conventions ..........................................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............18
7.1
Demographic and Baseline Characteristics ........................................... 18
7.2
Medical History.................................................................................... 20
7.3
Previous Treatment and Concomitant Medications ............................... 20
8.0
Patient Disposition...............................................................21
9.0
Study Drug Exposure and Compliance..............................22
10.0
Efficacy Analysis .................................................................23
10.1
General Considerations......................................................................... 23
10.2
Primary Efficacy Analysis.................................................................... 23
10.3
Secondary Efficacy Analyses ............................................................... 24
10.4
Additional Efficacy Analyses ............................................................... 25
10.5
Handling of Multiplicity....................................................................... 27
10.6
Efficacy Subgroup Analysis ................................................................. 27
11.0
Safety Analysis.....................................................................28
11.1
General Considerations......................................................................... 28
11.2
Analysis of Adverse Events.................................................................. 28
11.2.1
Treatment-Emergent Adverse Events.................................................... 28


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11.2.2
Adverse Events of Special Interest........................................................ 30
11.3
Analysis of Laboratory Data................................................................. 32
11.3.1
Assessment of Shifts from Baseline in Liver-Specific Laboratory 
Variables.............................................................................................. 33
11.3.2
Hy's Law Cases .................................................................................... 33
11.4
Analysis of Vital Signs and Weight ...................................................... 34
12.0
Summary of Changes ..........................................................35
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 36
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .................................................................. 36
13.0
Appendix..............................................................................36
14.0
References............................................................................36
List of Tables
Table 1.
Visit Windows for Analysis of Efficacy Variables, Laboratory 
Parameters and Vital Signs (Induction Study)....................................... 14
Table 2.
Visit Windows for Analysis of Endoscopy Variables (Induction 
Study)................................................................................................... 14
Table 3.
Visit Windows for Analysis of IBDQ, SF-36 and WPAI 
(Induction Study).................................................................................. 14
Table 4.
Equivalent Steroid Dose ....................................................................... 17
Table 5.
Criteria for Potentially Clinically Significant Vital Sign Findings ......... 35
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
Figure 2.
8-Week Double-Blind Induction Study................................................... 7


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis for Japan sub-study to 
be completed by the AbbVie Global Statistics Department for study Protocol M14-033 
Amendment 3 dated 16 June 2016.  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 SAP for the 8-Week Double-Blind Induction Study of 
Protocol M14-033 for Japan sub-study.
Study M14-033 consists of a main study and a Japan sub-study.  This SAP version is 
developed solely for the Induction Japan Sub-Study following the Protocol Amendment 3.
This analysis plan describes the primary and secondary efficacy analyses as well as the 
safety analysis for the Induction Japan Sub-Study under the Protocol Amendment 3.
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 for Japan Sub-Study
The study objective for Japan Sub-Study is to evaluate the safety and efficacy of higher 
induction and maintenance dosing regimens in subjects with moderately to severely active 
ulcerative colitis and to show the consistency of efficacy between Japanese population 
and integrated population of Japanese and western subjects. 
4.2
Design Diagram
This is a Phase 3, double-blind, randomized, multicenter study of higher versus standard 
adalimumab dosing regimens for induction and maintenance therapy in subjects with 
moderately to severely active UC (Mayo Score of 6 to 12 points with an endoscopy 


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subscore of 2 or 3, confirmed by a central reader).  For all Mayo Score evaluations 
throughout the study, the stool frequency and the rectal bleeding subscores will be 
calculated based on entries recorded in daily electronic patient diaries.
The study was designed to enroll 840 subjects (504 subjects in the higher induction dose 
regimen and 336 subjects in the standard induction dose regimen) at approximately 
125 sites for the main study and 100 subjects (60 in the higher induction dose regimen and 
40 in the standard induction dose regimen) at 21 sites for Japan Sub-Study 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.
This study will include:
An up to 21 days Screening Period
An 8-Week Double-Blind Induction Study
A 44-Week Double-Blind Maintenance Study
A 70-Day Follow-Up Period
During both the Induction Study and the Maintenance Study, visit week designations will 
represent weeks since first adalimumab dose in the Induction Study.  Week 0 (Baseline) 
will reflect the date of first adalimumab dosing in the Induction Study.  Week 8 will 
represent the final assessment in the Induction Study and the beginning of the 
Maintenance Study.  Week 52 will represent the final assessment in the Maintenance 
Study (representing 44 weeks of maintenance treatment in the Maintenance Study).  A 
subject's participation in the study is anticipated to be up to 65 weeks.  There is a ± 3 day 
window for all study visits.  An effort will be made to bring subjects back to their original 
scheduled visit (calculated from Baseline) if they are out of the visit window.
A schematic of the study design is presented in Figure 1.




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safety data with the higher induction dose regimen.  The randomization will be stratified 
by:
Previous infliximab use, and
Baseline corticosteroid use.
The higher induction dose regimen of 160 mg at Weeks 0, 1, 2, and 3, followed by 40 mg 
at Weeks 4 and 6 leads to a total adalimumab dose over 8 weeks that is approximately 
twice that of the standard induction regimen (720 mg versus 320 mg) as shown in 
Figure 2 below.
Figure 2.
8-Week Double-Blind Induction Study
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit.


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At Week 4, all subjects who were on oral corticosteroids at Baseline will have their 
corticosteroid dose tapered according to the proposed tapering schedule outlined in the 
protocol.  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.
44-Week Double-Blind Maintenance Study
At the conclusion of the 8-Week Double-Blind Induction Study, subjects will return to the 
study site and will be re-randomized via IRT into the 44-Week Double-Blind 
Maintenance Study of the main study to one of three treatment groups in a 2:2:1 ratio:  
Adalimumab 40 mg eow.
Adalimumab 40 mg every week (ew).
Adalimumab Therapeutic Drug Monitoring (TDM) regimen (exploratory).
The TDM regimen in the maintenance period will not be applied to the Japan sub-study 
because of logistical challenges in obtaining adalimumab serum concentration results 
within the time period specified in the main study. At the conclusion of the 8-Week 
Double-Blind Induction Study, subjects will return to the study site and will be re-
randomized using the same stratification variables as the main study via IRT into the 
44-Week Double-Blind Maintenance Study to one of two treatment groups in a 1:1 ratio 
with the same stratification from the main study:
Adalimumab 40 mg eow
Adalimumab 40 mg every week (ew)
Throughout the study, subjects will only be allowed to change the dosage of UC-specific 
concomitant medications as specified below:
At Week 4, all subjects who are taking oral corticosteroids from Baseline will have their 
corticosteroid therapy tapered according to the proposed tapering schedule specified in the 
Protocol.  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.


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Subjects taking corticosteroids at Baseline who have a loss of satisfactory clinical 
response per the Investigators 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 from the point forward.  These subjects will 
continue to be evaluated in the safety population.
70-Day Follow-Up/Premature Discontinuation
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects who end study participation early will have a premature discontinuation (PD) 
Visit.  All subjects 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 AEs.  The 
70 day follow-up phone call will not be required for any subject who initiates commercial 
adalimumab.
4.3
Sample Size
An additional 100 subjects has been determined as the proper sample size for the Japan 
Sub-Study based on the following rationale. Using the same assumptions as the main 
study with the following:
Remission rate for induction treatment at 8 weeks: 35% in the high dose group and 20% 
in the standard dose group
Remission rate for maintenance treatment at 52 weeks among Week 8 responders: 48% in 
the high dose group and 30% in the standard dose group
Overall response rate for induction treatment at Week 8: 50%
α = 5%, power = 95% for induction study
α = 5%, power = 90% for maintenance study
The precisions of point estimations of remission rates in Japanese population are included 
within the 95% CI of remission rates in integrated population will be within 20% with 
100 subjects. With this sample size, the probability to show consistency between 


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Japanese population and integrated population will be greater than 80% using the 
method 2 shown in the "Basic principles on global clinical trials."
4.4
Final Analysis of Induction Japan Sub-Study
The final analysis of the primary endpoint, ranked secondary efficacy variables and 
additional efficacy variables for the Induction Study only as well as safety data collected 
from Baseline through double-blind Week 8 will be performed after the last subject in the 
ITT (Section 5.1 for definition) population completes the 8-week double-blind Induction 
Study of the Main Study and Japan Sub-Study.  A database lock will be performed and 
any discrepant data will be clarified before the lock.  The statistical methods for the 
analysis of the primary endpoint are outlined in Section 10.2.  The statistical methods for 
the analyses of the ranked secondary efficacy endpoints are outlined in Section 10.3.
4.5
Derived, Defined and Transformed Variables
The following defined variables will be used:
Full Mayo Score
○
Full Mayo Score is defined as the composite score of UC disease activity 
based on the subscores of stool frequency (0 – 3), rectal bleeding (0 – 3), 
physician's global assessment (0 – 3) and endoscopy (0 – 3).  This score 
ranges from 0 – 12 points with higher scores representing more severe 
disease (also see Section 6.0 for the rules for calculation of rectal bleeding 
and stool frequency subscores).
○
Clinical Response is defined as a decrease in Full Mayo Score of ≥ 3 points 
and ≥ 30% from Baseline, PLUS a decrease in the rectal bleeding subscore 
[RBS] ≥ 1 or an absolute RBS ≤ 1.
○
Clinical Remission is defined as Full Mayo Score ≤ 2 with no 
subscore > 1.
Partial Mayo Score
○
Partial Mayo Score is defined as the composite score of UC disease 
activity based on the subscores of stool frequency, rectal bleeding, and 
physician's global assessment and DOES NOT include the endoscopy 


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subscore.  This score ranges from 0 – 9 points also see Section 6.0 for the 
rules for calculation of rectal bleeding and stool frequency subscores.
○
Clinical Response per Partial Mayo Score is defined as a decrease in 
Partial Mayo Score ≥ 2 points and ≥ 30% from Baseline, PLUS a decrease 
in RBS ≥ 1 or an absolute RBS ≤ 1.
○
Clinical Remission per Partial Mayo Score is defined as Partial Mayo 
Score ≤ 2, with no subscore > 1.
Adapted Mayo Score
○
Adapted Mayo Score is defined as Full Mayo Score minus the Physician's 
Global Assessment (PGA) subscore.
○
Clinical Remission per Adapted Mayo Score is defined as an Adapted 
Mayo Score ≤ 2, with stool frequency subscore ≤ 1, RBS of 0, and 
endoscopic subscore ≤ 1.
○
Clinical Response per Adapted Mayo Score is defined as a decrease in the 
Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, PLUS a 
decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
IBDQ Response
○
IBDQ Response is defined as at least a 16 point increase from Baseline in 
total Inflammatory Bowel Disease Questionnaire (IBDQ) score.
Endoscopic Improvement
○
Endoscopic Improvement is defined as endoscopy subscore of 0 or 1.
Endoscopic Remission
○
Endoscopic Remission is defined as endoscopy subscore of 0.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The Japanese population is defined as all Japanese subjects who were randomized at 
Japanese sites.  The following populations will be used for analyses in the Japan Sub-
Study:


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The integrated ITT (I-ITT) dataset includes all randomized subjects (at both Japanese sites 
and all other sites in the main study). The Japan ITT (J-ITT) dataset includes all Japanese 
subjects who were randomized at Japanese sites only and will be used for efficacy
analyses of Japanese subjects separately from other subjects in the main study.
The integrated Safety set consists for Induction Study of all subjects (from both Japanese 
sites and those sites following the parent protocol) who received at least one dose of study 
medication. The Japan Safety set for Induction Study consists of all randomized Japanese 
subjects from Japanese sites who received at least one dose of study medication.
5.2
Variables Used for Stratification of Randomization
At Baseline, subjects will be randomized 3:2 to one of two double-blinded adalimumab 
induction dosing regimens (higher dose or standard dose) for the Induction Study.  The 
randomization will be stratified by previous infliximab use and baseline corticosteroid 
use. The randomization schedules will be prepared separately for the main study and the 
Japan sub-study by the Statistics Department of AbbVie.
6.0
Analysis Conventions
Definition of Baseline
The baseline visit date is the date when the first dose of study drug was received during 
Induction Study and referred to as Day 1 or Week 0.  The baseline value for a variable is 
defined as the last non-missing value before the first dose of study drug during Induction 
Study.  When dosing times or observation times are not collected, it is assumed that 
observations obtained on the day of the first dose of study drug (Day 1) are prior to the 
first dose of study drug and therefore baseline values.
Definition of Final Observation
Final Observation in the 8-week double-blind Induction Study is defined as the last 
non-missing observation collected within 70 days following the last dose of study drug for 
subjects who are not re-randomized, and on or before the day of the first dose of study 


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drug in the 44-week double-blind Maintenance Study for subjects who entered the 
Maintenance Study.  Of note, the efficacy, laboratory, and vital sign evaluations 
performed on the day of first dose of study drug in the double-blind Maintenance Study 
will be included in the efficacy and safety analyses for the Induction Study.  AEs onset on 
the date of the first dose of the Maintenance Study will be attributed to the Maintenance 
Study.
Definition of Treatment Compliance
Compliance (%) is defined as the number of injections received divided by the number of 
injections planned (rounded to 0.1) during the subject's participation in the Induction 
Study. 
Definition of Rx Days (Days Relative to the First Dose of Study Drug)
Rx Days are calculated for each time point of interest and provide a quantitative measure 
of days between an event and the first dose date.  The Rx Day during the Induction Study 
is calculated as the event date minus the date of first dose of the Induction 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 the first dose date.  By this calculation algorithm the first dose day 
is Rx Day 1, while the day prior to the date of first dose is defined as Rx Day –1 (there is 
no Rx Day 0). Rx days are used to map actual study visits to the protocol specified study 
visits during the Induction Study (Rx Day A), as defined below.
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 along with 
a window around the target day will be selected to represent the corresponding visit.  
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 


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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 target 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.
Table 1.
Visit Windows for Analysis of Efficacy Variables, Laboratory 
Parameters and Vital Signs (Induction Study)
Scheduled Week
Nominal Day
Time Window (Rx Day A Range)
Week 0a
1
≤ 1
Week 1
8
2 – 11
Week 2
15
12 – 22
Week 4
29
23 – 43
Week 8a
57
44 – 71b
Rx Day A = date of visit – date of first study drug injection in the Induction Study + 1
a.
hs-CRP and fecal calprotectin collections are scheduled at Screening/Week 0 and Week 8 per protocol.
b.
Minimum of Day 71 or the date of the first injection in the Maintenance Study, if applicable.
Table 2.
Visit Windows for Analysis of Endoscopy Variables (Induction 
Study)
Scheduled Week
Nominal Day
Time Window (Rx Day A Range)
Week 0
1
≤ 1
Week 8
57
2 – 71a
Rx Day A = date of visit – date of first study drug injection in the Induction Study + 1
a.
Minimum of Day 71 or the date of the first injection in the Maintenance Study, if applicable.
Table 3.
Visit Windows for Analysis of IBDQ, SF-36 and WPAI (Induction 
Study)
Scheduled Week
Nominal Day
Time Window (Rx Day A Range)
Week 0a
1
≤ 1
Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8a
57
44 – 71b
Rx Day A = date of visit – date of first study drug injection in the Induction Period + 1


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a.
SF-36 and WPAI collections are scheduled at Week 0 and Week 8 per protocol.
b.
Minimum of Day 71 or the date of the first injection in the Maintenance Study, if applicable.
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 value 
will be considered as 'Not Achieved.' In addition, subjects who prematurely discontinue 
from the study drug will be considered as 'Not Achieved' for all subsequent visits after 
discontinuation.
Observed Case (OC)
The OC analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the OC analysis 
for that visit.  In addition, the OC analysis will not use values after premature 
discontinuation of study drug.
Mixed-Effect Model Repeated Measure (MMRM)
The repeated measure analysis will be conducted using mixed model including observed 
measurements at all visits.  Data collected after premature discontinuation of study drug 
will be excluded from the analysis.  The mixed model includes the categorical fixed 
effects of treatment, visit and treatment-by-visit interaction, stratification factors at 
randomization, and the continuous fixed covariates of baseline measurement.  An 
unstructured variance covariance matrix will be used.


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Last Observation Carried Forward (LOCF)
The LOCF rule will be used to impute for missing continuous and categorical efficacy 
data.  Baseline and Pre-Baseline values will not be used to impute the missing Post-
Baseline values.  Missing values after Study Day 1 will be imputed using the latest non-
missing value after Day 1 and prior to the missing value.  If there are no non-missing 
values after Baseline, then the LOCF value will be missing.  If a subject has missing 
values for a specific visit, the data will be imputed using LOCF only for the period which 
the subject started.
Rules for Calculation of Stool Frequency Subscore and Rectal Bleeding Subscore
The diary entries on the days the subjects take endoscopy preparation medications, the 
day of endoscopy procedure, and 2 days after endoscopy procedure will be excluded.  For 
the calculation of the stool frequency subscore and the rectal bleeding subscore at each 
visit, the most recent 5 available diary days from up to 14 days preceding the visit will be 
used.
To calculate these subscores when fewer than 5 days of diary data are available in the 
previous 14 days, the average will be based on the most recent 4 days will be used if only 
4 days are available, or the average will be based on the most recent 3 days will be used if 
only 3 days are available.
If the subject has fewer than 3 days of diary entries, the score for that subject at the visit 
will be considered missing, and the subject will be categorized as a non-responder (NRI) 
for any categorical endpoints relating to data for this visit.
Rounding to one decimal place will be applied to the calculation above for the subscores, 
Partial Mayo Score and Full Mayo Score.
The last day of the 5 days will be used to decide the actual visits that should be assigned 
to the Mayo Score and Partial Mayo Score data.


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Rules for Efficacy Assessment Based on Concomitant Treatment
Subjects in whom the UC-related systemic or rectal corticosteroids 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 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.
The equivalent steroid dose will be determined based on Table 4:
Table 4.
Equivalent Steroid Dose
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
Definition of Medication Use at Baseline
Medications are considered to be used at Baseline if the medication start date is on or 
before the first study drug dose date and the medication end date is on or after the 
first study drug dose date.  All medications with a start date after the first study drug dose 
date or an end date before the first dose date are excluded.


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Treatment Interruption
If the study drug treatment interruption is longer than 60 days and treatment re-
introduction is evaluated as not feasible, the subject will be considered as premature 
discontinuation from the study in all efficacy assessment after the last dose and all the 
aforementioned imputation rules apply.
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
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in I-ITT and J-ITT for Induction Study, demographic information and 
baseline values will be summarized by descriptive statistics.  Categorical data will be 
summarized by frequency and percentage; and quantitative data will be presented by n, 
mean, standard deviation, minimum, median, and maximum values.
The following demographic and baseline values will be summarized.
Continuous Variables:
Age [years]
Body weight [kg]
Height [cm]


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Body mass Index [kg/m2]
Blood Pressure (systolic/diastolic) [mmHg]
Pulse (bpm)
Respiratory rate (RPM)
Temperature [°C]
IBDQ score
Full Mayo score and its components (stool frequency, rectal bleeding, PGA, and 
endoscopy subscores)
Partial Mayo score
Adapted Mayo score
hs-CRP (mg/L)
Short Form 36 Health Survey (SF-36) and its components
WPAI and its components
Albumin (g/L)
Disease duration
Categorical Variables:
Sex [male/female]
Race [White, Black/African American, Asian, American Indian/Alaska Native, Native 
Hawaiian/Other Pacific Islander, Multirace]
Ethnicity [Hispanic/Latino, Japanese, None of these]
Tobacco use [user, ex-user, never used, unknown]
Alcohol use [drinker, ex-drinker, non-drinker, unknown]
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L) 
Disease extent (disease limited to rectum, left-sided, extensive/pancolitis)
Prior infliximab use (yes, no)
Region (US versus non-US)


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7.2
Medical History
Medical and Surgical History:  A complete medical and surgical history (which includes 
UC-onset date) and 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 
condition/diagnosis for J-ITT analysis set for Induction 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 for J-ITT 
analysis set 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 for J-ITT analysis set.  If PPD skin test is performed, induration 
will be summarized descriptively using n, mean, standard deviation, minimum values, 
median, and maximum values.  The frequency distribution of induration ≥ 5 mm and 
< 5 mm will be provided.  No statistical tests will be performed.
ECG Results:  ECG results at screening will be presented for J-ITT analysis set 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.
7.3
Previous Treatment and Concomitant Medications
Prior medications include all 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.


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Concomitant medications include medications with a start date prior to the Baseline date 
which are continuing after Baseline and all medications with a start date between the 
Baseline date and last study drug administration + 14 days or until first dose of 
maintenance study drug, whichever is earlier. All medications with an end date prior to 
the first dose date are excluded. If the start date is completely missing for a medication 
and if the stop date is before the baseline date, it is considered previous medication and 
not further evaluated.  In addition to start date being completely missing, if the stop date is 
also completely missing or the stop date is on or after the baseline date, it will also be 
considered as a concomitant medication.
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by counts and percentages for J-ITT 
analysis set for Induction Study by treatment group.  No statistical tests will be performed.
The number and percentage of subjects using immunosuppressants (defined as 
azathioprine, 6-mercaptopurine, or methotrexate), and anti-TNF therapies at any time 
prior to baseline will be tabulated.  Similarly, the use of oral corticosteroids, 
immunosuppressants (defined as azathioprine/6-mercaptopurine/methotrexate), oral 
aminosalicylates, and anti-TNF therapies at baseline will be tabulated.
8.0
Patient Disposition
Subject disposition will be present for subjects in the I-ITT and J-ITT analysis set for 
Induction Study using the following information by treatment group:
Number and percentages of subjects in various analysis sets by treatment group and by 
investigator and/or site number
Number and percentages of subjects completing Week 8 visit and discontinuing on or 
before Week 8 visit
Number and percent of subjects who prematurely discontinued the study (on or before 
Week 8) by primary reason and by any reason
Summary of protocol deviations will be provided.


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9.0
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized for the I-ITT and J-ITT analysis 
set using the mean, standard deviation, minimum, median, and maximum.  Exposure to 
study drug (total patient-years) will be summarized by treatment group for the Induction 
Study.
The number of injections received at each schedule time point will be summarized with 
frequencies and percentages for each treatment group for the Induction Study.
Study Drug Exposure (in Days) during the Induction Study
For subjects who discontinued from the Induction Study:  
Date of last dose of Induction Study drug – Date of first dose of Induction Study drug + 
14 days
For subjects who completed the Induction Study:  
Date of first dose of Maintenance Study drug – Date of first dose of Induction Study drug
The date of last dose of Induction Study drug is defined as the date of last study drug 
injection before the date of re-randomization into Maintenance Study. The date of 
first dose of Maintenance Study drug is defined as the date of first study drug injection on 
or after the date of re-randomization into Maintenance Study.
Study Drug Compliance:
Treatment compliance will be summarized for each treatment group in the ITT 
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 Induction Study.


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10.0
Efficacy Analysis
10.1
General Considerations
No formal statistical tests will be performed for Japan Sub-Study.  Statistical tests will be 
performed exploratory at the nominal significant 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 counts and percentages 
for discrete variables.  The analysis will be performed using SAS® (SAS Institute Inc., 
Cary, NC, USA).
10.2
Primary Efficacy Analysis
This section provides the details of the primary efficacy analysis for the Induction Study.
Primary Efficacy Variable:
The primary efficacy variable for the Induction Study is the proportion of subjects 
achieving clinical remission (defined as a Full Mayo score ≤ 2 with no subscore > 1) at 
Week 8.
Analysis Data Set for the Primary Efficacy Analysis:
The primary efficacy analysis will use the I-ITT and J-ITT analysis set for the Induction 
Study.
Imputation Method used for the Primary Efficacy Analysis:
The primary efficacy analysis will use the NRI method to impute the missing values at 
Week 8 for the Induction Study.  Subjects with missing primary endpoint data at Week 8 
will be classified as "Not Achieved."


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Statistical Method of the Primary Efficacy Analysis:
The primary analysis of the Induction Study will compare the subjects in the higher 
adalimumab induction regimen versus the standard adalimumab induction regimen in the 
ITT analysis set.  The difference between the treatment regimens in the proportion of 
subjects achieving clinical remission at Week 8 will be assessed using Cochran-Mantel-
Haenszel (CMH) test adjusted for previous infliximab use and baseline corticosteroid use.  
A CMH based two-sided 95% confidence interval (CI) for the difference in the 
proportions between the treatment groups will be calculated.  Breslow Day test for 
homogeneity of odds ratios will be performed as well.
As sensitivity analyses, logistic regression including treatment, the randomization 
stratification factors, region (US, Japan and other regions) for only the I-ITT analysis set, 
and additional clinically important factors such as IMM use at Baseline, Baseline CRP, 
and disease severity at Baseline will also be performed for the primary endpoint.
A cross table of Week 8 responder/remitter status per site reader and central reader within 
I-ITT and J-ITT will be generated to summarize the discrepancies if there are any.
10.3
Secondary Efficacy Analyses
Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for the 
Induction Study are:
1.
Proportion of subjects achieving endoscopic improvement (endoscopic 
subscore of 0 or 1) at Week 8.
2.
Proportion of subjects with fecal calprotectin below 150 mg/kg at Week 8.
3.
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from Baseline) 
at Week 8.
4.
Proportion of subjects achieving clinical response (per Full Mayo score) at Week 8.


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5.
Proportion of subjects achieving endoscopic remission (endoscopic subscore of 0) 
at Week 8.
6.
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 6) at Week 8.
7.
Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ 
fatigue item score ≥ 1) at Week 8.
As all these endpoints are categorical variables, NRI method of imputation, as described 
for the primary efficacy analysis, will be used for the missing values.
For Induction Study endpoints, the difference between the higher adalimumab induction 
treatment group versus the standard adalimumab induction treatment group will be 
assessed using I-ITT and J-ITT analysis set.  The difference in proportions of subjects 
between treatment groups will be analyzed using the two-sided Cochran-Mantel-Haenszel 
(CMH) test adjusted for previous infliximab use and baseline corticosteroid use in the ITT 
analysis set for the secondary endpoints at Week 8.  Additionally, the CMH based 
two-sided 95% confidence interval (CI) for the difference in the proportions between the 
treatment groups will be calculated.
10.4
Additional Efficacy Analyses
Additional pre-specified endpoints in the Induction Study:
All-cause and UC-related hospitalization and surgery rates during
Weeks 0 – 8.
Change from Baseline in histologic score at Week 8.
Proportion of subjects achieving clinical remission per Adapted Mayo Score at Week 8.
Proportion of subjects achieving clinical remission defined as Adapted Mayo score ≤ 2 
with no subscore > 1 at Week 8.
Relationship between histologic subscores and endoscopic improvement (endoscopy 
subscore of 0 or 1) at Week 8.
Relationship between histologic scores and endoscopic subscore of 0 at Week 8.


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Proportion of subjects achieving clinical remission per Partial Mayo score over time.
Proportion of subjects achieving clinical response per Partial Mayo score over time.
Proportion of subjects with SFS of 0, RBS of 0 and endoscopic subscore of 0 at Week 8
Proportion of subjects with SFS ≤ 1 over time
Proportion of subjects with RBS of 0 over time
Change from Baseline in hs-CRP over time.
Change from Baseline in IBDQ total and domain score over time.
Proportion of subjects with IBDQ total score ≥ 170 over time.
Change from Baseline in Mayo score, Partial Mayo score, Adapted Mayo score and Mayo 
subscores over time.
Change from Baseline in laboratory and nutritional parameters (e.g., hemoglobin, 
hematocrit, albumin, total protein concentration, and weight).
Change from Baseline in subject-reported stool frequency (absolute values).
Change from Baseline in work productivity and impairment questionnaire (WPAI) scores 
over time.
Change from Baseline in SF-36 score over time.
Change from Baseline in fecal calprotectin over time.
Time to achievement of clinical remission (per Partial Mayo score)
Time to achievement of clinical response (per Partial Mayo score)
Change in presence of extraintestinal manifestations over time.
For categorical variables the difference in proportions of subjects between treatment 
groups will be analyzed similarly as the ranked secondary endpoints and the CMH based 
two-sided 95% confidence interval (CI) for the difference in the proportions between the 
treatment groups will be calculated for I-ITT and J-ITT analysis set.
For the continuous endpoints the difference in change from baseline between treatment 
groups over time will be analyzed using a Mixed-Effect Model Repeated Measure 
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stratification variables and Baseline values.  Parameter estimates with 95% confidence 
interval and P value will be provided.
NRI for missing data will be used for categorical endpoints.  Mixed-Effect Model 
Repeated Measure (MMRM) model will be applied for the continuous endpoints, where 
applicable.
Events of hospitalization and surgery will be identified by blinded adjudication of the 
serious adverse events (SAEs).  Subjects in the safety analysis set for the Induction will be 
included in the all-cause and UC-related hospitalization and surgery rates analyses during 
the Induction Study.
All-cause hospitalization is defined as SAEs resulting in admission to the hospital or 
prolongation of an existing hospitalization for any reason.  UC-related hospitalizations are 
defined as hospital admissions or prolongation of an existing hospitalization due to AEs 
or complications that are related to UC and included the following categories:  UC-related 
surgery, hospitalizations for nonsurgical UC-related events, such as UC-related flares, and 
hospitalizations related to the complications/extra-intestinal manifestations of UC.
Unadjusted incidence rates will be used to assess the risk of all-cause and UC-related 
hospitalization and surgery rates during Weeks 0 – 8. The difference between the 
two treatment groups will be determined using Chi-square test.
10.5
Handling of Multiplicity
No multiplicity adjustment will be applied for Japan Sub-Study.
10.6
Efficacy Subgroup Analysis
The subgroups listed below will be used in subgroup analyses of the primary endpoint of 
Induction Study.
Sex (male, female)
Age (≤ median, > median)


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Race (white, non-white) for only the I-ITT analysis set
Baseline corticosteroid use (yes, no)
Baseline immunosuppressant use (yes, no)
Baseline Mayo Score (≤ 9, > 9)
Baseline Mayo Score (≤ median, > median)
Prior exposure to anti-TNF (yes, no)
Baseline weight (≤ median, > median)
Presence of pancolitis at Baseline (yes, no)
Disease duration at Baseline (≤ median, > median)
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
Baseline hs-CRP (≤ median, > median)
Baseline albumin (≤ median, > median)
11.0
Safety Analysis
11.1
General Considerations
All safety analyses will be performed on the safety analysis set for the Induction Study.  
The safety variables will be summarized by treatment regimen 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 Induction Study are defined as events that begin or 
worsen either on or after the first dose of the study medication and up to the first dose of 
the study medication in Maintenance Study for those who are re-randomized at Week 8, 
or 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 medication in the Induction Study for subjects who
are not re-randomized.


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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, and AEs by maximum severity will be 
summarized by number and percentage.
The number and percentage 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 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 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-
emergent 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).


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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.
11.2.2
Adverse Events of Special Interest
If the AEs of special interest occur, the associated AE category of special interest will be 
summarized by number and percentage of subjects experiencing an AE of interest.  The 
AEs of special interest will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) for the following AE categories:
Any Infections AE
Any Serious Infection AE
Any Legionella Infection AE
Any Diverticulitis AE
Any Opportunistic Infection AE (Excluding Oral Candidiasis and TB)
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


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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 AE
Any Myocardial Infarction Related AE
Any Cerebrovascular Accident Related AE
Any Congestive Heart Failure Related AE
Any Pulmonary Embolism Related AE
Any Interstitial Lung Disease AE
Any Intestinal Perforation AE
Any Pancreatitis AE
Any Stevens-Johnson Syndrome AE
Any Erythema Multiforme Related AE
Any Worsening/New Onset of Psoriasis
Any Demyelinating Disorder (Including Multiple Sclerosis, Guillain-Barré Syndrome, 
and Optic Neuritis and Others)
Any Amyotrophic Lateral Sclerosis AE
Any Reversible Posterior Leukoencephalopathy Syndrome (RPLS) AE
Any Hematologic Disorders AE (Including Pancytopenia)
Any Liver Failure and Other Liver Event AE (Except Gall Bladder Related)
Any Humira Administration Related Medication Errors AE
Any Injection Site Reaction AE
Any AE Leading to Death


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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 excluded 
from 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 in the Induction Study.  Treatment group differences for changes from 
Baseline will be analyzed using a one-way Analysis of Variance (ANOVA) and 95% CI 
for treatment difference will be presented for selected laboratory parameters.
Shift tables from Baseline to the final value (the last assessment during each treatment 
period) according to the normal range will be provided for each hematology, clinical 
chemistry parameter and urinalysis parameter.  The laboratory data will be categorized as 
low, normal, or high based on the normal ranges of the laboratory used in this study.  The 
shift tables will tabulate the number and percentage of subjects with Baseline values 
within/above the normal range versus final and post-baseline values below the normal 
range and with Baseline values below/within the normal range versus final and post-
baseline values above the normal range.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 3.0 (or later) of 
Grade ≥ 3 will be provided.  For each of these subjects, the whole course of the parameter 
will be listed.  For subjects with laboratory values with CTC Grade ≥ 3, all of the 
laboratory parameters for those subjects will be listed.


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11.3.1
Assessment of Shifts from Baseline in Liver-Specific 
Laboratory Variables
Baseline and post-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 that cross tabulate the subjects' as deemed 
appropriate:
Category of the baseline value versus category of the final value,
Category of the baseline value versus maximum category
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.
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.


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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 treatment group:  
ALT ≥ 3 × ULN
ALT ≥ 5 × ULN
ALT ≥ 10 × ULN
ALT ≥ 20 × ULN
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
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
ALT ≥ 2.5 × ULN, or
AST ≥ 2.5 × ULN, or
Alkaline Phosphatase ≥ 2.5 × ULN, or
Total Bilirubin ≥ 1.5 × ULN.
11.4
Analysis of Vital Signs and Weight
All vital signs and weight data collected after first dose of maintenance study drug will be 
excluded from this analysis.
The following vital signs are measured at every visit during the Induction Study.


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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 5.
Table 5.
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
This is the first version of the SAP for 8-Week Double-Blind Induction Japan SubStudy.


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12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The statistical changes between SAP Version 1.0 and the latest version of protocol are 
listed below:
!
Added an additional efficacy analysis: proportion of subjects with IBDQ total 
score ≥ 170 over time.
!
Updated the rules for efficacy assessment based on concomitant medication 
per latest analysis conventions for immunology clinical studies.  Only UC-
related systemic or rectal corticosteroids will be used for censoring purpose, 
and will have last non-missing value prior to censoring carried forward for 
non-categorical assessments from that point forward.
!
Added the ranked #6 secondary endpoint (Section 10.3): Proportion of subjects 
achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 6) at Week 8.
!
Added the ranked #7 secondary endpoint (Section 10.3): Proportion of subjects 
achieving response in IBDQ fatigue item (increase of IBDQ fatigue item score 
≥ 1) at Week 8.
The addition of ranked #6 and #7 secondary endpoints is based on recent FDA’s feedback 
from Upadacitinib UC program to consider specific questions or domains within IBDQ 
that are most relevant to IBD patients.
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
This is the first version of the SAP for 8-Week Double-Blind Induction Japan SubStudy.
13.0
Appendix
None.
14.0
References
None.