A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected Via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)
Phase: PHASE4
Conditions: Rheumatoid Arthritis, Musculoskeletal and Connective Tissue Diseases
Sponsor: AbbVie

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
1
1.0
Title Page
Clinical Study Protocol M14-500
A Phase 4 Trial Assessing the ImPact of Residual 
Inflammation Detected via Imaging TEchniques, 
Drug Levels and Patient Characteristics on the 
Outcome of Dose TaperIng of Adalimumab in 
Clinical Remission Rheumatoid ArThritis (RA) 
Subjects (PREDICTRA)
Incorporating Administrative Changes 1, 2 and 3, 
and Amendment 1
AbbVie Investigational
  Product:
Adalimumab
Date:
25 February 2016
Development Phase:
4
Study Design:
A Phase 4, multicenter, randomized, double-blind parallel-group 
study:  dose tapering of adalimumab controlled by withdrawal, in 
subjects with rheumatoid arthritis in stable clinical remission
EudraCT Number:
2014-001114-26
Investigators:
Investigator information is on file at AbbVie
Sponsor:
For Non-EU Countries:
AbbVie
1 North Waukegan Road 
North Chicago, IL  60064
For EU Countries:
AbbVie Deutschland GmbH 
& Co. KG (AbbVie) 
Knollstrasse 50
67061 Ludwigshafen 
Germany
Sponsor/Emergency
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02198651

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
15 May 2014
Administrative Change 1
15 July 2014
Administrative Change 2
10 March 2015
Administrative Change 3
21 May 2015
The purpose of this amendment is to:  
●
Throughout protocol:  Reduce sample size population from 334 to 
approximately 200 enrolled subjects.
Rationale:  The sample size was evaluated to ensure a certain level of 
precision for the estimation of the correlation coefficient between Baseline 
magnetic resonance imaging (MRI) score and the occurrence of flare.  
Recently published data have shown overall a high rate of 
flare/relapse/treatment failure and that sub-clinical synovitis might be a 
predictor of flare upon biological disease-modifying anti-rheumatic drug 
(bDMARD) withdrawal.  Based on the review of these data, a sample size of 
150 in the dose tapering arm has been recalculated to meet the study 
objectives.
●
Section 1.2, Synopsis, Section 3.3.1, Additional Considerations on Key Study 
Parameters, Section 5.1, Overall Study Design and Plan:  Description, 
Section 5.2.1, Inclusion Criteria, Inclusion Criterion 4, Section 5.2.2, 
Exclusion Criteria, Exclusion Criterion 1, Section 5.3.1.1, Study Procedures, 
allow for 3 variables of the Disease Activity Score DAS28 (c-reactive protein 
(CRP) or erythrocyte sedimentation rate (ESR)) to satisfy inclusion criteria 
purposes of patients in stable remission defined as DAS28 < 2.6 for 
≥6 months and exclusion criteria of patients with DAS28 (CRP or ESR) 
≥2.6 within 6 months prior to Screening.
Rationale:  To align with clinical practice and other clinical studies when the 
Patient Global Assessment (PGA) is not routinely documented and because the 
DAS28 with three variables is validated. 

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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●
Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan:  
Description:  Inclusion Criteria 3, 5, 6 and 7, change period of time for 
required stable medications (e.g., methotrexate (MTX) stable dose for 
≥12 weeks; other DMARDS at stable dose for ≥ 12 weeks and 
steroids/NSAIDs stable for ≥ 4 weeks) up to Week 0 instead of up to 
Screening.
Rationale:  As per previous studies and treatment effect of csDMARDs, a 
period of stable medication prior to inclusion (and not screening) is enough to 
ensure medication which could affect risk of flare is stable.
●
Section 1.2, Synopsis, Section 3.3.1, Additional Considerations on Key Study 
Parameters, Section 5.2.3.1, Prior Therapy, Section 5.6.3, Suitability of 
Subject Population, Inclusion Criterion 3, allow for up to 20% of subjects to be 
included in the study if on stable other csDMARDs and/or on monotherapy 
adalimumab (no csDMARDs) for at least 12 weeks prior to Week 0.  Once the 
limit of 20% of enrolled subjects on other csDMARDs or no csDMARDs is 
met, only subjects on concomitant methotrexate will be allowed into the trial.
Rationale:  To align with clinical routine practice as shown in several 
registries and other real world evidence in which around 30% – 34% of 
patients are not taking concomitant MTX with a bDMARD and still include the 
majority of patients treated with concomitant stable MTX.  The primary 
analysis of association between baseline MRI and flare remain unchanged.  
Concomitant use of treatment will be examined in the sensitivity analysis to 
account for potential differential effect.
●
Section 1.2, Synopsis, clarify language regarding MRI scans.
Rationale:  To clarify that if both hands/wrists are affected then the dominant 
hand and wrist should be scanned.
●
Section 1.2, Synopsis and Section 5.2.3.2, Concomitant Therapy, Inclusion 
Criterion 3, add that intra-muscular methotrexate is allowed as a concomitant 
therapy.
Rationale:  To align with current methotrexate therapies. 
●
Section 1.2, Synopsis, increase potential number of sites and countries where 
the study will be conducted.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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Rationale:  To accurately reflect the number of sites and countries that are 
planned to ensure timely enrollment of the study. 
●
Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan:  
Description, Section 5.3.1, Efficacy and Safety Measurements Assessed and 
Flow Chart, extend screening period to up to 28 days (instead of 21); screening 
may be exceptionally extended upon justification and further consultation with 
the Study Designated Physician.
Rationale:  To allow enough time for screening procedures and to align the 
Week 0 visit with the pre-scheduled adalimumab injection. 
●
Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan:  
Description:, allow for an extension of the Lead-in Period to up to 6 weeks 
(instead of 4 weeks) if required to provide enough time for Lead-in procedures.
Rationale:  To align the Week 4 visit with the next pre-scheduled adalimumab 
injection and to provide adequate time for study procedures during the lead-in 
period (namely MRI) prior to Baseline Week 4 Visit.
●
Section 1.2, Synopsis, Inclusion Criterion 7, include the use of tramadol or 
other equivalent opioids and/or non-opioid analgesics to be at a stable dose 
and/or therapeutic scheme for at least 4 weeks prior to the Week 0 visit.
Rationale:  To allow for other equivalent opioids to Tramadol available in 
some countries to be used. 
●
Section 5.1, Overall Study Design and Plan:  Description, add further 
clarification on the importance of stopping commercial adalimumab when the 
subject enrolls in the study. 
Rationale:  To ensure subjects are not taking commercial adalimumab during 
the study. 
●
Section 5.1, Overall Study Design and Plan:  Description, increase the dosing 
window during the double-blind period to ± 3 days.
Rationale:  To allow for flexibility of scheduling within a period which does 
not affect treatment efficacy and allows for adjustment of the visit scheduling 
accommodating weekends.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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●
Section 5.1, Overall Study Design and Plan:  Description, allow for a local 
MRI report to be viewed for safety reasons on findings not related to 
rheumatoid arthritis.
Rationale:  To ensure the safety of the subject. 
●
Section 5.1, Overall Study Design and Plan:  Description, clarify that during 
the Open-Label Rescue Arm csDMARDs including MTX (initiation and/or 
dose or administration mode change) are included.  Excluded csDMARDs that 
are not allowed include azathioprine, cyclophosphamide and d-penicilamine.
Rationale:  To ensure the safety of the subject while on rescue therapy. 
●
Section 5.1, Overall Study Design and Plan:  Description, Table 1, Study 
Activities, table note "d.," add an option for a shortened Early Termination 
Visit for those subjects terminating the study in the Lead-in period from 
Week 0 up to Week 4. 
Rationale:  To allow for a shortened version of the Early Termination Visit
(reasons for discontinuation, review of adverse events and Investigational 
Product and Diary return)  for those subjects on open-label adalimumab who 
have not yet been randomized since these subjects have not changed any of 
their previous treatment and will not be analyzed for the primary or secondary 
objectives. 
●
Section 5.1, Overall Study Design and Plan:  Description, add that all subjects 
who discontinue the study will have a follow-up phone call approximately 
70 days after the last administration of study drug. 
Rationale:  To obtain information on any new or ongoing adverse events for 
all subjects.
●
Revised timing of first dose of Open-Label Rescue arm at the Flare 
Unscheduled Visit in Section 5.1, Overall Study Design and Plan:  
Description.
Rationale:  To allow for an immediate start of the Open-Label Rescue Arm (at 
least 1 day after last dose).
●
Add "A CXR may be required for evaluation of active TB" in Table 1, Study 
Activities, table note "g.," Section 5.1, Overall Study Design and Plan:  
Description.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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Rationale:  To reinforce that a CXR may be required to evaluate active TB.
●
Section 5.2.2, Exclusion Criteria, remove azathioprine from exclusion criteria 
to allow for patients who have been previously, but are not currently, treated 
with azathioprine and who have no other severe diseases to be included.
Rationale:  Patients who are in clinical remission for at least 6 months and on 
treatment with adalimumab for at least 1 year are not expected to develop any 
prior azathioprine exposure related complications as per absence of evidence 
in a literature review.
●
Section 5.2.3.1, Prior Therapy, Section 5.2.3.2, Concomitant Therapy, allow 
for a decrease in the dose of methotrexate or other csDMARDS during the 
12 weeks prior to Week 0 and throughout the study. 
Rationale:  To allow for a dose decrease in the case of an event of 
intolerability (or other safety issues) related to methotrexate or other 
csDMARDs.
●
Section 5.2.3.1, Prior Therapy, allow for an interruption of up to 
two non-consecutive doses of adalimumab within the past 12 months but not 
during the 12 weeks prior to Week 0 if due to a non-RA related event 
(e.g., infection, surgery).
Rationale:  To align with clinical practice and product interruptions due to, 
for example, an infection as also described in prescribing information.
●
Section 5.2.3.2, Concomitant Therapy, add that subjects should take a dietary 
supplement of oral folic acid 5 mg once weekly "or per local guidelines per the 
investigator's discretion" if taking concomitant MTX.
Rationale:  To allow for folic acid dosage to conform with current clinical 
practice per local guidelines.
●
Correct timing of urine pregnancy test collection from the Baseline visit to 
Week 0 in Table 1, Study Activities, table note "l.," Section 5.3.1, Efficacy and 
Safety Measurements Assessed and Flow Chart, and also in Section 5.3.1.1, 
Study Procedures.
Rationale:  To correct an inadvertent error.  Urine pregnancy test is due at 
the Week 0 visit and not Baseline visit per Exclusion Criterion 21.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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●
Revise text in Table 1, Study Activities, table note "l." in Section 5.3.1, 
Efficacy and Safety Measurements Assessed and Flow Chart, to state that 
urine pregnancy samples will be performed locally. 
Rationale:  To correct in advertent error in the protocol and to make 
consistent with Section 5.3.1.1.
●
Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow Chart, 
remove table note "d." from Table 1, Study Activities.  Study Activities 
regarding using the ESR at Screening for assessment at Day 1. 
Rationale: To avoid confusion since the ESR taken at each visit should be 
used to calculate the DAS 28 (ESR) on the day of the current visit. 
●
Section 5.3.1.1, Study Procedures, add that the 3 variable DAS28 (ESR) score 
can be used to evaluate flare during the trial when the PGA score is not 
available upon discussion with the Study Designated Physician.
Rationale:  To allow for evaluation of the flare when the PGA score is not 
available through the electronic reported outcome devices. 
●
Clarify in Section 5.3.1.1, Study Procedures, that the Clinical Disease Activity 
Index (CDAI) and Simplified Disease Activity Index (SDAI) will be 
calculated as part of the statistical analysis.  Calculation is not required by the 
site.
Rationale: To clarify that calculation is not required by the site.
●
Remove in Table 1, Study Activities, the Clinical Disease Activity Index 
(CDAI) and Simplified Disease Activity Index (SDAI).
Rationale:  To clarify that calculation is not required by the site.
●
Revise the measurement unit of ESR in Section 5.3.1.1, Study Procedures, 
from mm/Hg to the correct unit mm/Hr.
Rationale:  To correct a typographical error.
●
Remove the word "locally" referring to performance of TB Screening in 
Section 5.3.1.1, Study Procedures.
Rationale:  To conform to the protocol where TB screening could be done 
centrally or locally.
●
Revise language to the duration of treatment in Section 5.5.1, Treatments 
Administered.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
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Rationale:  In order to maintain consistent wording throughout the protocol.
●
Add the Complaint and Product Complaint definition to Section 6.0, 
Complaints, Section 6.2.1, Definition and Section 6.2.2, Reporting as well as 
the reporting requirements for Product Complaints.
Rationale:  To comply with current AbbVie standards.
●
Add 24-hour medical surveillance contact information in Section 6.1.5, 
Adverse Event Reporting.
Rationale: To update protocol with AbbVie's standard 24-hour medical 
surveillance information in case the Study Designated Physician is 
unavailable.
●
Add information regarding the Electronic Patient Reported Outcomes (ePROs) 
in Section 10.3, Electronic Patient Reported Outcomes (ePROs).
Rationale:  To provide additional information on how data is collected and 
reviewed. 
●
Revise Injection Instructions in Appendix C, Injection Instructions – Pre-Filled 
Syringe – Sample.
Rationale:  To correct an error in how many syringes the subject will take 
home at one time.
●
Remove tuberculosis language specific to the Czech Republic.
Rationale:  The Czech Republic is not participating in the trial.
●
Appendix K, Short Form-36 (SF-36) Health Survey Questionnaire – Sample:, 
update the Short Form-36 (SF-36).
Rationale:  To include the version used for electronic patient reported 
outcomes.
●
Corrected minor typographical errors throughout the document.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix P.

Adalimumab
M14-500 Protocol Amendment 1
EudraCT 2014-001114-26
9
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-500
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  25 February 2016
Protocol Title:
A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques Drug 
Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical 
Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)
Objectives:
The primary objective is to investigate the association between residual disease activity at Baseline as 
detected by magnetic resonance imaging (MRI) and the occurrence of flares in RA subjects randomized 
to an adalimumab dose tapering regimen controlled by adalimumab withdrawal.
The Secondary Objectives are:
!
To assess the occurrence and severity of flares and the time to flare in both taper and withdrawal 
arms.
!
To investigate the association between Double-Blind Baseline (dbBaseline) subject 
demographic and disease characteristics and the occurrence of flares.
!
To investigate the association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares.
!
To evaluate the effectiveness of rescue therapy with open-label adalimumab 40 mg every other 
week (eow) over 16 weeks in subjects experiencing a flare. 
!
To assess the change in rheumatoid arthritis MRI scoring system (RAMRIS) scores from 
Baseline to Final visit in the taper, withdrawal and Open-Label Rescue Arms.
!
To investigate the MRI-flare associations in sub-groups of subjects who meet additional clinical 
remission criteria at dbBaseline including simplified disease activity index (SDAI) ≤ 3.3, 
clinical diseases activity index (CDAI) ≤ 2.8 and ACR/EULAR 2011 boolean-based remission, 
as well as to describe the course of disease and patient reported outcome (PRO) measures in the 
taper, withdrawal and Open-Label Rescue Arms overall and per dbBaseline subgroup.
!
To assess the rate of anti-adalimumab antibodies (AAA) positive subjects in the taper and 
withdrawal arms.
The study also has the following exploratory objectives:
!
In the subgroup of subjects with a Baseline Ultrasound (US) assessment: 
o
To investigate the association between Baseline ultrasound scores and the occurrence of 
flares. 
o
To investigate the association between the Baseline ultrasound scores and Baseline MRI
RAMRIS scores.
o
To describe the change in the ultrasound scores from Baseline to the time of the occurrence 
of a flare in the taper and withdrawal arms.
!
To investigate the association between biomarker values at dbBaseline (and their change over 
time) and the occurrence of flares.

Adalimumab
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EudraCT 2014-001114-26
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Investigators:  Investigator information is on file at AbbVie.
Study Sites: Approximately 72 sites in North America, Europe and Australia
Study Population:
Subjects age ≥ 18 years diagnosed with RA, on a stable dose of adalimumab 40 mg subcutaneously (sc) 
eow (for ≥ 12 months prior to Week 0 Visit) in combination with methotrexate (MTX) (at stable dose for 
≥ 12 weeks prior to Week 0 Visit) or if not on MTX, another allowed conventional synthetic 
disease-modifying anti-rheumatic drugs (csDMARDs) at stable dose or no csDMARDs for ≥ 12 weeks 
prior to Week 0 Visit) and in documented clinical remission, defined as DAS28 erythrocyte 
sedimentation rate (ESR) < 2.6 or DAS28 c-reactive protein (CRP) < 2.6, for ≥ 6 months prior to the 
Screening Visit and DAS28 (ESR) < 2.6 at the Screening Visit.  Patients who are not treated with 
concomitant stable dose of MTX are limited to a maximum of 20% of the study population.
Number of Subjects to be Enrolled:  Approximately 200  
Methodology:
This is a Phase 4, multicenter, randomized, double-blind, parallel-group study in subjects with RA who 
are in stable clinical remission defined as DAS28 (ESR) or DAS28 (CRP) < 2.6 for at least 6 months 
prior to the Screening Visit.  Though the cut-off for clinical remission of DAS28 (CRP) may not be 
equivalent to the DAS (ESR), in clinical practice both are frequently used to define remission as < 2.6.  
Both ESR or CRP and 4 or 3 (when Patient Global Assessment [PGA] is not available) variables DAS28 
will be allowed for the purposes of identifying subjects for Screening; however, throughout the study 
clinical remission will be defined by the more stringent 4 variables DAS28 (ESR) < 2.6 criteria.  At 
Screening, only subjects with confirmed 4 variables DAS28 (ESR) < 2.6 will be considered for inclusion 
in the study.
The study activities will start with a Screening Period of up to 28 days to confirm inclusion/exclusion 
criteria including a DAS28 (ESR) assessment of < 2.6.
Subjects who have signed the Informed Consent and who fulfill all Screening criteria will enter the 
study.  The study starts with a 4-week Lead-In Open-Label (OL) Period during which stable DAS28 
(ESR) clinical remission in 2 assessments 4 weeks apart will be confirmed.  Subjects will receive 
adalimumab 40 mg sc eow starting at the Week 0 Visit of the Lead-In Period; this will be approximately 
2 weeks after their last commercial Humira®.  If needed for study procedures completion or injection 
scheduling adjustment, the lead-in period can be extended for up to 2 more weeks in which case the 
Week 4 Visit study procedures will occur up to 6 weeks after the Week 0 Visit.
At Week 4, the end of the Lead-In Period, subjects will have a dbBaseline visit.  Subjects must have a 
confirmed DAS28 (ESR) remission at two time points in order to be randomized:
1.
DAS28 (ESR) < 2.6 at the Lead-In Period Week 0
2.
DAS28 (ESR) < 2.6 at the dbBaseline visit Week 4
Subjects who meet the remission criteria will be randomized (5:1) to one of two double-blind arms and 
followed for additional 36 weeks in the Double-Blind Period: 
1.
A reduced frequency of adalimumab 40 mg sc every 3 weeks (q3wks):  taper arm, or
2.
Adalimumab placebo sc q3wks:  withdrawal arm.

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Methodology (Continued):
All subjects who are taking concomitant MTX (any dose oral, subcutaneous [sc] or intramuscular [im]) 
and/or other csDMARDs at a stable dose for at least 12 weeks prior to Week 0 Visit will maintain the 
regimen throughout the Lead-In and Double-Blind Periods of study.  Subjects who have not been taking 
any csDMARDs for at least 12 weeks prior to the Week 0 Visit, will also maintain this regimen 
throughout the Lead-In and Double-Blind Periods of study.
Any other allowed RA concomitant medications should also be kept stable throughout the Lead-In and 
Double-Blind Periods of the study; these medications and MTX will be received by local prescriptions. 
During the Double-Blind Period, subjects will be evaluated every 6 weeks for efficacy, including 
detection of flares, PROs, safety and laboratory assessments at scheduled visits on:  Weeks 4, 10, 16, 22, 
28, 34 and 40 (Final visit).
Other unscheduled visits will occur in the suspected event of a flare.  During the interval between 
scheduled visits, subjects will be asked to contact their physicians in case of feeling their disease is 
worsening:  an unscheduled visit will be performed within 2 weeks of contact with the site to assess if 
subjects are experiencing a flare.
Subjects with a confirmed flare (defined as an increase from dbBaseline in DAS28 [ESR] of > 0.6 AND 
a DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 
[ESR]) at any time point (at a scheduled or unscheduled visit) will undergo Flare Week 0 visit 
procedures and will be immediately switched to an Open-label rescue arm initiating adalimumab 40 mg 
eow rescue therapy.
In the Open-Label Rescue Arm, subjects will be further evaluated at Flare Weeks 4, 10 and 16 for 
efficacy, PROs, safety and laboratory assessments.
During this period, further treatment escalation/change will be allowed based on the Investigator's 
medical judgment.  Any treatments escalation/change will be documented.  At Flare Week 0, all subjects 
will be requested to initiate weekly at home self-assessment of their RA disease activity by using 
Routine Assessment of Patient Index Data (RAPID)-3 questionnaires until Week 16.
See study schematic below:

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Methodology (Continued):
A high-field contrast MRI of the most affected hand (2nd to 5th MCP) and wrist will be performed on all 
subjects during the Lead-In Period (prior to the dbBaseline visit) and at Final/Early Termination Visit.  If 
both sides are considered equally affected, the MRI of the dominant hand (2nd to 5th MCP) and wrist will 
be performed.  
The acquired MRI images will be centrally read and Investigators will be blinded to the results.  Subjects 
should be randomized only when the MRI has been confirmed to be received and complete by Central 
Imaging.
In sites that meet pre-specified ultrasound requirements and who wish to participate in the ultrasound 
portion of the study, subjects will undergo US assessment using Gray Scale Ultrasonography (GSUS) 
and Power Doppler Ultrasonography (PDUS) consisting of a systematic longitudinal and transverse 
multiplanar examination of 46 joints and 18 tendon/tendon compartment during Lead-In or at dbBaseline 
Visit prior to randomization and at the Flare Week 0 Visit (if applicable).  US will be performed and 
assessed by local Ultrasonographer independent of the clinical assessor who will be blinded to the US 
scores.
Pharmacokinetics (PK) and immunogenicity will be assessed based on serum adalimumab trough 
concentrations and serum anti-adalimumab antibodies (AAA), respectively.  Blood samples for 
adalimumab concentrations and measurements of AAA will be taken prior to dosing at dbBaseline 
(Week 4), at Weeks 10, 16, 28, 40 and at Early Termination, Flare Weeks 0, 4 and 16 (if applicable).
A panel of inflammatory biomarkers:  matrix metalloproteinase 3 (MMP3), Collagen neo-epitope 
(C1M), Type III collagen neo-epitope (C3M), Matrix metalloproteinase-mediated c-reactive protein 
(CRPM), Matrix metalloproteinase-degraded citrullinated vimentin (VICM), Serum amyloid-associated 
protein (SAA), Interleucin-6 (IL-6), Chemokine (C-X-C motif) ligand 10 CXCL10 and CXCL13 will be 
assessed at dbBaseline (Week 4), Weeks 10, 16, 28, 40 or at Early Termination, Flare Weeks 0, 4 and 
16 (if applicable) on blood samples taken prior to dosing.  At the time of analysis, other potential 
biomarkers identified as adding value to predict flare in this patient population may be included.
Additional optional samples for future biomarker research will be collected.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
!
Male or female subjects ≥ 18 years of age.
!
Subject has a diagnosis of RA as defined by the 1987 revised ACR classification criteria and/or the 
ACR/EULAR 2010 classification criteria (any duration since diagnosis).
!
Subject must meet the following criteria:
o
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to Week 0 Visit;
o
Must be treated with concomitant MTX at a stable dose (oral, sc or im at any dose) for at least 
12 weeks prior to Week 0 Visit or if not on MTX, must be treated with other allowed 
csDMARDs at stable dose for at least 12 weeks prior to Week 0 Visit or if not treated with 
csDMARDs must maintain this regimen for at least 12 weeks prior to Week 0 Visit.
!
Subject must be in sustained clinical remission based on the following:
o
At least one documented 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 
(CRP) < 2.6 (or calculated based on documented components of the DAS28) in the patient chart 
6 months or longer prior to the Screening Visit;
o
4 variables DAS28 (ESR) assessed at Screening < 2.6, with all components including ESR 
assessed at Screening.

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
If subjects are receiving concomitant allowed csDMARDs (in addition or not to MTX) the dose must 
be stable for at least 12 weeks prior to the Week 0 Visit (e.g., chloroquine, hydroxychloroquine, 
sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and aurothioglucose] 
and/or leflunomide).
!
If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent must be 
< 10 mg/day and the dose must be stable for at least 4 weeks prior to the Week 0 Visit.
!
If subjects are receiving concomitant non-steroidal anti-inflammatory drugs (NSAIDs), tramadol or 
other equivalent opioids and/or non-opioid analgesics, the dose and/or therapeutic scheme must be 
stable for at least 4 weeks prior to the Week 0 Visit.
!
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.
Main Exclusion:
!
Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or calculated based 
on documented components of the DAS28) assessed within 6 months prior to the Screening Visit 
≥2.6.
!
Subject is on an additional concomitant biological disease-modifying anti-rheumatic drug 
(bDMARD) (including but not limited to abatacept, anakinra, certolizumab, etanercept, golimumab, 
infliximab, rituximab or tocilizumab).
!
Subject has been treated with intra-articular or parenteral corticosteroids within the last 4 weeks 
before Screening.
!
Subject has undergone joint surgery within 12 weeks of Screening (at joints to be assessed by MRI 
and/or ultrasound).
!
Subject has a medical condition precluding an MRI (e.g., magnetic activated implanted devices –
cardiac pace-maker, insulin pump, neurostimulators, etc. and metallic devices or fragments or clips 
in the eye, brain or spinal canal and in the hand/wrist undergoing MRI).
!
Subject has a medical condition precluding a contrast MRI with gadolinium (e.g., nephrogenic 
systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast 
agent, pregnancy or breastfeeding, severe renal insufficiency with an estimated Glomerular Filtration 
Rate [eGFR] below 30 mL/min/1.73 m2 at Screening, hepato-renal syndrome, severe chronic liver 
function impairment).
!
Subject has been treated with any investigational drug of chemical or biologic nature within a 
minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to the Screening Visit.
Investigational Product:
Adalimumab
Dose:
Lead-In Period:  Adalimumab 40 mg OL eow for 4 weeks
Double-Blind Period:  Adalimumab 40 mg q3wks for 36 weeks
Open-Label Rescue Arm:  Adalimumab 40 mg OL eow for a minimum 
of 16 weeks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe

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Reference Therapy:
Placebo for the Double-Blind Period
Dose:
0.8 ml q3wks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe
Duration of Treatment:
The duration of treatment will include a 4-week Lead-In Period (adalimumab 40 mg sc eow) followed by 
a 36-week, randomized, Double-Blind Period with 2 arms:  taper arm (adalimumab 40 mg sc q3wks) 
controlled by withdrawal matching placebo arm.  Open-Label Rescue Arm (adalimumab 40 mg sc eow) 
will be provided for 16 weeks (if applicable).  Therefore, the total duration of the study is 40 or 56 weeks 
(if applicable).
Criteria for Evaluation:
Efficacy:
Primary Efficacy Variables
!
The primary explanatory variables are the Baseline hand and wrist synovitis and bone marrow 
edema (BME) RAMRIS scores as well as a composite of both and the dependent variable is the 
occurrence of flare up to Week 40 in the tapering arm.
Secondary Variables
!
Time to flare
!
Flare severity
!
Proportion of subjects experiencing a flare
!
Subject demographics and clinical disease characteristics at dbBaseline, including
o
Smoking status, co-morbidities, anti-citrullinated peptide antibody (ACPA) status, Rheumatoid 
Factor (RF) status, disease duration, previous treatment with conventional synthetic Disease 
Modifying Anti-rheumatic Drugs (csDMARDs) or biologic Disease Modifying Anti-rheumatic 
Drugs (bDMARDs) or both, duration of adalimumab therapy, remission duration, disease 
activity, c-reactive protein (CRP) and Health Assessment Questionnaire (HAQ) score
!
Proportion of subjects who regain clinical remission (defined as DAS28 [ESR] < 2.6 and defined as 
DAS28 (ESR) decrease > 1.2 if DAS28 [ESR] was less than 2.6 at flare) in the Open-Label Rescue
Arm over time
!
Time to regain clinical remission in the Open-Label Rescue Arm
!
Proportion of subjects with low disease activity (defined as DAS28 [ESR] < 3.2)  in the Open-Label 
Rescue Arm over time
!
Change from Baseline in DAS28 (ESR), Clinical Disease Activity Index (CDAI) and Simplified 
Disease Activity Index (SDAI)
!
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI and CDAI:  DAS28 
[ESR] < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8) throughout the study
!
Change from dbBaseline to Week 40 or final Visit in MRI synovitis, BME and erosions RAMRIS 
scores
!
Change from Baseline in DAS28 (ESR), Clinical Disease Activity Index (CDAI) and Simplified 
Disease Activity Index (SDAI)
!
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI and CDAI:  DAS28 
[ESR] < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8) throughout the study

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Secondary Variables (Continued)
!
Change from dbBaseline to Week 40 or final Visit in MRI synovitis, BME and erosions RAMRIS
scores 
!
Change from Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) over time
!
Proportion of subjects with HAQ-DI normal (HAQ-DI ≤ 0.5) at dbBaseline and at Week 40
!
Change from dbBaseline in RAPID 3 scores assessed during Visits
!
Change from Flare Week 0 in RAPID 3 at home assessments
!
Change from dbBaseline in Swollen Joint Count (both 28 and 66 joints)
!
Change from dbBaseline in Tender joint Count (both 28 and 68 joints)
!
Change from dbBaseline  in Patient's Global Assessment of Disease activity 
!
Change from dbBaseline  in Patient's Global Assessment of RA pain 
!
Change from dbBaseline in Physician's Global Assessment of Disease activity
!
Change from dbBaseline in morning stiffness assessment
!
Change from dbBaseline in Sleep disturbance assessment
!
Change from dbBaseline in Treatment Satisfaction Questionnaire for Medication (TSQM)
!
Change from dbBaseline in Work Productivity and Activity Impairment (WPAI)
!
Change from dbBaseline in Short Form-36 (SF-36)
!
Change from dbBaseline in Functional Assessment of Chronic Illness Therapy – fatigue 
(FACIT-fatigue)
!
Change from dbBaseline in CRP
!
Change from dbBaseline in ESR
Exploratory Variables
!
Baseline and change from Baseline to the time of flare in PDUS and GSUS individual and 
composite scores of synovitis, synovial hypertrophy and tenosynovitis
!
dbBaseline and change from dbBaseline on biomarker values (MMP3, SAA, C1M, C3M, CRPM, 
VICM, IL-6, CXCL10, CXCL13)
Pharmacokinetics:
!
Adalimumab concentrations  measurement dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early 
Termination, Flare Weeks 0, 4 and 16 (if applicable)
!
AAA measurement at dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early Termination, Flare 
Weeks 0, 4, 10 and 16 (if applicable)
Interim Analysis for Double-Blind Baseline Characteristics:
There are few data describing patient disease characteristics, including markers of residual inflammation 
(such as sensitive imaging assessments and potential biomarkers) and drug levels in patients who are in 
sustained RA clinical remission on a stable treatment with a TNFi and MTX and/or with other 
csDMARDs(s) or in TNFi monotherapy.  An interim analysis will be conducted to describe the 
dbBaseline characteristics of this RA population.  It will be performed after the dbBaseline assessments 
and randomization of the entire study population have been completed.

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Criteria for Evaluation (Continued):
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical and 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.
Statistical Methods:
Efficacy:
Analysis for Primary Objective:
The association between the occurrence of flares and Baseline MRI RAMRIS scores will be examined 
using logistic regression, which is deemed as the main analysis to address the primary objective.  
Additional analyses will be performed to assess this association using various statistical methods.  
Specifically, descriptive statistics of Baseline MRI RAMRIS scores will be provided for the two groups 
of subjects who flare and who do not flare, and the between-group difference in the mean scores will be 
computed together with a 90% confidence interval (CI).  Linear regression will be used to model the 
relationship between the DAS28 (ESR) at flaring (or at end of study for subjects who do not flare) and 
the Baseline MRI RAMRIS scores.  Receiver operating characteristic (ROC) curve approach will also be 
utilized to investigate the potential flare prediction criteria based on MRI RAMRIS scores.  All model 
based analyses may adjust for dbBaseline clinical patient characteristics including disease duration, 
previous and concomitant treatment, etc. when appropriate.
Similar analysis will be conducted for RAMRIS synovitis scores, BME scores and the composite of 
both.
Analysis for Secondary Objectives:
Within the analyses to address the secondary objectives the association between dbBaseline disease 
characteristics and the occurrence of flares will be examined using similar analyses as for the primary 
objective.  In addition, characterization of flares, response to rescue therapy in subjects experiencing a 
flare and the clinical and patient reported efficacy outcomes for all trial subjects will be analyzed 
accordingly.
Pharmacokinetic:
Adalimumab trough serum concentrations will be summarized by treatment arm at each time point using 
descriptive statistics.  The association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares will be assessed.  In addition, pharmacokinetic model-based analyses may 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 study arm, and rates of AAA positive subjects 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:
Frequency tables and lists of subjects with treatment-emergent AEs by preferred term as in the Medical 
Dictionary for Regulatory Activities (MedDRA) 17.0 dictionary, by system organ class and by causality 
to the study medication as assessed by the Investigator will be provided.  Laboratory test values will be 
summarized over time.
Determination of Sample Size:
The planned total number of subjects enrolled into the Lead-In Period is approximately 200.
To estimate the odds ratio for the occurrence of flare with baseline MRI score based on historical MRI 
data, an effective sample size of 150 subjects in the dose tapering group will ensure a precision for the 
estimation with the width of 90% CI no more than 0.03 for an odds ratio 1.03, no more than 0.07 for an 
odds ratio 1.1, and no more than 0.14 for an odds ratio 1.2.  Such sample size will also ensure a precision 
for the estimation of a correlation coefficient ρ with the width of 90% CI of ρ no more than 0.26 for a 
mild correlation coefficient 0.28, no more than 0.18 for a moderate correlation coefficient 0.55, and no 
more than 0.13 for a higher correlation with ρ = 0.67.  Assuming a 30% flare rate, this sample size will 
provide the precision that the 2-sided 90% CI of the flare rate has a half width no more than 6%.
Under a 5:1 randomization ratio (dose tapering vs. withdrawal), a total of 180 subjects will be 
randomized.  Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
200 subjects will need to be enrolled into the Lead-In Period.

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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AAA
Anti-adalimumab antibodies
ACPA
Anti-citrullinated peptide antibody
ACR
American College of Rheumatology
ANA
Antinuclear antibodies
BCG
Bacillus Calmette-Guérin
bDMARD
Biological disease-modifying anti-rheumatic drug
BME
Bone marrow edema
C1M
Collagen neo-epitope
C3M 
Type III collagen
CDAI
Clinical Disease Activity Index
CDC
Center for Disease Control
CI
Confidence Interval
CRA
Clinical Research Associate
CRP
c-reactive protein
CRPM
Matrix metalloproteinase-mediated c-reactive protein
csDMARD
Conventional synthetic disease-modifying anti-rheumatic drug
CXCL10
Chemokine (C-X-C motif) ligand 10
CXCL13
Chemokine (C-X-C motif) ligand 13
CXR
Chest X-Ray
DAS
Disease Activity Score
dbBaseline
Double-Blind Baseline
DMARD
Disease-modifying antirheumatic drugs
DNA
Deoxyribonucleic acid
dsDNA
Double stranded deoxyribonucleic acid
ECG
Electro Cardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate 
eow
every other week
ESR
Erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism 

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FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
GSUS
Gray scale ultrasonagraphy
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBV
Hepatitis B Virus
HCG
Human Chorionic Gonadotropin
HCP
Health care professional
HIV
Human immunodeficiency virus
HRQoL
Health Related Quality of Life
i.a.
Intra-articular
IEC
Independent Ethics Committee
IgG1
Immunoglobulin
IgM
Immunoglobulin M
IGRA
Interferon-Gamma Release Assay
IL-6
Interleucin-6
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IV
Intravenous
LDA
Low disease activity
ln
Natural logarithm
LT
Liver transportation
MCP
Metacarpophalangeal joint
MedDRA
Medical Dictionary for Regulatory Activities
MMP3
Matrix metalloproteinase 3
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MTP
Metatarsophalangeal joint
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug
NYHA
New York Heart Association
OL
Open-label
OMERACT
Outcome Measures in Rheumatology
PA
Posterior-anterior

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PDUS
Power Doppler ultrasonography
PG
Pharmacogenetic
PGA
Patient's Global Assessment
PhGA
Physician's Global Assessment
PIP
Proximal Interphalangeal joint
PML
Progressive multifocal leukoencephalopathy
PK
Pharmacokinetics
PPD
Purified protein derivative
PRO
Patient Reported Outcome
q3wks
Every 3 weeks
QoL
Quality of Life
RA
Rheumatoid arthritis
RAMRIS
Rheumatoid arthritis MRI scoring system
RAPID-3
Routine Assessment of Patient Index Data
RF
Rheumatoid factor
ROC
Receiver operating characteristic
SAA
Serum amyloid-associated protein
sc
Subcutaneous
SDAI
Simplified Disease Activity Index
SF-36
Short Form-36
SJC
Swollen Joint Count
STIR
Short tau inversion recovery
TB
Tuberculosis
TJC
Tender Joint Count
TNF
Tumor Necrosis Factor
TNFi
Tumor Necrosis Factor inhibitor
TSQM
Treatment Satisfaction Questionnaire for Medication
US
Ultrasonography
VAS
Visual Analog Scale
VICM
Matrix metalloproteinase-degraded vimentin
WPAI
Work Productivity and Activity Impairment

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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................9
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................21
3.0
Introduction ...........................................................................26
3.1
Disease Overview ....................................................................................26
3.2
Adalimumab Overview............................................................................26
3.3
Rationale for the Study ............................................................................27
3.3.1
Additional Considerations on Key Study Parameters..............................29
3.4
Safety Information ...................................................................................34
3.5
Differences Statement..............................................................................34
3.6
Benefits and Risks....................................................................................35
4.0
Study Objectives....................................................................35
5.0
Investigational Plan...............................................................37
5.1
Overall Study Design and Plan:  Description ..........................................37
5.2
Selection of Study Population..................................................................45
5.2.1
Inclusion Criteria .....................................................................................45
5.2.2
Exclusion Criteria ....................................................................................48
5.2.3
Prior and Concomitant Therapy...............................................................51
5.2.3.1
Prior Therapy ...........................................................................................51
5.2.3.2
Concomitant Therapy...............................................................................53
5.2.3.3
Prohibited Therapy...................................................................................55
5.2.3.4
Rescue Therapy........................................................................................56
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Immunogenecity 
and Safety Assessments/Variables...........................................................57
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................57
5.3.1.1
Study Procedures .....................................................................................65
5.3.2
Drug Concentration Measurements .........................................................86
5.3.3
Biomarker Measurements ........................................................................87
5.3.4
Pharmacogenetic Measurements..............................................................87

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5.3.4.1
Handling/Processing of Samples .............................................................88
5.3.4.1.1
Serum Adalimumab Concentration and AAA Analysis ..........................88
5.3.4.1.2
Biomarker Analysis .................................................................................89
5.3.4.1.3
Pharmacogenetic Analysis.......................................................................89
5.3.4.2
Disposition of Samples ............................................................................89
5.3.4.3
Measurement Methods.............................................................................90
5.3.5
Efficacy Variables....................................................................................90
5.3.5.1
Primary Efficacy Variables......................................................................90
5.3.5.2
Secondary Variables ................................................................................90
5.3.5.3
Exploratory Variables ..............................................................................92
5.3.5.4
Pharmacokinetic Variables ......................................................................92
5.3.5.5
Pharmacogenetic Variables......................................................................92
5.3.6
Safety Variables.......................................................................................93
5.4
Removal of Subjects from Therapy or Assessment.................................93
5.4.1
Discontinuation of Individual Subjects....................................................93
5.4.2
Discontinuation of Entire Study...............................................................95
5.5
Treatments................................................................................................95
5.5.1
Treatments Administered.........................................................................95
5.5.2
Identity of Investigational Product...........................................................96
5.5.2.1
Packaging and Labeling...........................................................................96
5.5.2.2
Storage and Disposition of Study Drug ...................................................97
5.5.3
Method of Assigning Subjects to Treatment Groups...............................97
5.5.4
Selection and Timing of Dose for Each Subject......................................98
5.5.5
Blinding....................................................................................................98
5.5.5.1
Blinding of Investigational Product.........................................................98
5.5.6
Treatment Compliance.............................................................................99
5.5.7
Drug Accountability.................................................................................99
5.6
Discussion and Justification of Study Design........................................100
5.6.1
Discussion of Study Design and Choice of Control Groups..................100
5.6.2
Appropriateness of Measurements.........................................................101
5.6.3
Suitability of Subject Population ...........................................................101
5.6.4
Selection of Doses in the Study .............................................................102
6.0
Complaints ...........................................................................102

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6.1
Medical Complaints...............................................................................103
6.1.1
Definitions..............................................................................................103
6.1.1.1
Adverse Event........................................................................................103
6.1.1.2
Serious Adverse Events .........................................................................104
6.1.2
Adverse Event Severity..........................................................................105
6.1.3
Relationship to Study Drug....................................................................105
6.1.4
Adverse Event Collection Period...........................................................106
6.1.5
Adverse Event Reporting.......................................................................107
6.1.6
Pregnancy...............................................................................................108
6.1.7
Toxicity Management ............................................................................109
6.2
Product Complaint .................................................................................109
6.2.1
Definition ...............................................................................................109
6.2.2
Reporting................................................................................................110
7.0
Protocol Deviations..............................................................110
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................112
8.1
Statistical and Analytical Plans..............................................................112
8.1.1
Analysis Population ...............................................................................112
8.1.2
Planned Methods of Statistical Analysis................................................112
8.1.3
Analysis of Demographic Data and Double-Blind Baseline 
Disease Characteristics and Other Analyses..........................................113
8.1.4
Efficacy Analysis...................................................................................113
8.1.4.1
Analysis for Primary Objective .............................................................113
8.1.4.2
Analysis for Secondary Objectives........................................................114
8.1.4.3
Analysis for Exploratory Objectives......................................................115
8.1.5
Pharmacokinetic Analyses.....................................................................116
8.1.6
Safety Analysis ......................................................................................116
8.1.7
Interim Analysis for Double-Blind Baseline Characteristics.................117
8.1.8
Compliance ............................................................................................117
8.2
Determination of Sample Size ...............................................................117
8.3
Randomization Methods ........................................................................119
9.0
Ethics.....................................................................................119

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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................119
9.2
Ethical Conduct of the Study .................................................................120
9.3
Subject Information and Consent...........................................................120
10.0
Source Documents and Case Report Form 
Completion ...........................................................................121
10.1
Source Documents .................................................................................121
10.2
Case Report Forms.................................................................................122
10.3
Electronic Patient Reported Outcomes (ePROs) ...................................123
11.0
Data Quality Assurance ......................................................124
12.0
Use of Information...............................................................124
13.0
Completion of the Study .....................................................124
14.0
Investigator's Agreement....................................................126
15.0
Reference List ......................................................................127
List of Tables
Table 1.
Study Activities........................................................................................58
Table 2.
Clinical Laboratory Tests.........................................................................82
Table 3.
Identity of Investigational Products.........................................................96
Table 4.
Sample Size Assumptions......................................................................119
List of Figures
Figure 1.
Study Design Schematic ..........................................................................38
Figure 2.
Adverse Event Collection ......................................................................107
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................139
Appendix B.
List of Protocol Signatories....................................................................141
Appendix C.
Injection Instructions – Pre-Filled Syringe – Sample............................142
Appendix D.
Subject Dosing Diary – Sample.............................................................149

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Appendix E.
Joint Evaluation Worksheet – Sample ...................................................152
Appendix F.
DAS28 Joint Assessment.......................................................................154
Appendix G.
Health Assessment Questionnaire (HAQ-DI) – Sample........................155
Appendix H.
FACIT-Fatigue Scale (Version 4) English Version – Sample...............158
Appendix I.
Treatment Satisfaction Questionnaire for Medication (TSQM) –
Sample....................................................................................................159
Appendix J.
Work Productivity and Activity Impairment (WPAI) – Sample ...........164
Appendix K.
Short Form-36 (SF-36) Health Survey Questionnaire – Sample...........166
Appendix L.
RAPID-3 Questionnaire/Assessment (in office and at home) –
Sample....................................................................................................179
Appendix M.
MRI Assessments and Scoring – Sample ..............................................180
Appendix N.
Ultrasound Assessments and Scoring – Sample ....................................181
Appendix O.
ACR 1987 and the ACR/EULAR 2010 Criteria for Classifying 
RA..........................................................................................................183
Appendix P.
Protocol Amendment:  List of Changes.................................................186

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3.0
Introduction
3.1
Disease Overview
Rheumatoid arthritis (RA) is an autoimmune disorder with an estimated prevalence of 
approximately 1% in the population.1  The economic burden of RA is significant, 
resulting from both direct and indirect costs for the patient, including lost work income.2,3  
Over the last 15 years, the effectiveness of TNFi (tumor necrosis factor inhibitor) 
therapies in RA has been widely proven and the use of these agents both in early and 
established RA and for short and long-term treatment periods up to 10 years has been 
shown to improve disease course and halt structural progression.4-9
3.2
Adalimumab Overview
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody 
containing only human peptide sequences.  Adalimumab is produced by recombinant 
deoxyribonucleic acid (DNA) technology in a mammalian cell expression system.  It 
consists of 1,330 amino acids and has a molecular weight of approximately 
148 kilodaltons.  Adalimumab is composed of fully human heavy and light chain variable 
regions, which confer specificity to human 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 is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses.  Elevated levels of TNF play an important role in pathologic 
inflammation.  Adalimumab binds specifically to TNF and neutralizes the biological 
function of TNF by blocking its interaction with the p55 and p75 cell surface TNF 
receptors.  Adalimumab also modulates biological responses that are induced or regulated 
by TNF.  After treatment with adalimumab, levels of acute phase reactants of 
inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and 
serum cytokines rapidly decrease.

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Adalimumab was first approved in the United States and European Union (EU) for the 
treatment of RA in 2002 and 2003, respectively.  Additional indications have been 
approved in the United States and EU including psoriasis, psoriatic arthritis, ankylosing 
spondylitis, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis.  Additional 
updates regarding approved indications can be found in the current edition of the 
Investigator Brochure.
3.3
Rationale for the Study
The treat to target recommendations advocate that the primary goal of treating subjects 
with RA is to maximize long-term Health Related Quality of Life (HRQoL) through 
control of symptoms, prevention of structural damage, normalization of function and 
social participation.1  Abrogation of inflammation is the most important way to achieve 
these goals.  The aimed targets have been defined as clinical remission or low disease 
activity (LDA), depending on disease duration and accumulated damage.  The widespread 
use of (biological disease-modifying anti-rheumatic drugs) bDMARDs, mainly TNFi, 
helps patients to achieve these goals and thus have become an integral part of the standard 
of care of RA.10,11
For patients treated with bDMARDs who achieve clinical remission, a question at the 
center of several recent clinical trials has been whether biologics need to be maintained at 
a stable dose or can be withdrawn or tapered.  Even with an increasing introduction of 
these treatment regimens in routine clinical practice, the evidence supporting their 
effectiveness is equivocal.  Furthermore, patient outcomes in early RA treated with initial 
combination of methotrexate (MTX) and aTNFi versus in established RA have been very 
different.12,13
In early RA patients, controlled withdrawal studies have resulted in somehow different 
outcomes for different TNFi compounds:  whilst the OPTIMA14 trial showed that the 
majority of early RA MTX-naïve patients in stable LDA were able to maintain disease 
control for 52 weeks after discontinuing adalimumab, in the PRIZE study,15 on the other 

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hand, withdrawing etanercept was associated with a higher number of patients losing their 
status of clinical remission.
In established RA, withdrawing TNFi or other bDMARDs has been associated with 
relapses or RA flares in a higher proportion of patients then in early RA.13  Data from 
both open-label uncontrolled studies16-19 and few controlled trials20-23 has indicated that in 
patients treated with bDMARDs after incomplete response to csDMARDs, 
discontinuation of  the biologic therapy without triggering loss of disease control can only 
be achieved in some of them.
Research has also been conducted investigating the outcomes of TNFi dose tapering (dose 
reduction or increased interval of drug administration) treatment strategies in RA patients 
achieving the target of LDA or remission.  Studies have shown that a certain proportion of 
patients can maintain remission following a tapering strategy for 48 weeks,20 54 weeks21
and up to 18 months.24  However, the data show also that a considerable proportion of 
these patients experienced an RA flare or loss disease control following dose reduction.
Thus, despite the existing evidence on dose reduction in RA, several questions that are 
critical if considering the implementation of this practice in clinical practice remain 
unanswered:25  Who are the patients who can maintain clinical control upon tapering?  
Which patient and or disease characteristics are predictive for the risk of flare versus the 
maintenance of response following a tapering regimen?  Is it feasible to devise a patient 
selection strategy or algorithm to inform dose tapering in daily clinical care?  Is 
re-institution of normal dose/dosing regimen of TNFi in case of flares effectively 
providing patients the same level of disease control they had before?
The overarching aim of the study we propose here is to attempt to provide answers to all 
these questions.  The objectives of the study aim to study the association of patient 
characteristics, with a particular focus on residual inflammation, with the development of 
flares following a prevailing dose tapering strategy.

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3.3.1
Additional Considerations on Key Study Parameters
Rheumatoid Arthritis Flares
The occurrence of flares, their detection, as well as their characterization has been subject 
of numerous studies.  Several flare definitions have been proposed and have been 
submitted to validation analyses in the context of RA clinical trials.22,24,26  An increase in 
DAS28(ESR) higher then 1,2 has been accepted as being clinical meaningfully 
representing a true worsening of the disease;27 However, this definition of flare is often 
not capturing  patients with  meaningful disease activity.28  A European Expert Consensus 
panel defined, for patients previously in clinical remission, a flare when an increase in 
DAS28 (ESR) of > 0.6 AND a DAS28 (ESR) > 2.6 occurs.  Thus, in order to capture 
meaningful worsening of RA over time flare will be defined as an increase from 
dbBaseline in DAS28 (ESR) of > 0.6 AND a DAS28 (ESR) > 2.6 or an increase in 
DAS28 (ESR) of ≥ 1.2 irrespective of DAS28 (ESR).
Clinical Remission Defined by DAS28 < 2.6
DAS28 (CRP) has been validated in comparison with DAS28 (ESR) and data indicated 
that both measures are useful for assessing disease activity in patients with rheumatoid 
arthritis.29  Accordingly, both scores can and have been included as an outcome variable 
in clinical trials, and have been used in clinical practice to define disease activity 
e.g., clinical remission (< 2.6).  Despite the fact that both scores are reflecting accurately 
disease activity, the cut-off points for disease activity indexes, including clinical 
remission, might be slightly different for DAS28 (CRP):  the percentage of patients 
meeting the definition of remission (< 2.6) might be slightly higher for DAS28-CRP than 
DAS28-ESR.30,31
In clinical practice it's relatively frequent to use the also validated 3 variables DAS2832 or 
instead of the most widely used DAS28 4 variables due to difficulties on getting 
documented patient global assessment (PGA) in a Visual Analogue Scale (VAS).  
Moreover, a recent study has shown that despite the existence of individual patient 
baseline differences prior to treatment with TNFi, after 12 weeks of TNFi and particularly 

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for the lower range the 3 and 4 variables DAS28 (CRP).scores were similarly sensitive to 
change, highly correlated and the mean inter-score difference was very small.33  
Accordingly, for the purpose of identifying subjects on stable clinical remission for 
≥6 months for Screening, both DAS28 (ESR) and (CRP) 4 or 3 (when PGA is not 
available) variables documented as being lower than 2.6 for at least 6 months prior to 
screening will be accepted.  However, at Screening, only subjects with 4 variables DAS28 
(ESR) < 2.6 may be enrolled and throughout the study clinical remission is defined by the 
4 variables DAS28 (ESR) < 2.6.  Flare will be assessed based on DAS28 (ESR) 
evaluation at any time point throughout the study (with ESR measured in the same visit).
Concomitant Treatments for RA
The 2013 EULAR recommendations update propose that in RA patients who are in stable 
clinical remission particularly if also treated with concomitant csDMARDs(s) tapering a 
bDMARD is an option; the updated 2015 ACR guidelines also consider tapering RA 
treatments as an option for such a patient population.  Both treatment recommendations 
acknowledge that more data on tapering is needed as part of a research agenda.
It is the aim of this study to assess, in subjects treated in real life clinical practice 
conditions who have DAS28 < 2.6, if imaging-detected sub-clinical inflammation (and 
disease, patient and treatment patterns as well as adalimumab drug level characteristics) 
brings an additional benefit in predicting and informing clinicians about who has a higher 
risk of flare while treated with a reduced dose of adalimumab.
As this study goal is to include patients as treated in routine clinical practice, the patient 
population must be in line with both treatment recommendations and clinical practice.  
Accumulated data from registries and other real world evidence, such as CORRONA,34
US healthcare insurance claims database, 35 BSRBR,36 RABBIT,37 Nor-DMARD38 and 
ARTIS39 are showing that around 30% – 34% of patients being treated with bDMARDs 
including TNFi are on monotherapy even if at initiation of the bDMARD the vast 
majority of patients were on combination therapy.40  As such this study will include 
mainly patients who are in stable remission for more than 6 months as assessed by DAS28 

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< 2.6 and after at least 1 year of treatment with adalimumab with concomitant MTX for at 
least the last 12 weeks prior to inclusion; in order to be in line with the current clinical 
practice up to 20% of the study patient population may be composed of subjects who are 
not treated with concomitant stable MTX but instead are treated with other than MTX 
allowed csDMARDs or not treated with a csDMARD as long as this treatment regimen is 
stable for at least 12 weeks prior to Week 0.
Assessment of Residual Disease Activity Using Imaging Techniques
The use of sensitive imaging techniques, i.e., musculoskeletal ultrasonography (US) and 
magnetic resonance imaging (MRI) allows for the identification of residual inflammation, 
which has been correlated with structural damage progression and upcoming RA flares in 
patients in clinical remission.
US is an imaging technology increasingly used in rheumatologists' clinical practice.  
Among approximately 50% of subjects on TNFi with established clinical remission, 
ultrasound assessments have been able to detect remaining signals of synovitis in Power 
Doppler ultrasonagraphy (PDUS).32  These PDUS signals have been shown to be 
associated with a risk for progression and/or relapse/flare in several clinical trials.32-46
Despite its high use and validity in local clinical settings, the use of US has been limited 
in large clinical trial settings due to inter-operator and inter-observer variability, and the 
significant dependence on the expertise on the ultrasound assessor.46,47
MRI is a highly sensitive and standardized imaging technique suitable for clinical trials:  
Using MRI in RA has been shown to identify erosions otherwise not observed with 
conventional x-ray.48  Similarly like US, MRI assessments have shown signs of 
inflammation by synovitis and bone marrow edema (BME) in a high proportion of 
patients considered in clinical remission.49  It was further demonstrated that MRI signals 
of inflammation as detected by the Rheumatoid arthritis MRI scoring system (RAMRIS)50
validated scores are correlated with structural progression as measured by conventional 
x-ray and are suggested to indicate remaining disease activity.49,51,52

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Current European League Against Rheumatism (EULAR) recommendations on the value 
of imaging for diagnosis and monitoring RA patients recognize the value of MRI as well 
as US on the diagnosis and monitoring of RA (besides conventional x-ray).53  
Nevertheless, MRI is not used in daily clinical practice to monitor RA and will not replace 
the clinical value for disease activity assessment and practicality of US nor the value of 
conventional x-ray for assessment of disease damage and structural progression.  
However, its high sensitivity and reproducibility as well as low inter-observer 
variability,50 make it ideal for imaging detection of inflammation in a clinical trial 
setting.48  In addition, in RA patients who are in stable clinical remission and 
subsequently taper or withdraw a bDMARD, MRI may detect potential bone and cartilage 
deterioration. 
It is the primary objective of this study is to investigate the association between residual 
disease activity at Baseline as detected by magnetic resonance imaging (MRI) and the 
occurrence of flares in RA subjects submitted to an adalimumab dose tapering regimen 
controlled by adalimumab withdrawal.
Clinical Patient Characteristics
Several additional patient characteristics, some well proven as prognostic factors of more 
severe RA, have also been investigated in their potential association with the outcome of a 
tapering or withdrawal of TNFi treatment strategy; not limited but including the following 
parameters have, even if not consistently, been suggested to be potentially associated with 
loss of disease control upon a tapering strategy:11-13,17,21,25,54
●
Disease duration
●
Rheumatoid factor (RF) and/or Anti-citrullinated peptide antibody (ACPA) 
positivity 
●
Erosive disease
●
Smoking
●
Initial disease activity
●
Previous treatment with csDMARDs or bDMARDs

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●
Concomitant use of corticosteroids
●
Duration of treatment and remission with the bDMARD
●
CRP
●
Health Assessment Questionnaire – Disability Index (HAQ-DI)
Patient clinical characteristics and their association with the occurrence of flares upon 
tapering of adalimumab controlled by its withdrawal will be assessed.
Drug Monitoring
A drug-related hypothesis relates to individual differences in serum drug concentrations:  
patients with higher trough concentrations would be more likely to remain in remission 
following a dose tapering regimen than patients with lower trough concentrations.55,56
This concept has not been validated.  On the contrary, it has been shown that there is a 
high range of individual variability in both clinical response and adalimumab trough 
concentrations57 thus precluding recommendations for concentration-guided therapy 
(therapeutic drug monitoring).
Adalimumab trough concentrations at baseline and at several time points and their 
potential predictive value for flares will be investigated during this study.
Biomarkers
The potential predictive value of certain biomarkers for progressive destructive RA and 
their potential role in monitoring treatment response has been frequently investigated.58-60  
So far, a biomarker or set of biomarkers which would predict RA clinical course or 
disease progression has not yet been identified.  Recent findings suggest it may be 
possible to find surrogate serum biomarkers of active synovitis that could be useful in the 
follow-up of patients with RA in remission in order to identify risk of increase of disease 
activity.61-64

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Identification of biomarkers which may be of interest to understand the contributing 
factors for successful tapering are therefore part of the exploratory assessments of the 
study.
3.4
Safety Information
Adalimumab therapy has a well-established and well described safety profile based on 
extensive post marketing experience and continued clinical trial patient exposure since the 
first approved indication in 2002 for rheumatoid arthritis.  A detailed discussion of the 
pre-clinical toxicology, metabolism, pharmacology and safety experience with 
adalimumab can be found in the current Investigator's Brochure.  AbbVie is committed to 
continue to collect safety information including those events that may occur in this trial in 
order to confirm this established safety profile and to identify any unknown potential 
adverse reactions, rare events and those events with a long latency.  AbbVie is 
participating in an United States Food and Drug Administration (FDA)-requested, TNF
inhibitor class wide exploration of the rare appearance of malignancy in subjects who are 
30 years of age or younger at the time of diagnosis.  The risk of malignancy in this age 
group has not been established and is difficult to study due to its rarity. AbbVie 
appreciates your attention to the additional reporting requirements needed in this unlikely 
event, outlined in Section 6.1.5 under Adverse Event Reporting.
3.5
Differences Statement
This Phase 4 study is the first randomized, placebo-controlled, double-blind study, to 
evaluate the association between residual inflammation detected by MRI at Baseline and 
RA flares or maintenance of clinical remission outcome of a bDMARD dose tapering.  
The dbBaseline demographics and clinical patient characteristics, adalimumab drug 
levels, US detected joint inflammation and RA biomarkers and their association with the 
36-week outcomes of adalimumab tapering will also be assessed.  Open-label adalimumab 
40 mg every other week (eow) rescue treatment for subjects experiencing a flare will be 
investigated.

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3.6
Benefits and Risks
This study is being conducted in subjects previously treated with adalimumab for at least 
12 months and who achieved stable clinical remission for at least 6 months.  Thus, 
subjects enrolled have already been exposed to adalimumab.
The safety profile of adalimumab in RA and other approved indications is well 
established.  Adverse events in the categories of autoimmunity, demyelinating disorders, 
congestive heart failure, gastrointestinal disorders, hematologic events, hepatic events, 
hypersensitivity, immunosuppression, infections, malignancies, respiratory thoracic 
disorders, and vascular disorders have been observed with adalimumab therapy.
The treatment interventions in this study, dose tapering and withdrawal, are treatment 
algorithms used in clinical practice:11,24,26,65-68  In this study, subjects will be randomized 
(5:1) to a reduced dose of adalimumab 40 mg subcutaneous (sc) every 3 weeks (q3wks) 
(taper arm) or matching placebo (withdrawal arm).  Subjects will maintain a stable dose of 
MTX (any dose; oral, sc or im) and/or of any other additional concomitant RA medication 
as taken before enrollment into the study.
Subjects experiencing a flare at any time point will be switched to an Open-Label Rescue 
Arm and immediately provided adalimumab 40 mg eow for at least 16 weeks. 
AbbVie expects the results from this study to provide treating health care professionals 
(HCPs) with additional evidence potentially useful in characterizing the profiles of 
patients that might be considered for a tapering strategy and to identify those that might be 
at risk of flaring if submitted to a dose or interval modification.
4.0
Study Objectives
The primary objective is to investigate the association between residual disease activity 
at Baseline as detected by magnetic resonance imaging (MRI) and the occurrence of flares 
in RA subjects randomized to an adalimumab dose tapering regimen controlled by 
adalimumab withdrawal.

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The Secondary Objectives are:
●
To assess the occurrence and severity of flares and the time to flares in both 
taper and withdrawal arms.
●
To investigate the association between dbBaseline subject demographic and 
disease characteristics (and the occurrence of flares).
●
To investigate the association between dbBaseline adalimumab trough 
concentrations and the occurrence of flares.
●
To evaluate the effectiveness of rescue therapy with open-label adalimumab 
40 mg every other week (eow) over 16 weeks in subjects experiencing a flare.
●
To assess the change in rheumatoid arthritis MRI scoring system (RAMRIS) 
scores from Baseline to Final visit in the taper, withdrawal and Open-Label 
Rescue Arms.
●
To investigate the MRI-flare associations in sub-groups of subjects who meet 
additional clinical remission criteria at dbBaseline including simplified disease 
activity index (SDAI) ≤ 3.3, clinical diseases activity index (CDAI) ≤ 2.8 and 
ACR/EULAR 2011 boolean-based remission, as well as to describe the course 
of disease and patient reported outcome (PRO) measures in the taper, 
withdrawal and Open-Label Rescue Arms overall and per dbBaseline 
subgroup.
●
To assess the rate of anti-adalimumab antibodies (AAA) positive subjects in 
the taper and withdrawal arms.
The study has also the following exploratory objectives:
●
In the subgroup of subjects with a Baseline Ultrasound (US) assessment:
○
To investigate the association between Baseline ultrasound scores and the 
occurrence of RA flares.
○
To investigate the association between the Baseline ultrasound scores and 
Baseline MRI RAMRIS scores.
○
To describe the change in the ultrasound scores from Baseline to the time 
of RA flare in the taper and withdrawal arms.

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○
To investigate the association between biomarker values at dbBaseline (or 
their change over time) and the occurrence of flares.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 4, multicenter, randomized, double-blind, parallel-group study.  The study 
duration will include a Screening period of up to 28 days, a 4-week Lead-In Period with 
open-label 40 mg adalimumab eow and a 36-week Double-Blind Period with 40 mg 
adalimumab/placebo q3wks; subjects who experience a flare at any time will enter a 
Rescue Arm and will be followed for 16 weeks.
The study design schematic is presented in Figure 1.

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Figure 1.
Study Design Schematic

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Screening Period (up to 28 days):
At the Screening Visit, prior to the Lead-In Period, subjects will receive a full explanation 
of the study design and study procedures, provide a written informed consent, and 
undergo the Screening procedures outlined in Table 1.  The Screening period may be 
exceptionally extended beyond 28 days upon justification and further consultation with 
Study Designated Physician.  The target population for the study consists of RA subjects 
on adalimumab treatment for at least 12 months and in stable clinical remission, as 
defined by a 4 or 3 (whenever PGA is not available) variables DAS28 (CRP) or DAS28 
(ESR) < 2.6 for at least 6 months prior to the Screening Visit, in combination with MTX 
(at a stable dose for ≥ 12 weeks prior to Week 0 Visit) or if not on MTX, in other allowed 
csDMARDs at a stable dose or not treated with a csDMARD for ≥ 12 weeks prior to 
Week 0 Visit.  Subjects with a documented DAS28 (CRP) or (ESR) < 2.6 (or availability 
of the 4 or at least 3 components that allow for calculation of a DAS28 score) at least 
6 months prior to Screening Visit may be screened.  However, for enrollment and 
throughout the study clinical remission will be defined by 4 variables DAS28 (ESR) 
< 2.6 criteria.
All screened subjects satisfying all the inclusion (including a DAS28 [ESR] assessment of 
< 2.6 evaluated at Screening) and none of the exclusion criteria will be enrolled into the 
study.  Confirmation of a DAS28 (ESR) < 2.6 assessed at the Screening and at the Week 0 
Visit is required prior to subject inclusion into the Lead-In Period.
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  All Screening procedures with the possible exceptions noted below will be 
repeated.  The subject must meet all inclusion and none of the exclusion criteria at the 
time of re-screening in order to qualify for the study.  There is no minimum period of time 
a subject must wait to re-screen for the study.  If the subject had a complete initial 
Screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon-Gamma Release Assay (IGRA; QuantiFERON-Tuberculosis 
[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

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are met and no more than 12 months have passed.  As appropriate, sites are encouraged to 
contact the AbbVie Study Designated Physician to confirm if subjects should or should 
not be re-screened.  If the re-screening visit is occurring within 4 weeks of last screening 
some other procedures may not be required upon discussion and agreement with Study 
Designated Physician.
Lead-In Period (4 Weeks):
Subjects who fulfill all Screening criteria will enter the study with a 4-week Lead-In OL 
Period:  subjects will receive adalimumab 40 mg sc eow starting at Week 0 of the Lead-In 
Period.  Week 0 will occur 2 weeks after the subject's last dose of commercial Humira®
(± 2 days) to keep in line with eow dosing.  At the Week 0 visit subjects will undergo the 
corresponding procedures as outlined in Table 1 including DAS28 (ESR) assessment to 
confirm remission using the ESR result from the same day of the visit.  If the subject 
enrollment is confirmed at the Week 0 visit, the subject will stop commercial Humira®
and initiate adalimumab investigational product open-label sc.  The first sc injection will 
be administered at the site at the end of the visit; the second injection will be given 
14 days thereafter (± 3 days) and every other week (± 3 days) until Week 4 dbBaseline 
Visit.  If needed the subject may be assisted by the study team for the self-injection of the 
syringe.  Subjects must undergo a high-field contrast MRI scan of the most affected hand 
(2nd to 5th MCP) and wrist during the Lead-In Period.  If both sides are considered equally 
affected the MRI of the dominant hand (2nd to 5th MCP) and wrist will be performed.
MRI images will be read centrally.  Further details regarding MRI requirements, 
procedures and central reading will be provided in an MRI manual.  The assessors will be 
blinded to the clinical assessments and the clinical Investigator will be blinded to the MRI 
assessments performed centrally.  A local report for safety reasons on urgent and RA 
inflammation related findings other than RA may be viewed by the investigator.  The 
dbBaseline Visit and randomization are not dependent on the results or report of the 
central reader.  Subjects should be randomized only when the MRI has been 
confirmed to be received and complete by Central Imaging.

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Sites will be asked at study-start if they want to participate and if they qualify for the 
optional US assessment, according to requirement described in Appendix N and in the US 
manual.  Sites that participate in US assessments will need to nominate a qualified 
Ultrasonographer to perform and locally assess the US during the Lead-In period or at the 
dbBaseline Visit; there will not be a central reading of the US images.  The 
Ultrasonographer will be blinded to the clinical assessments and the clinical Investigator 
will be blinded to the ultrasound assessments. 
If needed for procedural compliance (e.g., to allow MRI and its certification, for injection 
scheduling adjustment), the lead-in period can be extended up to 2 more weeks  in which 
case the DAS28 (ESR) assessment and all the dbBaseline Week 4 Visit study procedures 
will occur up to 6 weeks after the Week 0 Visit.  These cases or other exceptions related 
with further extension of the Lead-in period should be discussed with the Study 
Designated Physician.
Double-Blind Period:
A confirmed adequate MRI from the Lead-In Period is required before the dbBaseline 
visit.  At the end of the Lead-In Period, subjects will be assessed again for DAS28 (ESR) 
at the dbBaseline Week 4 visit.  At the Week 4 visit, if the subject does not meet the 
DAS28 (ESR) of < 2.6 or if the subject is unable to obtain confirmed and certified MRI 
scan images, the subject would need to be discontinued from the study at an Early 
Termination visit.
Subjects with a confirmed DAS28 (ESR) of < 2.6 at the dbBaseline visit, and as such 
fulfilling confirmed DAS28 (ESR) remission at 2 time points:  Day 1 of Lead-In and 
4 weeks later (or, exceptionally later) at the dbBaseline visit, will be randomized in a 
5:1 ratio to one of two double-blind arms and followed for an additional 36 weeks:
1.
a reduced frequency of adalimumab 40 mg sc to every 3 weeks (q3wks) (taper 
arm), or
2.
adalimumab placebo sc q3wks:  withdrawal arm.

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The randomized Double-Blind period will begin at the dbBaseline Visit (Week 4) and will 
continue with visits every 6 weeks until the Week 40 Visit.  The Week 40 visit will be 
considered the Final Visit.
At each scheduled visit during the double-blind period subjects will undergo the 
corresponding procedures as outlined in Table 1.  The initial assessments at each of these 
visits must include ESR assessment except if the blood puncture for this procedure is very 
painful (in which case subjects should first fulfill the patient questionnaires); if the 
calculated DAS score meets flare criteria described below, the visit then becomes a Flare 
Week 0 Visit; and the stipulated procedures are completed.
Visits, including the dbBaseline Visit should aim to be scheduled in line with the injection 
date (± 3 days); in this case, subjects should be reminded not to take their scheduled 
injection prior to coming for the visit.  The injections scheduled at the visits should occur 
at the site at the end of the visit.
During the interval between scheduled visits, subjects will be asked to contact their 
physicians in case they feel their disease is worsening:  an unscheduled visit will be 
performed within 2 weeks of contact with the site to assess if subjects are experiencing a 
flare.
For any subject missing 2 consecutive visits within the Double-Blind Period, the site must 
contact the AbbVie Study Designated Physician regarding the subject's continued 
participation in the study.
No study drug will be administered or injected at the Final Visit.
Flare at Scheduled Visit:
If during a scheduled visit a flare (defined by DAS28 [ESR] > 2.6 AND an increase from 
dbBaseline in DAS28 [ESR] > 0.6 or increase of DAS28 [ESR] ≥ 1.2 from dbBaseline 
DAS28 [ESR] score irrespective of DAS28 [ESR]) is confirmed, the regular visit will 
then turn into a Flare Week 0 Visit.

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At the Flare Week 0 Visit, subjects will undergo further study procedures as described in 
Table 1 under Scheduled/Unscheduled Flare Week 0 Visit and will be switched to 
Open-Label Rescue Arm starting with the first OL injection of adalimumab 40 mg sc at 
the end of the visit.  Subjects will be given at-home Routine Assessment of Patient Index 
Data (RAPID)-3 questionnaires (for self-assessment of disease activity) for weekly 
completion to be returned at every visit until the Flare Week 16 Visit.
Unscheduled Visit:
Subjects should be instructed (at every office visit) to contact the site if they feel their 
disease is worsening and will receive those instructions in the patient card.  If a subject 
contacts the site due to possible worsening of RA, an unscheduled visit to confirm his/her 
clinical status within 2 weeks of contact with the site.  Study procedures outlined in 
Table 1 should be followed including an initial DAS28 (ESR) assessment.  If a flare is not 
confirmed, the Unscheduled Visit is concluded and the subject will continue the regular 
scheduling of the Double-Blind Period Visits.
If a flare is confirmed, the unscheduled visit will turn into the Flare Week 0 Visit.
Flare at Unscheduled Visit:
At the Flare Week 0 visit subjects will undergo further study procedures as described in 
Table 1 under Scheduled/Unscheduled Flare Week 0 Visit and will be switched to the 
Open Label Rescue Arm starting with the first adalimumab 40 mg sc OL injection at the 
end of the visit if last study drug injection has occurred more than 1 day ago.  If not, OL 
adalimumab 40 mg will be provided for at home sc injection starting the next day.  
Open-Label Rescue Arm
In the open-label Rescue Arm subjects will receive OL therapy with adalimumab 40 mg 
eow.  After the first OL injection, adalimumab 40 mg will be administered sc eow.  
Subjects will be given RAPID 3 questionnaires (for self-assessment of disease activity) 
for weekly completion to be returned at every visit until the Flare Week 16 Visit.

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All subjects will have 16 weeks of follow-up in the Open-Label Rescue Arm.
The Flare Week 16 Visit will be the Final Visit.
During the Open-Label Rescue Arm, it is at the Investigator's discretion to initiate or 
change the subject's following RA concomitant medications:
●
Non-steroidal anti-inflammatory drugs (NSAIDs)
●
Analgesics
●
Corticosteroids (a dose up to a maximum of 15 mg oral prednisolone or 
equivalent/day and/or up to 3 injections intra-articular (i.a.) within the 
follow-up period of 16 weeks)
●
csDMARDs including MTX (initiation and/or dose or administration mode 
change) and excluding csDMARDs that are not allowed (e.g., azathioprine, 
cyclophosphamide, d-penicilamine)
Joints submitted to an i.a. injection of corticosteroids within the last 4 weeks prior to a 
visit will be excluded from the tender and swollen joint evaluation.  Four weeks after an 
i.a. injection, joints must be again evaluated and included in the scores.
All concomitant medications should be documented in the electronic Case Report Form 
(eCRF).  If additional RA medications are required, the Study Designated Physician must 
be contacted.
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination Visit.
Early Termination Visit
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects who prematurely discontinue while on the double blind and/or OL rescue period 
should complete the procedures outlined for the Early Termination/Final Visit in Table 1
as soon as possible after the last dose of study drug and preferably prior to the 
administration of new therapies.

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If subjects discontinue the study during the lead-in observational period from Week 0 up
to Week 4, prior to randomization, a shortened Early Termination visit is required for: 
returning study material and drug, assess any safety/adverse events, collect reason for 
discontinuation.  A 70-day follow-up call/visit will be required; the remainder of full 
Early Termination Visit study procedures can be completed per the investigator's 
discretion.
All subjects discontinuing the study will have a follow-up phone call approximately 
70 days after the last administration of study drug to obtain information on any new or 
ongoing adverse events.
5.2
Selection of Study Population
Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
200 subjects will be enrolled into the Lead-In Period.  The study is designed to randomize 
approximately 180 subjects in the Double-Blind Period to meet primary objective 
evaluation 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.
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1, Inclusion Criteria, and none of the exclusion criteria 
specified in Section 5.2.1, Exclusion Criteria, of this protocol.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets all of the following 
criteria:
1.
Male or female subjects ≥ 18 years of age.
2.
Subject has a diagnosis of RA as defined by the 1987 revised ACR classification 
criteria and/or the ACR /EULAR 2010 classification criteria (any duration since 
diagnosis).

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3.
Subject must meet the following criteria:
●
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to 
Week 0 Visit; 
●
Must be treated with concomitant MTX in a stable dose (oral, sc or im at any 
dose) for at least 12 weeks prior to Week 0 Visit or if not on MTX, must be 
treated with other allowed csDMARDs at stable dose for at least 12 weeks 
prior to Week 0 Visit or if not treated with csDMARDs must maintain this 
regimen for at least 12 weeks prior to Week 0 Visit.
4.
Subject must be in sustained clinical remission based on the following:
●
At least one documented 4 or 3 (if PGA is not available) variables DAS28 
(ESR) or DAS28 (CRP) < 2.6 (or calculated based on documented components 
of the DAS28) in the patient chart 6 months or longer prior to the Screening 
Visit;
●
4 variables DAS28 (ESR) assessed at Screening < 2.6 (with all components 
including ESR assessed at Screening).
5.
If subjects are receiving allowed concomitant csDMARDs (in addition or not to 
MTX) the dose must be stable for at least 12 weeks prior to the Week 0 Visit 
(e.g., chloroquine, hydroxychloroquine, sulfasalazine, gold formulations [including 
auranofin, gold sodium thiomalate, and aurothioglucose] and/or leflunomide).
6.
If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent 
must be < 10 mg/day and the dose must be stable for at least 4 weeks prior to 
Week 0 visit.
7.
If subjects are receiving concomitant NSAIDs, tramadol or other equivalent opioids 
and/or non-opioid analgesics the dose and/or therapeutic scheme must be stable for 
at least 4 weeks prior to the Week 0 Visit.
8.
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 

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47
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 include the 
following (see local informed consent for more detail):
●
Oral (except for low-dose progestin-only [lynestrenol and norestisteron]), 
injectable or implanted hormonal contraceptives started for 90 days prior to 
study drug administration;
●
Intrauterine device (IUD);
●
Intrauterine system (for example, progestin-releasing coil);
●
A vasectomized male partner;
●
Abstinence from vaginal intercourse (when in line with preferred and usual 
lifestyle of the subject)
9.
Subject is judged to be in good health as determined by the Principal Investigator 
based upon the results of medical history, laboratory profile, physical examination, 
performed during Screening and based on documented 12-lead ECG and x-ray 
performed within 12 months prior to dbBaseline or if not available or documented, 
performed at Screening.
10.
Subject is judged to have no contra-indications for the use of adalimumab as 
determined by the Investigator.
11.
Subject has a documented negative TB Screening assessment within 12 months 
prior to Screening Visit or if latent TB infection, subject has had a minimum of 
2 weeks (or per local guidelines whichever is longer) of TB prophylaxis prior to 
treatment with adalimumab and had or is completing a full course of TB 
prophylaxis.
If these requirements are not met, subject must perform a TB screening assessment: 
subject has a negative TB screening assessment and if there is a strong suspicion of 
TB exposure the subject must be evaluated by a TB expert (Section 5.3.1.1).  If the 

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subject has evidence of latent TB infection, the subject must initiate and complete 
at least the first 2 weeks (or per local guidelines whichever is longer) of TB 
prophylaxis prior to Week 0.
12.
Subjects must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections.
13.
Subjects must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol.
Rationale for Inclusion Criteria
1 – 7
To select the adequate subject population for this study disease.
9 – 12
For the safety of the study subjects.
8
The impact of adalimumab on pregnancies is unknown.
13
In accordance with harmonized GCP.
5.2.2
Exclusion Criteria
A subject will be excluded from the study if he/she meets any of the following criteria:
1.
Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or 
calculated based on documented components of the DAS28) assessed within 
6 months prior to the Screening Visit ≥ 2.6.
2.
Subject is on an additional concomitant bDMARD (including but not limited to 
abatacept, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab or 
tocilizumab).
3.
Subject has been treated with intra-articular or parenteral administration of 
corticosteroids within the last 4 weeks before Screening.
4.
Subject has undergone joint surgery within 12 weeks of Screening (at joints to be 
assessed by MRI and/or ultrasound).

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5.
Subject has a history of chronic arthritis diagnosed before age 16 years, and history 
of gout, psoriatic arthritis or other rheumatic inflammatory disease apart from RA.
6.
Subject has a medical condition precluding an MRI (e.g., magnetic activated 
implanted devices – cardiac pace-maker, insulin pump, neurostimulators, etc. and 
metallic devices or fragments or clips in the eye, brain or spinal canal and in the 
hand/wrist undergoing MRI).
7.
Subject has a medical condition precluding a contrast MRI with gadolinium 
(i.e., nephrogenic systemic fibrosis, previous anaphylactic/anaphylactoid reaction 
to gadolinium containing contrast agent, pregnancy or breastfeeding, severe renal 
insufficiency with an estimated Glomerular Filtration Rate [eGFR] below 
30 mL/min/1.73 m2, hepato-renal syndrome, severe chronic liver function 
impairment).
8.
Subject has been treated with any investigational drug of chemical or biologic 
nature within a minimum of 30 days or 5 half-lives (whichever is longer) of the 
drug prior to the Screening Visit.
9.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Screening Visit or oral anti-infectives within 14 days prior to 
the Screening Visit.
10.
Prior exposure to biologics that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML) (i.e., natalizumab [Tysabri®], 
rituximab [Rituxan®], or efalizumab [Raptiva®]) or prior treatment with 
cyclophosphamide.
11.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
12.
History of invasive infection (e.g., listeriosis and histoplasmosis), human 
immunodeficiency virus (HIV).
13.
Subjects with any active viral infection that based on the Investigator's clinical 
assessment make the subject an unsuitable candidate for the study.

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50
14.
Hepatitis B:  HBs Ag positive (+) or detected sensitivity on the hepatitis B 
(HBV)-DNA PCR qualitative test for HBc Ab/HBs Ab positive subjects 
(Section 5.3.1.1).
15.
Chronic recurring infections or active TB.
16.
Subject currently uses or plans to use anti-retroviral therapy at any time during the 
study period.
17.
History of moderate to severe congestive heart failure (New York Heart 
Association [NYHA] class III or IV), recent cerebrovascular accident and any other 
condition which would put the subject at risk by participation in the study.
18.
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.
19.
History of clinically significant drug or alcohol abuse in the last 12 months.
20.
Clinically significant abnormal screening laboratory results as evaluated by the 
Investigator.
21.
Positive pregnancy test at Screening or Week 0.
22.
Female subjects who are breastfeeding or considering becoming pregnant during 
the study.
23.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
Rationale for Exclusion Criteria
1 – 5
To select the adequate subject population for this study
6 – 20, 23
For the safety of the study subjects
21, 22
The impact of adalimumab on pregnancies is unknown

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The Investigator should contact the AbbVie study designated physician if there are any 
questions regarding inclusion and exclusion criteria and eligibility.
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of screening, 
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 eCRF.
The AbbVie Study Designated Physician identified in Section 6.1.5 Adverse Event 
Reporting 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, anti-neoplastics, or other drugs which have a risk of malignancy as 
stated in their label and other relevant dosing information to estimate total exposure will 
be collected in the source documents and appropriate eCRF pages.  At the time of the 
reported malignancy adverse event, sites will be asked if any of the prior and concomitant 
medications contributed to the event.  Any medications used prior to the study will be 
captured on the appropriate eCRF.  Information on the reason for use, date(s) of 
administration including start and end dates, highest maintained dose, dosage information 
including dose, route and frequency, and reason for stopping the medication will be 
collected in the source documents and appropriate eCRF pages.
5.2.3.1
Prior Therapy
All prior drug therapies for RA including csDMARDs and bDMARDs since initial 
diagnosis, must be recorded on the source documents and on the appropriate eCRF along 
with the dates of first and last dose, dosage/maximum dosage taken, route of 
administration and reason for use and for discontinuation, if known.

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For each subject that is screened for the study, any other medication (including, but not 
limited to, over-the-counter medicines such as aspirin, antacids, vitamins, mineral 
supplements, and herbal preparations) taken 4 weeks prior to Week 0 Visit and throughout 
the end of the study must be recorded on the appropriate eCRF along with the date(s) of 
administration, reason for use, dosage, route and frequency.
Adalimumab use for ≥ 12 months prior to Week 0 Visit is required per protocol; date of 
first use, dosage, maximum dosage and reason for use as well as RA disease activity score 
at time of first dose and all subsequent disease activity assessments (if available) should 
be documented and must be recorded on the appropriate eCRF.  A maximum of 
2 non-consecutive adalimumab injections could have been skipped over the last 
12 months but not during the 12 weeks prior to the Week 0 Visit.  Reason(s) for a 
previously missed dose should be documented and cannot be due to an intentional 
tapering of medication (e.g., infection, surgery, lack of medication).  Also there must be 
no evidence of DAS28 ≥ 2.6 during the last 6 months prior to screening as per exclusion 
criteria.  A discussion with Study Designated Physician is recommended.  MTX use at a 
stable dose (any dose; oral, sc or im) for ≥ 12 weeks prior to Week 0 Visit is required for 
at least 80% of subjects recruited; for those subjects on concomitant MTX, date of 
first use, dosage, maximum dosage and reason for use as well as RA disease activity score 
at time of first dose and all subsequent disease activity assessments (if available) should 
be documented and must be recorded on the appropriate eCRF.  A decrease in the dose of 
MTX due to an event of tolerability (or other safety) related with MTX is allowed during 
the 12 weeks period prior to the Week 0 Visit and throughout the study as long as well 
documented.
Subjects who are not taking MTX in a stable dose for ≥ 12 weeks prior to Week 0 can be 
enrolled (up to 20% of overall study population) as long as their allowed csDMARD 
treatment has been stable for at least 12 weeks prior to Week 0 or if not treated with a 
csDMARD this regimen is stable for at least 12 weeks prior to Week 0 Visit.  In these 
cases, csDMARD date of first use, dosage, maximum dosage and reason for use as well as 
RA disease activity score at time of first dose and all subsequent disease activity 

Adalimumab
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assessments (if available) should be documented and must be recorded on the appropriate 
eCRF.  A decrease in the dose of csDMARD due to an event of tolerability or other safety 
related is allowed during the 12 weeks period prior to the Week 0 Visit and throughout the 
study as long as well documented.
When no csDMARDs has been used for at least 12 weeks prior to Week 0 Visit, date and 
reasons for stopping previous csDMARDs must be recorded in the eCRF.  The allowed 
RA concomitant medications should be kept stable throughout the Lead-In and 
Double-Blind Periods of the study.
5.2.3.2
Concomitant Therapy
Each vaccine and all medications except study drug, administered to a subject during the 
study should be recorded in the eCRF as a concomitant medication.  All concomitant 
medications will be provided by local prescription.
Methotrexate:
All subjects who were on MTX at inclusion must maintain a stable dose (any dose; oral, 
intra-muscular or sc) from the 12 weeks prior to Week 0 Visit and throughout the study in 
the randomized double-blind arms.  In the event of tolerability (or other safety) issues 
related with MTX, the doses can be decreased and/or resumed as needed during the study 
and these changes documented.
Other Disease-Modifying Antirheumatic Drugs (DMARDs), Corticosteroids or 
Other Medications for RA:
Allowed other concomitant csDMARDSs (chloroquine, hydroxychloroquine, 
sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and 
aurothioglucose] and leflunomide) must be at a stable dose for at least 12 weeks prior to 
Week 0 Visit and at a stable dose throughout the study in the randomized double-blind 
arms.  In the event of tolerability (or other safety) issues related with the csDMARDs, the 
doses can be decreased and/or resumed as needed during the study and these changes 
documented.

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Concomitant use of oral corticosteroids (< 10 mg/day oral prednisone or equivalent) is 
allowed during the study and should be kept at a stable dose from 4 weeks prior to 
Week 0 Visit and throughout the study in the randomized double-blind arms.
Concomitant use of oral NSAIDs, tramadol or other equivalent opioids and non-opioid 
analgesics is allowed during the study and should be kept at a stable dose and/or 
therapeutic scheme from 4 weeks prior to Week 0 Visit and throughout the study in the 
randomized double-blind arms.  In the event of tolerability (or other safety) issues, the 
doses of NSAIDs may be skipped, decreased and/or resumed as many times as needed 
during the study.  On the days that subjects are scheduled to be seen in clinic, no regularly 
scheduled NSAIDs should be used within 12 hours of the subject's clinic visit.
Doses of all the RA treatment concomitant medications must remain stable throughout 
study participation (except as medically required due to an AE and in the rescue therapy 
arm; Section 5.3.4.1.2).
Folic acid supplementation during the study treatment period:  All subjects treated with 
concomitant MTX should take a dietary supplement of oral folic acid 5 mg once weekly 
or per local guidelines per the investigator's discretion throughout the treatment period.  
Folate should not be administered on the day that MTX study medication is taken, nor on 
the following day.
For subjects who require isoniazid (INH) for TB prophylaxis consideration should be 
given to administer pyridoxine (Vitamin B6) to prevent peripheral neuropathy.
MTX, folic acid and any other concomitant RA medications will be received by local 
prescriptions.
The AbbVie Study Designated Physician should be contacted if there are any questions 
regarding concomitant or prior therapy(ies).

Adalimumab
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5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:
●
All bDMARDs with a potential therapeutic impact on the disease being 
studied including but not limited to the following:
○
Infliximab (Remicade®);
○
Etanercept (Enbrel®);
○
Ustekinumab (Stelara®);
○
Natalizumab (Tysabri®);
○
Anakinra (Kineret®);
○
Abatacept (Orencia®);
○
Rituximab (Rituxan®);
○
Tocilizumab (Actemra®);
○
Golimumab (Simponi®);
○
Certolizumab (Cimzia®);
○
Belimumab (Benlysta®);
○
Infliximab biosimilar(s) (Remsima®, Inflectra®).
●
Live vaccines (during the study and for 70 days after the last dose of study 
drug).
●
Rifampin/Pyrazinamide combination.
●
Anti-retroviral therapy.
●
Other than allowed csDMARDs (e.g., azathioprine, cyclophosphamide, 
d-penicilamine).
●
Opioid analgesics (other than tramadol or other equivalent opioid analgesics) 
or marijuana.
●
Any investigational drug of chemical or biologic nature.
●
Medications that may have potential for drug interaction with MTX should be 
administered with caution and careful ongoing monitoring.

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On the days that subjects are scheduled to be seen in clinic, no opiates/analgesics 
(including regularly scheduled NSAIDs) should be used within 12 hours of the subject's 
clinic visit.
Subjects may be discontinued from the study if any of the above prohibited medications 
are used during the study.
Contact the AbbVie Study Designated Physician identified in Section 6.1.5 if there are 
any questions regarding prohibited therapy(ies).
5.2.3.4
Rescue Therapy
The Open-Label Rescue Arm consists of adalimumab 40 mg eow as detailed in 
Section 5.1.
During the Open-Label Rescue Arm, it is at the Investigator's discretion to initiate or 
change the subject's following concomitant medications for RA:
●
NSAIDs
●
Analgesics
●
Corticosteroids (in a dose up to a maximum of 15 mg oral prednisolone or 
equivalent/day and up to 3 injections i.a. within the follow-up period of 
16 weeks)
●
csDMARDs including MTX (initiation and/or dose or administration mode 
change) and excluding not allowed csDMARDs (e.g., azathioprine, 
cyclophosphamide, d-penicilamine)
All concomitant medications should be documented in the eCRF.  If additional RA 
medications are required, the Study Designated Physician must be contacted.

Adalimumab
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5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Immunogenecity and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Subjects will be allowed a visit window of ± 7 days for all study visits (with the exception 
of the Screening Period, Lead-In Period and the dbBaseline Visit).  For the lead-in period 
and the dbBaseline period a visit window of ± 3 days is recommended.  For exceptional 
cases, the Study designated Physician should be consulted.  If a subject has an out of 
window visit, the next visit should occur as originally scheduled based on the first date of 
study drug administration (Week 0) between Weeks 0 and 4 Visits.  Once the subject is 
randomized, all doses should be based on the date of randomization (Week 4).
All study data will be recorded in the source documents and on the appropriate eCRF.
Study procedures will be performed as outlined in the schematic presented in Table 1.

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Table 1.
Study Activities
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Xb
Medical History
X
X
Alcohol and Nicotine 
Use
X
Full Physical Exam
X
X
Symptom-directed 
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs/Weight/ 
Heightc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
28 and 66 – Swollen 
Joint Count (SJC)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
28 and 68 – Tender 
Joint Count (TJC)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician's Global 
Assessment (PhGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Adalimumab
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Table 1.
Study Activities (Continued)
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Patient's Global 
Assessment (PGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain Visual Analog 
Scale (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sleep Disturbance 
VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stiffness Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Flare Severity 
Assessment 
X
DAS28 (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Assessment 
Questionnaire –
Disability Index 
(HAQ-DI)
X
X
X
X
X
X
X
X
X
X
X
X
X
Functional Assessment 
of Chronic Illness 
Therapy-fatigue 
(FACIT-fatigue)
X
X
X
X
X
X
X
X
X

Adalimumab
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Table 1.
Study Activities (Continued)
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Treatment Satisfaction 
Questionnaire for 
Medication (TSQM)
X
X
X
X
X
X
X
X
X
Work Productivity and 
Activity Impairment 
(WPAI)
X
X
X
X
X
X
X
Short Form-36 (SF-36)
X
X
X
X
X
X
X
X
Routine Assessment of 
Patient Index Data 
(RAPID-3)
X
X
X
X
X
X
X
X
X
X
X
X
X
RAPID-3 for at Home 
Disease Assessment
Xe
Ultrasound 
Assessment
Xf
Xf
Electro Cardiogram 
(ECG)
Xg
Chest X-ray (CXR) 
Xg
MRI
Xi
Xh,i
Xh,i
Xh,i

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61
Table 1.
Study Activities (Continued)
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind 
Baseline becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
TB Screeningj
Xg
HBV Screening
Xg
Pregnancy Tests
Xk
Xl
X
X
X
Chemistry/Hematology
X
X
X
X
X
X
X
X
X
X
ESR 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
RF/ACPA
X
X
X
X
Biomarkersq
X
X
X
X
X
X
X
X
X
Optional Biomarkers 
for additional researchq
X
X
X
X
X
X
X
X
X
Optional 
Pharmacogenetic (PG) 
Sample-DNAm
X
X
X
X
Optional 
Pharmacogenetic 
Sample – ribonucleic 
acid (RNA)m
X
X
X
X
X
X
X
X
X

Adalimumab
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62
Table 1.
Study Activities (Continued)
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Blood samples for PKn
X
X
X
X
X
X
X
X
X
X
Blood samples for 
AAAn
X
X
X
X
X
X
X
X
X
X
Antinuclear antibodies 
(ANA)/Double 
stranded 
deoxyribonucleic acid 
(dsDNA)
X
X
X
X
Urinalysiso
X
X
X
X
X
X
X
X
Monitor Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and Concomitant 
Therapy Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
Enrollment
X
Randomization
X
Dispense Study Drug
X
Xr
X
X
X
X
X
X
X
X
dbBaseline = Double-Blind Baseline; ET = Early Termination; UV = Unscheduled Visit; F/U = Follow-Up

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Table 1.
Study Activities (Continued)
a.
Screening must include a documented DAS28 (ESR) assessment prior to the Lead-In Period.  An additional DAS28 (ESR) assessment must be completed at dbBaseline 
Week 4 in the Lead-In Period to confirm inclusion in the trial.
b.
Before study drug administration, all inclusion and exclusion criteria should be re-confirmed based on assessments completed during the Screening period.
c.
Height will be measured at Screening only.  Weight will be measured at Screening and Final/Early Termination Visit.
d.
For those subjects who have entered the study at Week 0 but are early terminated before the Week 4 visit, a short Early Termination visit is allowed.  This visit would include 
reason for discontinuation, review of adverse events, and investigational product/diary return.  This will be followed by a 70-day follow-up call/visit.  Additional assessments 
are allowed per the Investigator's discretion.
e.
Subjects are given a questionnaire to take home and fill out every week after flaring to be returned to the site at each visit.
f.
US Gray Scale and Power Doppler with a systematic longitudinal and transverse multiplanar examination of 46 joints and 18 tendon/tendon compartments.  US will be 
performed on all subjects at sites that participate in the US assessment.  Ultrasound can be performed in the Lead-In Period or at the Double-Blind Baseline Visit prior to 
randomization. 
g.
Not required if subject has documented assessment within 12 months of Screening and meets inclusion and none of the exclusion criteria.  If there is no evidenceor if there is 
doubt in the results, then they need to be assessed at Screening.  A CXR may be required for evaluation of active TB.
h.
To be completed if ≥ 12 weeks after last MRI.  
i.
High-field adequate contrast MRI of the most affected or dominant hand (2 – 5 metacarpophalangeal joints [MCP]) and wrist (if both sides are considered equally affected) 
must be confirmed at dbBaseline that it was received and marked as complete by the Central Reader.
j.
A repeat TB test must be performed one year after the date of the previous test (± 2 months).  The repeat TB test can occur at any visit. 
k.
All females of childbearing potential will have a serum pregnancy test at Screening.
l.
All females of childbearing potential will have a urine sample collected at the Week 0 visit prior to study enrollment and atstudy discontinuation/completion.  The samples 
will be tested locally by designated study personnel.  Monthly pregnancy tests will be performed throughout the study if required by country regulatory authorities.  Any 
subject with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior to enrollment or continuation in the study.  Investigators 
may conduct more frequent urine pregnancy testing as necessary according to their judgment.
m.
Subjects will sign a separate informed consent if they agree to participate in pharmacogenetic research.
n.
PK and AAA samples are to be drawn prior to study drug injection.
o.
Dipstick urinalysis will be completed by the central lab at all required visits.  A microscopic analysis will be performed inthe event the dipstick results show protein, ketones 
or blood greater than negative or glucose greater than normal.

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Table 1.
Study Activities (Continued)
p.
If the subject has a confirmed flare in a scheduled or unscheduled visit during the Double-Blind Period, this visit then becomes the Flare Week 0 Visit.
q.
Biomarkers are to be drawn prior to study drug injection and will be evaluated per Table 2.  Additionally, (and only for subjects who consent) samples will be banked for 
future research.
r.
The dbBaseline injection should occur at the site.

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5.3.1.1
Study Procedures
General Guidance for Visits
At any visit, the study procedures must always start with the ESR blood test (except for 
the Screening Visit when the Informed Consent must be obtained) so that within the time 
frame of the visit the result will be used for the DAS28 (ESR) assessment.
Informed Consent
An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved, 
study-specific informed consent will be reviewed, signed and dated by the subject or their 
legally authorized representative before any study-related procedures are undertaken, or 
before any medications are withheld from the subject in order to participate in this study.  
Participation in further then pre-specified biomarker research analysis is optional, as 
indicated in the main consent.  A separate consent is required from each subject in order 
to participate in the optional pharmacogenetic analysis.  Details about how informed 
consent will be obtained and documented are provided in Section 9.3.
Inclusion/Exclusion Criteria
Subject will be eligible for study enrollment if he/she meets all inclusion criteria and none 
of the exclusion criteria at both the Screening and Week 0 of the Lead-In Period.
At the dbBaseline Visit (Week 4), in order for the subject to be randomized, another 
4 variables DAS28 (ESR) must be completed and fulfill the requirement of < 2.6.  The 
ESR from the dbBaseline Visit must be used for this assessment.  If the subject does not 
meet the DAS28 (ESR) requirement of < 2.6 at the dbBaseline (Week 4), the subject must 
be discontinued from the trial.  
Medical and Surgical History
A complete non-RA related and/or co-morbidities medical and surgical history, as well as 
history of tobacco and alcohol use, will be obtained from each subject during the 
Screening Visit.  A list of each subject's specific RA related medical and surgical history, 

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including disease duration, prior treatments, disease activity at diagnosis (if available) and 
at initiation of adalimumab, time to and duration of remission after initiating adalimumab, 
time on adalimumab, should be recorded at Screening.  Additionally, if available from the 
last 12 months, detailed documentation referring to TB screening and/or liver 
transportation (LT) prophylaxis, chest x-ray, ECG and hepatitis B screening will be 
recorded at Screening.  An updated medical history will be obtained prior to study drug 
administration at Day 1 of Lead-In and updated as necessary throughout the study on the 
eCRF.
A detailed medical history with respect to TB exposure needs to be documented.  This 
information needs to include Bacillus Calmette-Guérin (BCG) vaccination, cohabitation 
with individuals who have had TB, and/or who reside or work in TB endemic locations.
Physical Examination
A complete physical exam will be performed at the designated study visits in Table 1.  
Physical examination findings that are related or part of each subject's medical history 
should be captured on the appropriate eCRF page.  The physical exam at the dbBaseline 
Visit will serve as the dbBaseline exam for the entire study.
A symptom-directed physical examination can be performed at any other visits if, in the 
opinion of the Investigator, it is warranted by the subject's AE status or on review of 
symptoms.  Any clinically significant physical examination findings after dosing should 
be recorded as adverse events.
Vital Signs/Weight/Height
Vital sign determinations of sitting blood pressure, heart rate, respiratory rate and body 
temperature will be obtained at each visit.  Each subject's height will be measured at the 
Screening Visit only.  Each subject's weight will be measured at the Screening and 
Final/Early Termination visits.  All measurements will be recorded in metric units where 
applicable.

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Tender Joint Count (TJC) and Swollen Joint Count (SJC) Assessment
Swollen Joint Count
An exam of 66 joints (Appendix E) will be performed at the Screening Visit and all 
subsequent study visits.  The joints to be examined for swelling are the same as those 
examined for tenderness, except the hip joints are excluded.  Joint swelling will be 
classified as present ("1"), absent ("0"), replaced ("9"), or no assessment ("NA").  For 
DAS28 (ESR) calculation, the 28 joints assessment will be used (Appendix F).
Tender Joint Count
An exam of 68 joints (Appendix E) will be performed at the Screening Visit and at all 
subsequent study visits by pressure and joint manipulation.  Joint pain/tenderness will be 
classified as present ("1"), absent ("0"), replaced ("9"), or no assessment ("NA").  For 
DAS28 (ESR) calculation, the 28 joints assessment will be used (Appendix F).
The TJC and SJC should be performed by the clinical assessor who will be blinded to the 
subject's MRI and US results.  It is the responsibility of the Principal Investigator to 
ensure all assessors are qualified to perform joint assessments.  If possible, each subject 
should have the same assessor throughout the study as much as possible.
Physician's and Subject's Global Assessment and Assessment of Pain Sleep 
Disturbance by Visual Analog Scale (VAS)
VAS will be used to assess the physician's and subjects global assessment of disease 
activity and the subject's assessment of pain.  Each VAS consists of a horizontal 100 mm 
line anchored at either end by opposite adjectives reflecting the spectrum/severity of the 
parameters assessed:

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●
Physician's global assessment of disease activity (current status)
The Physician will rate global assessment of subject's current disease activity 
ranging from 0 to 100 (see example below):
Mark the line below to indicate the subject's rheumatoid arthritis disease 
activity (independent of the subject's self-assessment).
0
100
Very Low
Very High
●
Subject's global assessment of disease activity (within last 24 hours)
The subject will rate the severity of the RA symptoms and how he/she is doing 
from 0 to 100.  This assessment will be used for the DAS28 (ESR) calculation 
in this study (see example below):
Please place a vertical mark on the line below to indicate how well your 
rheumatoid arthritis has been doing during THE LAST 24 HOURS:
0
100
Very Well
Very Poorly
●
Subject's assessment of pain (within last week)
The subject will rate the severity of pain from 0 to 100 (see example below):
Please place a vertical mark on the line below to indicate how much pain you 
have had due to rheumatoid arthritis IN THE PAST WEEK:
0
100
No Pain
Severe Pain

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●
Subject's assessment of sleep disturbance (within last week)
The subject will rate the severity of sleep disturbance from 0 to 100 (see 
example below):69
How much of a problem has sleep (i.e., resting at night) been for you IN THE 
PAST WEEK?
Please place a vertical mark on the line below that best describes how much of 
a problem sleep has been for you on a scale of 0 – 100.
0
100
Sleep is no 
problem
Sleep is a 
major 
problem
The VAS assessments are to be performed at all study visits beginning at the dbBaseline 
Visit.
Morning Stiffness Assessment
Duration of morning stiffness reported by subjects as the average daily length during the 
past week in minutes (from time of awaking to time of maximal improvement) will be 
captured in the eCRF.70
Severity of subject's morning stiffness will be assessed by a numeric rating-scale (NRS) 
with a 0 to 10 score range on the below self-reported questionnaire:71
●
Subject's assessment of morning stiffness severity (within last week)
The subject will rate the severity of morning stiffness from 0 to 10 in a 
numeric rating-scale where 0 is "not severe" and 10 is "very severe" (see 
example below):

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Please place an "X" in the box below to indicate how severe was your morning
stiffness IN THE PAST WEEK:
0
1
2
3
4
5
6
7
8
9
10
Not Severe
Very 
Severe
DAS28 (CRP) and DAS28 (ESR)
The 4 variables DAS28 (ESR)29,72 will be completed at all designated study visits listed in 
Table 1.  The DAS28 (ESR) should be calculated using all parameters including ESR 
from the current visit.
The 4 variables DAS28 (ESR) calculation used for study eligibility, enrollment and 
monitoring will be calculated by the eCRF as below.  Upon discussion with the SDP, the 
3 variable DAS28 (ESR) can be used during the trial to evaluate flare if the PGA score is 
not available.  For the purpose of chart review for study eligibility and inclusion, the 
3 variable DAS28 (ESR) can be used when the Subject's Global Assessment of Disease 
Activity (PGA) is not available.
4 variables DAS28 (ESR):
DAS28-ESR(4) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × natural logarithm 
(ln)(ESR#) + 0.014 × Global Health (GH»)
3 variables DAS28 (ESR):
DAS28-ESR(3) = [0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × ln(ESR#)] × 1.08 + 
0.16
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
#
ESR refers to Erythrocyte Sedimentation Rate evaluated at the site at current visit and expressed in mm/hr 
(1st hour).
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).

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4 or 3 (if PGA is not available) variables DAS28 (CRP)29 maybe calculated based on 
patient chart review for study Screening as below:
4 variables DAS28 (CRP):
DAS28-CRP (4) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(CRP&+1) + 0.014 
× GH» + 0.96
3 variables DAS28 (CRP):
DAS28-CRP (3) = [0.56 × √ (TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(CRP& + 1)] ×
1.10 + 1.15
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
CRP refers to the c-reactive protein lab value.  CRP unit in the DAS28 (CRP) equation is expressed as mg/L.
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).
Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI)
CDAI73 and SDAI73,74 will be completed at visits according to the scheduled in Table 1.  
The SDAI and CDAI will be calculated as part of the statistical analysis using all 
parameters including CRP from the same visit (and as such calculated at the next Visit).
SDAI = (28TJC*) + (28SJC*) + PhGA**" + PGA« + CRP&
CDAI = (28TJC*) + (28SJC**) + PhGA" + PGA***
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
"
PhGA refers to Physician's global assessment of disease activity.
&
CRP refers to the c-reactive protein lab value.  CRP unit in the DAS28 (CRP) equation is expressed as mg/L.
*** PGA refers to the Subject's Global Assessment of Disease Activity (PGA).

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Other Patient Reported Outcomes
Subjects will complete the following questionnaires according to the schedule in Table 1:
●
Health Assessment Questionnaire – Disability Index (HAQ-DI)75 to assess the 
physical function and health-related quality of life of each subject 
(Appendix G).
●
Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-fatigue)76
to assess current fatigue as it's part of the RA symptoms and frequently 
associated with flaring (Appendix H).
●
Treatment Satisfaction Questionnaire for Medication (TSQM)77 to assess 
satisfaction with current RA treatment (Appendix I).
●
Work Productivity and Activity Impairment (WPAI)78 to assess impact of RA 
on work productivity and non-work activity limitation (Appendix J).
●
Short Form-36 Health Survey Questionnaire (SF-36),79 a general measure to 
assess health and well-being (Appendix K).
Flare Severity Assessment
At the Flare Week 0 Visit, severity of flare80 as assessed by a numeric rating-scale (NRS) 
with a 0 to 10 score range will be recorded:
●
Physician's assessment of Flare severity
Physician will rate the severity of flare from 0 to 10 as follows:
0
1
2
3
4
5
6
7
8
9
10 
Not Severe
Very 
Severe
●
Subject's assessment of Flare severity
Subjects will rate the severity of their flare from 0 to 10 in a numeric 
rating-scale where 0 is "not severe" and 10 is "very severe" (see example 
below):

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Please make an "X" on the box below to indicate how severe your flare is:
0
1
2
3
4
5
6
7
8
9
10 
Not Severe
Very 
Severe
RAPID 3 at Office and In-Home Disease Assessment
Routine Assessment of Patient Index Data (RAPID-3)81 a validated disease activity score 
assessing physical function, patient global assessment for pain and patient global health 
will be completed at each scheduled visit (Appendix L).
Additionally, at the Flare Week 0 visit, subjects will be given a RAPID-3 questionnaire 
assessment and asked to complete the answers weekly at home without calculating the 
scores (and return at each visit thereafter) until Flare Week 16.
Musculoskeletal Ultrasound (US) 
Investigators will, at study start indicate, state if they want to participate in the optional 
US assessments or not.  If they decide to and the pre-requirements criteria are met (as per 
the Ultrasound manual), they should perform US for every subject they recruit at time 
points indicated by the protocol; exceptions are allowed upon discussion with Study 
Designated Physician.  For sites participating in the ultrasound assessments, all subjects 
from the site should undergo the US scans and assessments as per protocol;
For the sites participating in the optional US assessment, high-end ultrasound equipment 
is recommended.  The US must be performed by a Rheumatologist with Ultrasonography 
verifiable training and/or certification and at least 3 years of regular US experience; prior 
experience in multicenter ultrasound study(ies) is recommended, otherwise training will 
be provided.  The Ultrasonographer must be independent of the clinical Investigator and 
will be blinded for subject characteristics; he/she should be the same person throughout 
the study, and a back-up with same qualifications should be appointed.  All personnel who 
perform study-related US examinations must have been previously trained by the sponsor 
or sponsor representative as part of this study.  The assessments and scoring will be 

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locally performed and afterwards the report of US assessments from all subjects will be 
sent to the central Imaging vendor.  For the first subject enrolled and for the first subject 
with flare assessments further procedures for quality assessment are required (as per 
ultrasound manual).  US should be done after clinical examination and prior to injecting 
study medication.  It is recommended that subjects are in rest for around 2 hours and have 
not been drinking coffee or smoking (for the last 8 hours) or taking NSAIDs (for the last 
12 hours) prior to the US assessment.
The optional US will be performed during the Lead-In Period or at the dbBaseline Visit 
prior to randomization and at Flare Week 0 Visit (when applicable and at or up to 7 days 
after the visit) to assess synovial hypertrophy, tenosynovitis and erosions through gray 
scale ultrasonography (GSUS) and synovitis/vascularization through Power Doppler 
Ultrasonography (PDUS).
The US assessment will consisted of a systematic longitudinal and transverse multiplanar 
examination of 46 joints and 18 tendon/tendon compartments:
●
The following bilateral joints were investigated for the presence of 
intra-articular B-mode synovial hypertrophy (SH) and synovial Power Doppler 
(PD) signal:  glenohumeral (i.e., posterior and axillary recesses and biceps 
sheath), elbow (i.e., anterior, posterior and lateral recesses), wrist 
(i.e., radiocarpal, midcarpal, and distal radioulnar joints; dorsal recesses), 
first through fifth metacarpophalangeal (MCP) (i.e., dorsal recesses), 
first through fifth proximal interphalangeal (PIP) of the hands (i.e., dorsal and 
palmar recesses), hip (i.e., anterior recess), knee (i.e., anterior and parapatellar 
recesses), ankle joints (i.e., anterior, lateral, and medial recesses of tibiotalar 
joint; and medial and lateral recesses of subtalar joint), and second through 
fifth metatarsopharlangeal joints (i.e., dorsal recess).
●
The following bilateral tendon will be assessed for GS and Doppler 
tenosynovitis 2nd, 4th and 6th extensor compartments at the wrist,
2nd – 5th finger flexor tendons, tibialis posterior and peroneal tendons.

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The 46-joint assessment complemented with 18 tendon compartments assessment will 
provide more data than the reduced scoring and potentially increase sensitivity to change 
and correlate with risk of flare.82,83
Synovial hypertrophy (SH), synovial power Doppler (PD), GS and Doppler tenosynovitis 
will be defined and scored according to the Outcome Measures in Rheumatology Clinical 
Trails (OMERACT) as per more details provided in Appendix N.  Sites participating must 
have the qualified personnel as well as available US machines meeting the minimum 
requirements as described together with more detailed instructions including the scoring 
system in a separate US manual.
12-Lead Electrocardiogram (ECG)
If this is not available, a resting 12-lead ECG will be performed at the designated study 
visits in Table 1.  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 Clinical Research 
Associate (CRA) and kept with subject's source documents onsite.
For subjects with a normal ECG taken within 12 months 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 Study Designated Physician before enrolling the subject.  Subjects can have a 
repeat ECG at any time during the study as warranted based on the opinion of the 
Investigator.
Chest X-Ray (CXR)
All subjects will undergo a standard CXR (posterior-anterior [PA] and lateral views) at 
the Screening Visit to rule out the presence of TB or other clinically relevant findings.  
The CXR will not be required if the subject had a previous normal chest x-ray within 

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12 months of Screening, provided all protocol required documentation is available at the 
site (as outlined below).
Subjects can have a repeat CXR at any time during the study as warranted based on the 
opinion of the Investigator.
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 
(1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.
Magnetic Resonance Imaging (MRI)
An MRI of the most affected or of the dominant hand (2nd to 5th MCP) and wrist (if both 
sides are considered equally affected) will be performed to all subjects during the Lead-In 
Period (prior to dbBaseline Visit) and the Final/Early Termination Visit (if last MRI 
≥12 weeks before).
In order to assess inflammatory as well as destructive changes in RA joints, High-field 
MRI with gadolinium will be performed.
A central imaging laboratory designated by AbbVie will analyze the required digital 
images and the OMERACT RAMRIS scoring for synovitis, erosions, BME and 
tenosynovitis will be calculated.
MRI assessors will be blinded for subject characteristics and the clinical assessors will be 
blinded for MRI scores in order to maintain the independence of the results and allow for 
an association analysis.
Procedures for MRI requirements, sequences and digital imaging processing to the vendor 
will be provided in a separate manual and in Appendix M.

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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 Bacille Calmette-Guérin (BCG) administration.
Subjects that have a negative PPD or IGRA test and are considered at risk for having 
latent TB (any immunosupressed patient with a strong suspicion of TB exposure and no 
prior vaccination with Bacille Calmette-Guérin) need to be evaluated by a TB expert 
before Week 0.
Subjects at risk for TB exposure are defined as:
●
subjects that have household contact with a person with active TB
●
subjects living in areas with high incidence of TB
●
subjects that frequently visits areas with high prevalence of active TB 
If a subject had a negative PPD or IGRA test within 12 months 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 Study Designated Physician.
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."

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Subjects who have had an ulcerating reaction to a PPD skin test in the past should 
not be re-exposed and should not be tested at Screening but will be considered 
PPD positive.
If there are sites where the accepted testing materials are not available an 
alternative may be substituted, but the method must be submitted and approved by 
AbbVie prior to use with study subjects.
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 
1) calcified granulomas, 2) pleural scarring/thickening, and 3) signs of active TB. The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.  If the CXR demonstrates changes suggestive of previous TB 
(e.g., calcified nodule, fibrotic scar, apical or basilar pleural thickening) or other findings 
that are clinically significant, the Principal Investigator must contact the AbbVie Study 
Designated Physician before enrolling the subject.
If the PPD or the IGRA test is positive or the subject has a CXR or TB expert opinion 
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 the United 
States Center for Disease Control (CDC) and Prevention 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.  The prophylactic treatment must be maintained during the 
study until its recommended full course is completed.
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.

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In the event both a PPD test and an IGRA test are performed, the result of the IGRA test 
will supersede the result of the PPD test.  If the IGRA test is indeterminate, the site should 
repeat the test with another blood sample or perform a PPD test.  If the second IGRA test 
is also indeterminate, the subject is considered to be positive and should initiate TB 
prophylaxis.
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.
Annual TB Testing:
For subjects with a negative TB test at Screening (or within the last 12 months of 
Screening), either an annual PPD or IGRA test will be required for any subject 
participating in the trial 52 weeks after their last TB test (± 2 months).  If the annual TB 
screen is positive (PPD is positive or the IGRA test is positive), a CXR may be required 
for evaluation of active TB.  For any subject with a positive annual TB screen, the site 
should contact the AbbVie Study Designated Physician for further discussion.  Subjects 
found to have latent TB, will be required to start a course of CDC recommended 
prophylaxis or prophylaxis per local guidelines as soon as possible.  Any positive TB 
screen after the subject has started the study, should be reported as an AE.
An annual TB screen with PPD or IGRA testing will not be required for subjects who 
have been treated for latent or active TB or have had a positive TB test (PPD or IGRA) at 
any time (prior to the study, Screening, annual evaluation, or testing performed at any 
time point during the study).  For such subjects, annual evaluation by a physician for 
clinical signs/symptoms of active TB (including a directed TB history and physical exam 
including lungs, lymph nodes and skin) or newly identified TB risk factors will be 
required 52 weeks after the previous TB test.  For any subject with clinical 
signs/symptoms of active TB or newly identified TB risk factors, a CXR may be required 
for evaluation of active TB, and it is recommended to contact the Study Designated 
Physician for further guidance.

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Hepatitis B Testing
If a subject had a negative hepatitis B virus (HBV) result within 12 months prior to 
Screening and all protocol required documentation is available, these tests repetition are 
not required.  At screening subjects must be assessed for high risk of exposure to 
hepatitis B since their last test.  If high risk is suspected, a hepatitis B test should be 
performed.
If not or no proper documentation is available all the following procedures are requested:
●
Subjects will be tested for the presence of 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).  If test results are positive for HBc Ab or HBs 
Ab, HBV DNA PCR will be performed and any result that meets or exceeds 
detection sensitivity will be exclusionary.
Pregnancy Tests
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential.  At the Week 0 Visit, subjects of childbearing potential will have a 
urine pregnancy test performed locally by designated study personnel.  Investigators may 
conduct more frequent urine pregnancy testing as necessary according to their judgment.  
If any urine pregnancy test is positive, a serum pregnancy test will be performed by the 
central laboratory.  A lactating or pregnant female will not be eligible for participation or 
continuation in this study.
All women of childbearing potential will have a repeat urine pregnancy test at the Final 
Study Visit performed locally by designated study personnel.

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Laboratory Tests
Blood and urine samples will be obtained for clinical laboratory tests.  Samples will be 
obtained at the designated study visits in Table 1.  Samples will be obtained for the 
laboratory tests listed in Table 2.
When blood draws are performed as part of a clinic visit, the draws should be performed 
after completion of questionnaires and vital sign measurements, and before study drug 
administration.  Urine samples will be obtained for macroscopic urinalysis (dipstick done 
at the central laboratory which will include specific gravity, pH, protein, glucose, ketones, 
blood and nitrites) and a microscopic urinalysis at Screening.  For all other visits that 
require a urinalysis, the central laboratory will perform a urine dipstick analysis and if the 
results are abnormal, the central laboratory will perform a microscopic urinalysis.
If needed, according to previous sections, blood samples for hepatitis B will be obtained 
at Screening Visit only.  A subject will not be eligible for study participation if test results 
indicate chronic or current hepatitis B infection.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  The central laboratory chosen for this study will provide instructions 
regarding the collection, processing and shipment of appropriate samples.
The laboratory results will be provided by the central laboratory to the investigative site 
where they will be reviewed, signed and dated by the Investigator and filed as source data.  
For any abnormal value outside of the reference range, the Investigator will indicate on 
the report if the result is clinically significant (CS) or not clinically significant (NCS).  All 
abnormal laboratory test results that are considered clinically significant by the 
Investigator will be followed to a satisfactory resolution.

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Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Red Blood Cell 
(RBC) count
White Blood Cell 
(WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count 
(estimate not 
acceptable)
Blood Urea Nitrogen 
(BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol (total, HDL, 
LDL)
Total protein
Glucose
Triglycerides
Specific gravity
Ketones
pH
Protein
Glucose
Leukocytes
Nitrite
Blood
ESR
CRP
RF Immunoglobulin M (IgM)
ACPA
ANA
Anti dsDNA
Serum pregnancy (Human 
Chorionic Gonadotropin 
[bHCG]) testing
Hepatitis B surface antigen (if 
applicable)
Quantiferon-TB Gold (if 
applicable)
Biomarkers
Matrix metalloproteinase 3 
(MMP-3)
Type I Collagen neo-epitope 
(C1M)
Type III collagen neo-epitope 
(C3M)
Matrix metalloproteinase 
mediated c-reactive protein 
(CRPM)
Matrix metalloproteinase-
degraded citrullinated 
vimentin (VICM)
Serum amyloid-associated 
protein (SAA)
Interleucin-6 (IL-6)
Chemokine (C-X-C motif) 
ligand 10 (CXCL-10)
Chemokine (C-X-C motif) 
ligand 13 (CXCL-13)
Pharmacogenetic DNA/mRNA 
(Optional) 
Additional biomarkers 
(Optional)

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Biomarker Laboratory Assessments
Samples will be obtained for biomarker analysis at the designated study visits in Table 1:  
dbBaseline, Week 10, 16, 28, 40, Early Termination Visit, and (if applicable) at Flare 
Weeks 0, 4 and 16 and as described in more detail under Section 5.3.3.  The samples 
collected will be used to evaluate the following biomarkers:
●
MMP-3, C1M, C3M, CRPM, VICM, SAA, IL-6, CXCL-10, CXCL-13
At the time of analysis, other potential biomarkers identified as adding value to predict 
flare in this patient population may be included.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for samples to be stored for possible future research 
of new biomarkers.
Serum Adalimumab Concentrations
Samples will be obtained for serum adalimumab concentrations at the designated study 
visits in Table 1 and described in more detail under Section 5.3.2.
Anti-Adalimumab Antibodies
Samples will be obtained for anti-adalimumab antibodies at the designated study visits in 
Table 1 and described in more detail under Section 5.3.2.
Pharmacogenetic Sample
Samples will be obtained for pharmacogenetic analysis (DNA/mRNA) at the designated 
study visits in Table 1 and described in more detail under Section 5.3.4.
Adverse Events
Adverse events will be assessed at every study visit from the first dose of study drug at 
Week 0 Lead-In through the Final/Early Termination Visit, and during the 70-day phone 
call or clinic visit (if applicable).  Subjects may discontinue adalimumab treatment at any 

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time during study participation.  Subjects that end study participation early will have an 
Early Termination/Final 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 adverse events.  Refer to Section 6.1.4 for additional information.
Prior and Concomitant Therapy Assessment
Any medication that the subject is receiving at the time of Screening or receives during 
the study must be recorded on the source documents as well as the appropriate eCRF.  
Previous prescription medications or physician-administered treatments used for RA prior 
to study entry will be recorded.  See Section 5.2.3 for full details regarding documentation 
of prior and concomitant therapy.
Enrollment
The subject will not be assigned a screening number for this study.  Subject numbers will 
be centrally assigned by the Interactive Response Technology (IRT), in consecutive order 
at each site at Screening.  Each subject will be assigned a unique subject number.
Subjects who meet the inclusion criteria for the Lead-In Period and do not meet any of the 
exclusion criteria will be enrolled in the 4-week Lead-In Period.
Upon confirmation of inclusion criteria including DAS (ESR) < 2.6, all Screening 
laboratory results must be reviewed, signed and dated by the Principal Investigator prior 
to the Lead-In Day 1 visit.  Subjects will not be enrolled into the Lead-In Day 1 period of 
the study if laboratory or other Screening results abnormalities are deemed clinically 
significant by the Principal Investigator.
Randomization
Upon confirmation of the DAS requirements, subjects will be randomized to receive 
either adalimumab 40 mg subcutaneous (SC) at the dbBaseline Visit (Arm 1) followed by 
dosing every 3 weeks until flare or matching placebo (Arm 2) in a 5:1 ratio double-blind 
fashion to the treatment groups.

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Dispense Study Drug
Adalimumab during the Lead-In Period and Open-Label Rescue Arm as well as 
adalimumab/placebo study drug during the Double-Blind Period will be administered to 
subjects by study site medical staff, by him/herself or by a designee (friend, family 
member or health care professional) throughout the study in accordance with Appendix C.
Once the limit of 20% of enrolled subjects on other csDMARDs or no csDMARDs is met, 
only subjects on concomitant methotrexate will be allowed into the trial.
Subjects or a designated family member or friend will be trained to administer study 
medication, if needed or considered appropriate, during the first visit or several times.  
This training must be documented in the subject's source document.
Subjects or a trained designated family member or friend or a health care professional will 
administer the injections of the study medication in the subject's home or in the clinic 
during the weeks the subjects are not in the office for scheduled study visits.
Subjects will maintain a Subject Dosing Diary for all study medication administered 
outside of the study visit (i.e., at home).  The Subject Dosing Diary will be reviewed and 
verified for compliance at each clinic visit.  All relevant dosing information will be 
retained by study personnel.  Additionally, any discernible departure from the protocol 
regarding study drug administration will be documented appropriately.  A sample of the 
Subject Dosing Diary is presented in Appendix D.
For subjects that cannot/will not self-administer study drug or do not have adequate 
support (friend, family member or healthcare professional) at home, administration will 
occur in the clinic.
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, 

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subjects should be instructed to contact the site immediately with any signs or symptoms 
of a reaction.
For subjects who deviate from the dosing schedule, every effort should be made to bring 
the subject back to the original dosing schedule as soon as possible.
The subject must be instructed to return study drug at each clinic visit for the purpose of 
compliance assessment and drug accountability as detailed in Section 5.5.7.
5.3.2
Drug Concentration Measurements
Blood samples for the pharmacokinetic (PK) measurement of serum adalimumab levels 
and anti-adalimumab antibody (AAA) concentrations will be taken at the following visits, 
as specified in Table 1:
●
Blood samples will be collected at dbBaseline, Weeks 10, 16, 28, 40/Early 
Termination Visit.
●
Subjects who flare will have blood samples collected at the Flare Weeks 0, 4, 
10 and 16.
Collection of Samples for Serum Adalimumab Concentration and AAA Analysis
Blood samples for serum adalimumab concentration and AAA will be collected prior to 
dosing by venipuncture into appropriately labeled 4 mL evacuated serum collection tubes 
without gel separator.  Sufficient blood will be collected to provide approximately 2 mL 
serum for the adalimumab assay.  The central laboratory will provide supplies for sample 
collection, processing, storage and shipment.  Please refer to the central laboratory manual 
for specific instructions on sample collection, processing, storage and shipment.  
Additional PK/AAA assays may be analyzed (where allowed by local guidelines).

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5.3.3
Biomarker Measurements
Blood samples for biomarker analysis will be collected at dbBaseline, Weeks 10, 16, 28 
and 40/Early Termination.  Subjects who flare will have blood samples collected at Flare 
Weeks 0, 4 and 16.
Collection of Samples for Biomarker Measurements
Blood samples for biomarker analysis will be collected by venipuncture into an 
appropriately labeled 6 mL evacuated serum collection tube without gel separator.  
Sufficient blood will be collected to yield approximately 2.4 mL of serum for each 
sample.   
In addition, at the time of blood draw for biomarkers, subjects in certain countries (where 
allowed by local guidelines) will have the option for the following samples to be collected 
and stored for possible future research:
A blood sample will be collected by venipuncture into an appropriately labeled 6 mL 
evacuated serum collection tube without gel separator.  Sufficient blood will be collected 
to yield approximately 2.4 mL of serum for each sample.
5.3.4
Pharmacogenetic Measurements
Blood samples for the optional pharmacogenetic (PG) measurement will be taken at the 
following visits, as specified in Table 1:  Blood samples for the optional analysis of DNA 
are collected at dbBaseline and Final/Early Termination Visit.
Blood samples for the optional analysis of RNA is collected at dbBaseline, Weeks 10, 16, 
28, 40/Early Termination.  Subjects who flare will have optional blood samples collected 
at Flare Weeks 0, 4 and 16. 
Collection of Samples for Pharmacogenetic Measurements
For each subject who consents to provide samples for pharmacogenetic analysis:

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●
One 3 mL whole blood sample for DNA isolation will be collected.  The 
sample collection tube will minimally be labeled with "PG-DNA," protocol 
number, subject number and the study visit.
●
Two 2.5 mL whole blood samples for mRNA isolation.  The sample collection 
tubes will be labeled with "PG-mRNA" or "BB-RNA," protocol number, 
subject number and study visit.
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
5.3.4.1
Handling/Processing of Samples
The blood samples for adalimumab, AAA and biomarkers will be handled/processed as 
outlined below.  At the time of blood draw for biomarkers, subjects in certain countries 
(where allowed by local guidelines) will have the option for serum to be stored for 
possible future research.  Subjects will be able to decline storing samples for possible 
future research during the consenting process discussed further in Section 9.3.
5.3.4.1.1
Serum Adalimumab Concentration and AAA Analysis
The blood samples for adalimumab and AAA will be centrifuged within 30 – 60 minutes 
of collection using a centrifuge to separate the serum and should be documented in the 
source document.  Serum samples will be split into two aliquots, both being shipped to the 
central laboratory.  Split-2 aliquots should not be shipped with the split-1 aliquots from 
the same draw.  The serum samples will be transferred using plastic pipettes into screw 
capped polypropylene tubes provided by AbbVie and labeled with the drug name, type of 
sample (serum [SRM]), the protocol number, the subject number, the planned study day, 
and the assay type (PK Split1, PK Split2, AAA Split1, AAA Split2).  Serum samples will 
be frozen within 2 hours after collection and will remain frozen at –20°C or colder until 
shipped and should be documented in the source document.  Sites that do not have access 
to a –20°C or colder freezer will need to ship the samples the day they are collected.

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Additional detailed instructions for the handling and processing of samples will be 
provided from the central laboratory.
5.3.4.1.2
Biomarker Analysis
The central laboratory will provide the supplies for all biomarker sample collection, 
processing, storage and shipment.  Please refer to the central laboratory manual for 
specific instructions on biomarker sample collection, processing, storage and shipment.
Biomarker samples for possible future research will be collected from subjects who 
consent and stored frozen for exploratory analysis of non-genetic biomarkers related to 
the subject's disease, related conditions and/or response to study drug, in terms of 
tolerability and safety.  These samples may also be used for the development of diagnostic 
tests related to the disease.  Results of exploratory analyses, if any, will not be reported 
with the study summary.  AbbVie will store the samples in their Immunology Biobank, 
which is 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).  The samples will only be used for the purposes described 
here and in the informed consent.
5.3.4.1.3
Pharmacogenetic Analysis
Samples (DNA/mRNA) will be shipped frozen to AbbVie or a designated laboratory for 
long-term storage.  The DNA and mRNA samples will be stored in a secure storage space 
with adequate measures to protect confidentiality.  The samples will be retained while 
research on adalimumab (or drugs of this class) continues but no longer than 20 years.
Instructions for the preparation and shipment of pharmacogenetic samples will be 
provided in the laboratory manual.
5.3.4.2
Disposition of Samples
The frozen blood samples will be packed in dry ice sufficient to last 3 days during 
transport and shipped from the study site to central laboratory according to instructions 

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from the central laboratory manual.  An inventory of the samples included will 
accompany the package.  The central laboratory will then ship the samples to AbbVie for 
analysis.
5.3.4.3
Measurement Methods
Serum concentrations of adalimumab, AAA and biomarkers will be determined using 
validated ligand binding methods under the supervision of the Drug Analysis Department 
at AbbVie.
5.3.5
Efficacy Variables
5.3.5.1
Primary Efficacy Variables
The primary explanatory variables are the Baseline hand and wrist synovitis and bone 
marrow edema (BME) RAMRIS scores as well as a composite of both; the dependent 
variable is the occurrence of flare up to Week 40 in the tapering arm.
5.3.5.2
Secondary Variables
Secondary Variables Include the Following:
●
Time to flare
●
Flare severity
●
Proportion of subjects with a flare
●
Subject demographics and clinical disease characteristics at dbBaseline, 
including:
○
Smoking status, co-morbidities, anti-citrullinated peptide antibody (ACPA) 
status, Rheumatoid Factor (RF) status, disease duration, previous treatment 
with csDMARDs or bDMARDs or both, duration of adalimumab therapy, 
remission duration, disease activity, CRP and HAQ
●
Proportion of subjects who regain  clinical remission (defined as DAS28 
[ESR] < 2.6 or defined as DAS28 [ESR] decrease > 1.2 if DAS28 [ESR] was 
less than 2.6 at flare) in the Open-Label Rescue Arm over time
●
Time to regain clinical remission in the Open-Label Rescue Arm

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●
Proportion of subjects with low disease activity (defined as DAS28 [ESR]
< 3.2) in the Open-Label Rescue Arm over time
●
Change from dbBaseline in DAS28 (ESR), Clinical Disease Activity Index 
(CDAI), Simplified Disease Activity Index (SDAI)
●
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI 
and CDAI [DAS28 (ESR) < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8]) throughout the 
study
●
Change from Baseline to Week 40 or final Visit in MRI synovitis, BME and 
erosions RAMRIS scores
●
Change from dbBaseline in Health Assessment Questionnaire – Disability
Index (HAQ-DI) over time
●
Proportion of subjects with HAQ-DI normal (HAQ-DI ≤ 0.5) at dbBaseline 
and at Week 40
●
Change from dbBaseline in RAPID 3 scores assessed during Visits
●
Change from Flare Week 0 in RAPID 3 at home assessments
●
Change from dbBaseline in Swollen Joint Count (both 28 and 66 joints)
●
Change from dbBaseline in Tender Joint Count (both 28 and 68 joints)
●
Change from dbBaseline in Patient's Global Assessment of Disease activity 
●
Change from dbBaseline in Patient's Global Assessment of RA pain
●
Change from dbBaseline in Physician's Global Assessment of Disease activity
●
Change from dbBaseline in morning stiffness assessment 
●
Change from dbBaseline in Sleep disturbance assessment
●
Change from dbBaseline in Treatment Satisfaction Questionnaire for 
Medication (TSQM)
●
Change from dbBaseline in Work Productivity and Activity Impairment 
(WPAI)
●
Change from dbBaseline in Short Form-36
●
Change from dbBaseline in Functional Assessment of Chronic Illness 
Therapy – fatigue (FACIT-fatigue)
●
Change from dbBaseline in CRP
●
Change from dbBaseline in ESR

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5.3.5.3
Exploratory Variables
Exploratory Assessments Include:
●
dbBaseline and change from dbBaseline to the time of flare in PDUS and 
GSUS individual and composite scores of synovitis, synovial hypertrophy and 
tenosynovitis
●
dbBaseline and change from dbBaseline on biomarker values (MMP-3, SAA, 
C1M, C3M, CRPM, VICM, IL-6, CXCL10, CXCL13)
5.3.5.4
Pharmacokinetic Variables
Blood samples will be collected for the measurement of serum adalimumab 
concentrations prior to dosing at dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early 
Termination, Flare Weeks 0, 4, 10 and 16 (if applicable).  Blood samples will be collected 
for the measurement of AAA at dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early 
Termination, Flare Weeks 0, 4, 10 and 16 (if applicable).
5.3.5.5
Pharmacogenetic Variables
DNA samples may be sequenced and data analyzed for genetic factors contributing to the 
disease or subject's response to adalimumab, other study treatment, in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 
genes for drug metabolizing enzymes, drug transport proteins, genes within the target 
pathway, other genes believed to be related to the disease or to drug response.  Some 
genes currently insufficiently characterized or unknown may be understood to be 
important at the time of analysis.
Essentially all mRNAs present in the collected peripheral blood samples may be 
sequenced or measured using microarray and polymerase chain reaction (PCR) 
techniques.  The mRNA sub-study may be analyzed for RNA expression levels 
contributing to the subject's response to the disease or study treatment, in terms of 
pharmacokinetics, pharmacodynamics, efficacy, tolerability and safety.  Messenger RNA 

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analysis will be limited to studying response to disease or adalimumab therapy; no other 
analyses will be performed.
The samples (DNA/mRNA) may be analyzed as part of a multi-study assessment of 
genetic factors involved in the response to adalimumab, drugs of this class, or the disease 
state.  The samples may also be used for the development of diagnostic tests related to the 
disease.  The results of pharmacogenetic analyses may not be reported with the study 
summary.
5.3.6
Safety Variables
Screening assessments will include medical history, vital signs, physical examination, and 
clinical laboratory tests.  The following safety evaluations will be performed during the 
study:  concomitant medication review, adverse event (AE) monitoring, vital signs, 
physical examination (if required) and laboratory tests.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an adverse event, safety concerns or 
failure to comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:
●
Clinically significant abnormal laboratory result(s) or adverse event(s), as 
determined by the Investigator in consultation with the AbbVie Study 
Designated Physician.
●
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 

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as determined by the AbbVie Study Designated Physician (Section 5.2 and 
Section 7.0).
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie Study 
Designated Physician.
●
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 Study Designated Physician.
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the Termination Visit must be completed 
within 2 weeks of the last dose of study drug, and preferably prior to the initiation of 
another therapy.  If subjects discontinue the study during the lead-in observational period, 
prior to randomization, a short Early Termination visit is required for: returning study 
material and drug, assess any safety/adverse events, collect reason for discontinuation and 
a 70-day follow-up call/visit; the remainder of full Early Termination Visit study 
procedures can be completed per the investigator's discretion.  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 all subjects 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.

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All attempts must be made to determine the date of the last dose of study drug and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
For subjects entering the 4-week Lead-In Period, OL adalimumab 40 mg eow will be 
provided.  Drug will be sc self-administered every other week at approximately the same 
time of the day.
Starting at the dbBaseline visit, subjects who are eligible for randomization will receive 
the first dose of blinded drug:  adalimumab 40 mg/0.8 mL or matching placebo for 
adalimumab.  Drug will be subcutaneously administered as a 40 mg or placebo dose every 
3 weeks at approximately the same time of day.
Subjects who meet flare criteria will be entering an Open-Label Rescue Arm and OL 
adalimumab 40 mg will be administered every other week for 16 weeks.

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5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 3.
Table 3.
Identity of Investigational Products
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 for 
adalimumab
Parenteral
Pre-filled 
syringe
0.8 mL solution for injection Mannitol, 
Citric acid monohydrate, Sodium citrate, 
Disodium phosphate dihydrate, Sodium 
dihydrogen phosphate dihydrate, Sodium 
chloride, Polysorbate 80, Water for 
injections, Sodium hydroxide added as 
necessary to adjust pH
AbbVie
5.5.2.1
Packaging and Labeling
Investigational product will be packaged separately in 0.8 mL syringe containing either 
adalimumab 40 mg/0.8 mL or matching placebo for adalimumab.  Each dosing kit carton 
will contain a pre-filled syringe 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 C.

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5.5.2.2
Storage and Disposition of Study Drug
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 
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) deems the medication as 
acceptable.
All clinical supplies must be stored and locked in a secure place until they are dispensed 
for subject use or are returned to AbbVie.
Investigational products are for investigational use only and are to be used only within the 
context of this study.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  Subjects who meet the inclusion and none of the exclusion criteria in Section 5.2.1
and Section 5.2.1 will proceed to enter the study Lead-In Period and double-blind 
randomized period.  All subjects who enter the randomized period of the study will be 
centrally randomized at dbBaseline in a 5:1 ratio double-blind fashion using the IRT 
which will assign a randomization number and a treatment group according to the 
randomization scheme generated by AbbVie before the start of the study.  The treatment 
group assignment will be maintained by the IRT and not provided to the site, as the 
subject will be referred to by the subject number assigned at Screening.  The sites will be 
provided with appropriate kit number(s) for drug-dispensing purpose for each subject by 
the IRT.  Study drug will be dispensed at the study visits summarized in Table 1.

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5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study medication as outlined in Section 5.5.1 Treatments 
Administered.
If a subject should forget to administer the injection of study medication on their regularly 
scheduled dosing date, they should take the forgotten injection as soon as they remember 
the dose was missed up to the day of their next scheduled dose.  The subject should not 
administer two doses on the same day.
In the event the incorrect dose is taken or a dose is missed, the subject should be 
instructed to contact the site to determine how to proceed with dosing.  The subject must 
record all dosing information on the Subject-Dosing Diary Sheet.
Doses not administered (e.g., not taken before next dose is scheduled), should be recorded 
as not taken in the source.  The extra dose should be returned to the study site full.  The 
subject should resume their regular dosing schedule based on the first dosing date at 
dbBaseline.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team) the Investigator, study 
site personnel and the subject will remain blinded to each subject's treatment throughout 
the Double-Blind 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 Study 
Designated Physician (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.

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5.5.6
Treatment Compliance
The Investigator or his/her designated representatives will dispense study drug only for 
use by subjects enrolled in the study.
The subject or their qualified designee will administer all doses of study drug.  
Appropriate site staff will supervise the subject's administration of the study drug at 
required in-office study visits to ensure proper injection technique.  In order to document 
compliance with the treatment regimen, the subject will be given a dosing sheet 
(Appendix D) to record all injection dates and times.  Compliance information will be 
documented on the appropriate eCRF.  Subjects will be counseled on missed doses of 
medication.  If the subject does not return the dosing sheet, 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 dosing sheet is returned before completing on the 
applicable eCRF page.
5.5.7
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact, at the 
appropriate temperature (temperature recording devices [temptales] are provided in the 
shipments), and in the correct amounts.  This will be accomplished by documenting the 
condition of the shipment, verifying the kit numbers in the package against the Proof of 
Receipt (POR) or similar document included with each drug shipment, and documenting 
this verification by signing and dating the POR or similar document.  The original POR 
Note or similar document will be kept in the site files as a record of what was received.
In addition, an accurate running inventory of study drug will be kept by the site on a Site 
Drug Accountability log including date received, the lot number, kit number(s), date 
dispensed, subject number, and the identification with date of the person dispensing the 
drug.

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All empty IP boxes and used pre-filled syringes will be inventoried by the site.  Each 
subject will be given their own sharps disposal container to store used pre-filled syringes.  
Empty IP boxes and Sharps containers should be returned by the subject at each visit for 
accountability and compliance purposes and new containers issued as necessary.  Empty 
Boxes and returned Sharps containers will be retained (unless prohibited by local law) 
until the CRA is on site to confirm the returned medication.  CRAs and site staff will 
complete study medication accountability via study medication logs, source documents, 
subject dosing sheets, empty IP boxes and by visually inspecting the syringes in the 
Sharps container whenever possible.  Used Sharps containers should never be opened.  
Once the CRA has verified drug accountability at the site, the site staff and CRA will 
document that the used pre-filled syringes have been destroyed, using appropriate 
biohazard precautions, when appropriate.  A copy of the destruction methodology should 
be maintained at the site's facility.  After drug accountability has been completed at the 
site, unused medication will be destroyed on site according to local procedures or 
regulation or returned to a destruction facility by the CRA.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This Phase 4 study is designed to investigate the association between residual disease 
activity at baseline, and the occurrence of flares in RA patients on adalimumab who are in 
sustained clinical remission (DAS28 [ESR] < 2.6) and submitted to an adalimumab dose 
tapering regimen or withdrawal.  The randomization 5:1 including a control arm of 
withdrawal of adalimumab is introduced as a study design element to ensure the 
objectivity of flares assessments in the primary study arm.  For subjects who flare the 
Open-Label Rescue Arm will provide evidence on the effect of re-treatment with 
adalimumab eow.  The proposed sample size and 36-week duration of the Double-Blind 
Period is based on the estimated risk (of approximately 30%) and time to the occurrence 
of flare in subjects with established RA in clinical remission upon tapering or 
withdrawing TNFi therapy.20-22,24

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5.6.2
Appropriateness of Measurements
Standard statistical, clinical and laboratory procedures will be utilized in this study.  
Efficacy measurements in this study have been selected to assess disease activity and the 
occurrence of flares in subjects with RA using clinical scores that are standard and 
generally accepted.  Imaging techniques with MRI and US identifying subclinical 
inflammation (synovitis, etc.) have been correlated with risk of disease progression and 
flaring in RA patients otherwise in clinical remission.  Thus, assessing their association 
with occurrence of flaring (versus non-flaring) in a dose tapering or withdrawal treatment 
strategy is deemed appropriate.  The biomarker, PK analysis and the investigation of their 
correlation with patient outcomes is exploratory but relevant to gather more potential 
individual predictors for the clinical outcomes of tapering or withdrawal of adalimumab.
5.6.3
Suitability of Subject Population
Subjects age ≥ 18 years diagnosed with RA, on a stable dose of adalimumab 40 mg sc 
eow (for ≥ 12 months prior to Screening Visit) in combination with methotrexate (MTX; 
at stable dose for ≥ 12 weeks prior to the Screening Visit) or if not on MTX in a stable 
other allowed csDMARD or no csDMARD regimen for ≥ 12 weeks prior to Week 0 Visit) 
and in documented clinical remission (DAS28 [ESR] < 2.6 or DAS28 [CRP] 2.6) for 
≥6 months prior to the study are eligible for this study.  Patients who are not on stable 
concomitant MTX will be allowed as per current clinical practice, but limited to 20% of 
the study population.  This is the target population that in routine clinical practice is, in 
general, being considered for therapy tapering strategies.  The recently updated EULAR 
recommendations for the management of patients with RA11 provide some orientation to 
this extent but do not contain specific guidance to characterize the patients that could 
actually be submitted to a tapering regimen and do highlight this as an area of research 
interest.

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5.6.4
Selection of Doses in the Study
The recommended dose of adalimumab for adults with RA is 40 mg administered eow.  
Adalimumab 40 mg eow has demonstrated to improve clinical, function and to halt 
radiographic progression of RA for up to 10 years of treatment.10
Dose tapering strategies with adalimumab are starting with a prolongation of injection 
intervals to every 3 weeks.11,24,26,65-68  Thus the selection of patients suitable for drug 
tapering should be based on the clinical course of this initial dose tapering regimen.
In previous studies, a dose tapering strategy with increasing the interval of administration 
of adalimumab to every 3 weeks followed by withdrawal when possible has been tolerated 
by a significant proportion of patients.24,65-68  In this study, subjects who experience a flare 
at any time will initiate OL adalimumab 40 mg eow rescue therapy and will be allowed to 
add other treatments at the Investigator's discretion.
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 6.1.5).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2.

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6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
Investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (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 

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medical intervention, (meets protocol specific criteria [see 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 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).

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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The Investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
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.

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No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the Investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the Investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 70 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events and protocol-related nonserious 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 may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination/Final 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 adverse events.  
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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Figure 2.
Adverse Event Collection
SAEs and 
Protocol-Related 
Nonserious AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
70 Days
After Study 
Drug Stopped
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any nonserious event of 
malignancy in subjects 30 years of age and younger, whether related to study drug or not, 
the physician will notify the AbbVie Clinical Pharmacovigilance Team within 24 hours of 
the physician becoming aware of the event by entering the serious adverse event or 
nonserious event of malignancy in subjects 30 years of age and younger data into the 
electronic data capture (EDC) system.  Serious adverse events and nonserious events of 
malignancy in subjects 30 years of age and younger, that occur prior to the site having 
access to the Rave EDC system should be documented on the SAE Non-CRF Forms and 
sent to the Clinical Pharmacovigilance Team within 24 hours of being made aware of the 
adverse event.
FAX to:  
Email to:  
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:

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For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number:
Phone:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
Pregnancy in a study subject or a partner of a study subject must be reported to AbbVie 
within 1 working day of the site becoming aware of the pregnancy.  Subjects who become 
pregnant during the study must be discontinued (Section 5.4.1).  Pregnancies in study 
subjects and their partners will be collected from the date of the first dose through 
150 days following the last dose of study drug.
Information regarding a pregnancy occurrence in a study subject or a study subject's 
partner and the outcome of the pregnancy will be collected.  In the event of pregnancy 

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occurring in a subject's partner during the study, written informed consent from the 
partner must be obtained prior to the collection of any such information.
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 6.0 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 
2 weeks prior to the surgery.  If the subject must undergo emergency surgery, the study 
injections must be interrupted at the time of the surgery.  The injectable study medication 
can recommence at least 2 weeks after surgery once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 

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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.  The 
Principal Investigator is responsible for complying with all protocol requirements, and 

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applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the Principal Investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and their assigned CRO Clinical 
Monitor or the following AbbVie Clinical Monitors:
Primary Contact:
Alternate Contact:
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.
For the purposes of this protocol, reportable deviations are defined as:
●
Subject entered into the study even though she/he did not satisfy entry criteria
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn
●
Subject who received wrong treatment or incorrect dose
●
Subject who received excluded or prohibited concomitant treatment

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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
8.1.1
Analysis Population
The analysis population for both efficacy and safety assessment is All Treated Subjects.  It 
includes all subjects who have received at least one dose of double-blind study 
medication.
Unless otherwise specified, efficacy and other assessment will be primarily analyzed for 
subjects who are randomized to the adalimumab 40 mg q3 weeks arm (taper arm) and 
have received at least one dose of study medication.  Descriptive statistics will be 
provided for the subjects who are randomized to the placebo arm (withdrawal arm) and 
have received at least one dose of study medication.
In order to evaluate the impact of major protocol violations on the results of the trial, 
additional analysis of the primary efficacy assessment may be conducted on the per 
protocol population, which consists of all treated subjects who complete the study or 
otherwise have had a flare and are not major protocol violators.
8.1.2
Planned Methods of Statistical Analysis
Complete and specific details of the final statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock.  The analysis will be performed using SAS (SAS Institute Inc., Cary, NC, 
USA).
Unless otherwise stated, all statistical inference will be based on a 2-sided alpha-level of 
0.1.  No multiplicity adjustment will be conducted.  Descriptive statistics include the 
number of observations, mean, standard deviation, median, minimum and maximum for 
continuous variables; and counts and percentages for discrete variables.

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8.1.3
Analysis of Demographic Data and Double-Blind Baseline 
Disease Characteristics and Other Analyses
Demographic and double-blind Baseline characteristics for all randomized subjects will 
be summarized by treatment arm and descriptive statistics will be provided.
Medical history will be presented by count and percentage of subjects broken down by 
Body system and Diagnosis.  Prior and concomitant medication will also be summarized.
Treatment duration regardless of whether rescue therapy is received will be summarized 
for All Treated Subjects.
8.1.4
Efficacy Analysis
8.1.4.1
Analysis for Primary Objective
The primary objective is to investigate the association between Baseline hand and wrist 
synovitis and BME RAMRIS scores as well as a composite of both, and the occurrence of 
flares up to Week 40 in the tapering arm.  This association will be examined using logistic 
regression, which is deemed as the main analysis for the primary assessment.  The 90% 
confidence interval of the odds ratio will be calculated.  The 95% confidence intervals of 
the odds ratio will also be provided as an addition.
Additional analyses will be performed to assess this association using various statistical 
methods.  Specifically, descriptive statistics of Baseline MRI composite scores 
(RAMRIS) scores will be provided for the two groups of subjects who flare and who do 
not flare, and the between-group difference in the mean scores will be computed together 
with a 90% confidence interval.  Linear regression will be used to model the relationship 
between the DAS28 (ESR) at flaring (or at the end of the study for subjects who do not 
flare) and the Baseline MRI RAMRIS scores.  Receiver operating characteristic (ROC) 
curve approach will also be utilized to investigate the potential flare prediction criteria 
based on MRI RAMRIS scores.  All model based analyses may adjust for dbBaseline 
clinical patient characteristics including age, disease duration, previous and concomitant 

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treatment (such as use of MTX, use of csDMARD as versus TNFi monotheraphy), etc., 
when appropriate.
Similar analysis will be conducted for RAMRIS synovitis scores, BME scores and the 
composite of both.
For subjects who prematurely discontinue in the double-blinded period (i.e., prematurely 
discontinue prior to the detection of flaring), their last DAS28 (ESR) score will be used to 
impute their flare status.  All subjects who are classified as receiving rescue therapy will 
be treated as flare subjects.
8.1.4.2
Analysis for Secondary Objectives
To characterize the development of flares, the proportion of subjects who flare in the taper 
arm and withdraw arm and overall, and the 90% confidence interval of this proportion 
will be calculated.  Time to flare in these two arms will be summarized using 
Kaplan-Meyer survival techniques.  The proportion of subjects within each level of flare 
severity will also be computed for the taper arm and withdraw arm and overall, 
accompanied by a 90% confidence interval.
To investigate the association between the occurrence of a flare and the specified 
dbBaseline parameters similar analyses will be conducted as for the primary assessment.
To evaluate the effectiveness of re-treatment with adalimumab 40 mg eow as a rescue 
therapy after flaring, the proportion of flared subjects who regain clinical remission will 
be calculated with a 90% confidence interval, separately for subjects from the tapering 
arm and from the withdrawal arms.  To assess the time to regain clinical remission, the 
proportion of flared subjects who regain clinical remission will be summarized over time 
by the duration of rescue therapy, separated for subjects from the tapering arm and from 
the withdraw arm.
To describe the MRI change for subjects in the taper, withdraw and Open-Label Rescue 
Arms, the change from Baseline to end of study in MRI RAMRIS scores and its 

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individual component scores for synovitis and edema will be summarized separately for 
flared and non-flared subjects originated in the taper and withdraw arm respectively.
To describe the disease course of subjects in the taper, withdraw and Open-Label Rescue 
Arms, different clinical and health reported outcome measures, which are listed in 
Section 5.3.5.2 will be summarized over time separately for flared and non-flared subjects 
originated in the taper and withdraw arm respectively.
8.1.4.3
Analysis for Exploratory Objectives
The ultrasonographic assessments will be performed at dbBaseline and at flare.  
Descriptive statistics of ultrasonography (US) synovial inflammation (Power Doppler 
[PD]) and synovial hypertrophy (Gray Scale [GS]) scores at dbBaseline will be 
summarized for the flared and non-flared subjects to assess their association with the 
occurrence of RA flares.  In addition, the scores at flare as well as change from 
dbBaseline will be summarized.  Additional analyses to assess the association between 
dbBaseline ultrasonographic scores and the occurrence of a flare will be performed if 
deemed necessary.
To assess the association between dbBaseline US synovial inflammation (PD) and 
synovial hypertrophy (GS) scores and Baseline MRI synovitis RAMRIS score, linear 
regression approach will be used to modeling the relationship between the dbBaseline 
PDUS and GSUS scores and Baseline MRI synovitis RAMRIS score.
Biomarker values including dbBaseline and their change from dbBaseline over time will 
be summarized for the flared subjects and the non-flared subjects.  Additional analyses to 
assess the association between biomarker and the occurrence of a flare will be performed 
if deemed necessary.
The occurrence and time to flare from dbBaseline in the concomitant MTX, other 
csDMARDs and no csDMARDs patients will be analyzed for potential differential effect.

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8.1.5
Pharmacokinetic Analyses
Adalimumab serum concentrations will be summarized by treatment group at each time 
point using descriptive statistics including number of subjects, number of non-missing 
observations (nnmiss), mean, median, standard deviation, coefficient of variation (CV), 
minimum, and maximum as appropriate.  Individual subject concentrations versus time 
plots and mean concentration versus time plots by treatment group will be provided.  Data 
listings will be generated for individual subjects.  For the calculation of summary statistics 
and plots, concentration values below limit of quantification (LOQ) will be set to zero.
The association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares will be assessed as appropriate.  In addition, pharmacokinetic model 
based analyses may be performed with the focus on apparent clearance (CL/F) and 
apparent volume of distribution (V/F) of adalimumab.
AAA will be evaluated for each subject and each study arm, and rates of AAA positive 
subjects will be calculated.  As appropriate, the effect of AAA on adalimumab 
pharmacokinetics, efficacy variable(s), and treatment-emergent adverse events may be 
evaluated.
8.1.6
Safety Analysis
Treatment-emergent adverse events (AEs) will be summarized and reported.  
Treatment-emergent AEs are defined as AEs that begin either on or after the first dose of 
the study medication, through the end of the AE collection period as defined by the 
protocol.  The number and percent of subjects experiencing treatment-emergent AEs will 
be tabulated by treatment and by body system and Medical Dictionary for Drug 
Regulatory Activities (MedDRA®) preferred term.  In addition, summary of 
treatment-emergent AEs by severity and relationship to study drug will be presented.  
AEs, which are serious, severe, or life-threatening, or lead to premature study drug 
discontinuation will be listed and described in detail.

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Mean change in laboratories variable and vital signs variables at each visit will be 
summarized for all treated subjects.  The last evaluation prior to the first dose of 
double-blinded study drug will be used as dbBaseline for all analyses.  For selected 
parameters, a listing of all subjects with any laboratory determination meeting Common 
Toxicity Criteria (CTC) of Grade 3 or higher will be provided.  Shift tables for changes 
from dbBaseline according to the normal range will also be provided for lab variables.
8.1.7
Interim Analysis for Double-Blind Baseline Characteristics
There are few data describing patient disease characteristics including markers of residual 
inflammation such as sensitive imaging assessments and potential biomarkers as well as 
drug levels in RA patients who are in sustained clinical remission on a stable treatment 
with a TNFi and MTX and/or with other csDMARDs(s) or in TNFi monotherapy.  An 
interim analysis will be conducted to describe the dbBaseline characteristics of the RA 
population.  It will be performed after the dbBaseline assessments of the entire study 
population have been completed.  The study team will remain blinded to individual data.  
The details of the interim analyses/evaluation will be described in interim analysis charter.
8.1.8
Compliance 
Treatment compliance will be calculated for each subject as the number of injections 
actually received divided by the number of injections should have received during the 
subject's participation in the study (rounded to 0.1%).  Compliance will be summarized 
for All Treated Subjects.
8.2
Determination of Sample Size
The planned total number of subjects enrolled into the Lead-In Period is approximately 
200. 
A recently published study (DOSERA) showed that 56% (15/27 patients) of patients who 
were previously in low disease activity had treatment failure within 48 weeks after 
reducing the dose of etanercept; the median time to failure was 36 weeks (95% 
CI:15.6-NE).89  The STRASS study, also published in 2015, showed in a similar RA 

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patient population, that progressive tapering of TNFi therapy (adalimumab or etanercept) 
was associated with flare in 76.6% (49/64) of patients throughout the study duration; 
importantly, 28.8% of patients flared after the first step of tapering (adalimumab 40 mg  
q3 weeks or etanercept 50 mg q10 days) and the median time to flare was 9 months. 90  In 
another tapering study (DRESS) a cumulative incidence of short-lived flares in a 
progressive tapering of TNFi of 55% at 9 months (and 73% at 18 months) was observed.  
Among these studies, the DRESS study had the higher sample size with 121 patients in 
the taper arm but only 43% successfully tapered the TNFi.  None of these studies was 
designed or powered to evaluate predictors of flare neither found definite predictors upon 
further statistical analysis.  A proof of concept study conducted in 44 RA patients in 
clinical remission receiving treatment with a bDMARD has shown that residual synovial 
inflammation determined by comprehensive ultrasound assessment predicted relapse 
within a short term after discontinuation of the treatment.91
These data provided the rational for assuming a conservative flare rate of 30% and for our 
sample size calculation.
To estimate the odds ratio for the occurrence of flare with baseline MRI score based on 
historical MRI data, an effective sample size of 150 subjects in the dose tapering group 
will ensure a precision for the estimation with the width of 90% CI no more than 0.03 for 
an odds ratio 1.03, no more than 0.07 for an odds ratio 1.1, and no more than 0.14 for an 
odds ratio 1.2.  Such sample size will also ensure a precision for the estimation of a 
correlation coefficient ρ with the width of 90% CI of ρ no more than 0.26 for a mild 
correlation coefficient 0.28, no more than 0.18 for a moderate correlation coefficient 0.55, 
and no more than 0.13 for a higher correlation with ρ = 0.67.  Assuming a 30% flare rate, 
this sample size will provide the precision that the 2-sided 90% CI of the flare rate has a 
half width no more than 6%.
Sensitivity precision levels under various assumptions are presented in Table 4.

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Under a 5:1 randomization ratio (dose tapering versus withdrawal), a total of 180 subjects 
will be randomized.  Accounting for a 10% discontinuation rate during the Lead-In 
Period, approximately 200 subjects will need to be enrolled into the Lead-In Period.
Table 4.
Sample Size Assumptions
True Odds 
Ratio
Flare Rate
Sample Size (Dose 
Tapering Arm)
OR from Logistics 
Regression
(90% CI) : CI Width
Correlation
(90% CI) :
CI Width
1.03
30%
150
1.03
(1.02, 1.05) : 0.03
0.28
(0.14, 0.40) : 0.26
1.1
30%
150
1.1
(1.07, 1.14) : 0.07
0.55
(0.46, 0.64) : 0.18
1.2
30%
150
1.21
(1.15, 1.29) : 0.14
0.67
(0.61, 0.73) : 0.13
8.3
Randomization Methods
Subjects will be randomized to a standardized tapering scheme of adalimumab 40 mg sc 
every 3 weeks or placebo (drug withdrawal) in a 5:1 ratio at the beginning of 
double-blinded period of the study.  Subjects experiencing a flare at any time point will be 
re-treated with open label adalimumab 40 mg eow.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 

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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 ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
Investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (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.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for serum to be stored for possible future research.  

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The storage of these biomarker samples for possible future research is optional and 
subjects' may decline at any time.
A copy of the informed consent form will be given to the subject and the original will be 
placed in the subject's medical record.  An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
The decision to allow pharmacogenetic analysis assessment will be determined by local 
regulations.  Pharmacogenetic analysis will only be performed if the subject has 
voluntarily signed and dated a separate pharmacogenetic informed consent form, 
approved by an IRB/IEC, after the nature of the testing has been explained and the subject 
has had the opportunity to ask questions.  The separate pharmacogenetic informed consent 
must be signed before the pharmacogenetic testing is performed.  If the subject does not 
consent to the pharmacogenetic testing it will not impact the subject's participation in the 
study.
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.

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

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Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
10.3
Electronic Patient Reported Outcomes (ePROs)
An electronic patient-recorded outcomes (ePRO) device will be provided to subjects 
during screening and will be completed at all subject visits in the office.  An additional
device will be given to subjects at their flare Week 0 visit (if applicable) and will be 
completed at home weekly.  Site personnel will provide training on the proper use of the 
e-Diary.  These data will be uploaded to a server, the data on the server will be considered 
source, and maintained and managed by CRF Health.  Patient reported data are completed 
for each subject screened/enrolled in this study.  An ePRO tool called Trialmax, provided 
by the technology vendor CRF Health of Plymouth Meeting, PA, USA, will be used to 
collect this data.  The ePRO system is in compliance with Title 21 CFR Part 11.  
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 site investigator, as 
well as delegated personnel.  Such access will be removed from investigator 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 investigator at that time as a 
durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media. 
The electronic device may be programmed to allow data entry for only certain periods of 
time.  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, up until the generation, receipt and confirmation of the study 
archive.

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11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Please refer to the Investigator site contract for specific information related to publication 
practices.
AbbVie abides by the PhRMA Principles on Conduct of Clinical Trials and 
Communication of Clinical Trial results.  AbbVie's registrations and results disclosure 
adhere to all relevant state and federal laws.
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 and mRNA samples from 
this study will be for research purposes only and the results will not be suitable for clinical 
decision-making or patient management.  Hence, neither the Investigator, the subject, nor 
the subject's physician (if different than 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 in response to requests from health authorities.  
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.  

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Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The Investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.

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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for adalimumab and the 
product labeling 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 Phase 4 Trial Assessing the ImPact of Residual Inflammation 
Detected via Imaging TEchniques, Drug Levels and Patient 
Characteristics on the Outcome of Dose TaperIng of Adalimumab in 
Clinical Remission Rheumatoid ArThritis (RA) Subjects 
(PREDICTRA)
Protocol Date: 
25 February 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)

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15.0
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results from a 10-year prospective study.  Ann Rheum Dis.  2010;69(2)345-51.

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63.
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rheumatoid arthritis: longitudinal associations with inflammation and joint 
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definitions for ultrasonographic pathology.  J Rheumatol.  2005;32(12);2485-7.
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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
Global Medical Affairs
Statistics
Global Medical Affairs
Clinical
Pharmacokinetics
Bioanalytics
Regulatory Affairs
Clinical

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Appendix C.
Injection Instructions – Pre-Filled Syringe – Sample
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M14-500
Table of Contents
Dosing Schedule
General Information and Supplies
Injection Procedures

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Study Drug Dosing Schedule
Subject Number:  _____________________________________
You will require subcutaneous (SC) injections throughout the study.
Call you doctor at any time if you feel that your disease is worsening.
You will receive the following number of injections during the study:
●
At the Lead-In Week 0 Visit (the first visit to receive study medication for this 
study) you will receive 1 injection at the clinic (self-administer or receive help 
from site staff) and 1 injection to take 2 weeks after the Week 0 Visit.
●
At Week 4 at the start of the Double-Blind Period, you will receive 2 syringes.  
At the Week 4 Visit, you will administer the injection at the clinic.  You will 
take the other 1 syringe home to be administered at Week 7.  During the 
remainder of the Double-Blind Period (Weeks 10, 16, 22, 28 and 34), you will 
receive 2 syringes at each visit to be taken (one to be administered at the visit 
and the other to be taken at home 3 weeks later) at Weeks 10, 13, 16, 19, 22, 
25, 28, 31, 34 and 37, respectively.
●
If at any time you have a flare and it is confirmed, you will enter the Open 
Label Rescue Arm and start a Flare Week 0 Visit.  You must return all 
double-blind medication at the next visit. 
○
At the Flare Week 0 Visit, you will receive 2 syringes.  One injection of 
open-label adalimumab will be administered at the clinic.  You will take 
the other 1 syringe home to be administered 2 weeks later at Flare Week 2. 
○
At the Flare Week 4 and 10 Visits, you will receive 3 syringes at each visit 
(one to be administered at the visit and the other 2 to be taken separately at 
home every two weeks) to be taken at Flare Weeks 4, 6, 8, 10, 12, 14 
respectively. 
○
If your time of injection falls on a clinic day, you must inject study drug 
after all study procedures are performed (not prior).

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Throughout the study, you will receive active study medication (or placebo).  You or a 
trained designee will inject your study drug at the following timepoints: 
●
every other week in the Lead-In Period
●
every 3 weeks in the Double-Blind Period 
●
every other week in the Open-Label Rescue Arm
If you meet the criteria for flare at any time during the Double-Blind Period, you will 
receive rescue therapy (active study drug) for 16 weeks.  You will not administer study 
medication at your last visit.
Please return all used and unused syringes, the sharps container and empty boxes to the 
clinic on your next visit.  Used syringes should be placed in the special Sharps container 
provided.  All unused syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
contact your study center immediately for further instructions.  Please record any missed 
doses on your subject dosing sheet.
Remember to complete your dosing sheet after each injection and to call the doctor's 
office if you are having problems administering your study medication.
General Information
●
Pre-filled syringes with study medication will be labeled "Adalimumab" 
during the open-label period (Period 1) or during rescue therapy and 
"Adalimumab or Placebo" during the Double-Blind Period (Period 2).
●
Store all pre-filled syringes in your refrigerator at 36° to 46°F (2° to 8°C) in 
the original container until it is used.  NOT in the freezer.  Should the syringes 
accidentally become frozen, call your study doctor's office.
●
Protect the study medication from light.
●
Do not use a pre-filled syringe if the liquid is cloudy, discolored, or has flakes 
or particles in it.

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●
Do not drop or crush the study medication.  The pre-filled syringe is glass.
●
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) and 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.
●
Keep study medication, injection supplies, and all other medicines out of the 
reach of children.
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.

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

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

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Appendix D.
Subject Dosing Diary – Sample
To be completed for every study dose administered.  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.  
Please record the date, time of study drug administration, kit number, dose administered, 
injection location, initials of person administering study medication, and any comments.  
Instructions on proper study medication administration will be provided by your study 
doctor and should be followed for every injection.  Call the doctor's clinic if you are 
having problems administering your study medication.
Please bring your Sheet with you to each clinic visit.
If you have any questions or concerns at any time, please call the study coordinator or 
physician at the following number(s):

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Date
day/mm/yr
Day or Week#
Time of Study Drug 
Administrationa
Kit Number
Dose (mL) 
Administered
Injection Site 
(abdomen or thigh)
Initials of Person 
Administering Study 
Medication
Comments
31/MAY/12
EXAMPLE
0 9:3 0 hrs
123456
0.8 mL
abdomen
PG
Clinic injection
Lead-In Period
Week 0
      :        hrs
Week 2
      :        hrs
Randomized Double-Blind Period (once subject flares, mark N/A and move to Open-label Rescue Arm below)
Week 4
      :        hrs
Week 7
      :        hrs
Week 10
      :        hrs
Week 13
      :        hrs
Week 16
      :        hrs
Week 19
      :        hrs
Week 22
      :        hrs
Week 25
      :        hrs
Week 28
      :        hrs
Week 31
      :        hrs
Week 34
      :        hrs
Week 37
      :        hrs
Open-Label Rescue Arm (adalimumab every other week for 16 weeks (otherwise, please mark "N/A")
Flare Week 0
      :        hrs
Flare Week 2
      :        hrs
Flare Week 4
      :        hrs

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Date
day/mm/yr
Day or Week#
Time of Study Drug 
Administrationa
Kit Number
Dose (mL) 
Administered
Injection Site 
(abdomen or thigh)
Initials of Person 
Administering Study 
Medication
Comments
Open-Label Rescue Arm (adalimumab every other week for 16 weeks (otherwise, please mark "N/A")
Flare Week 6
      :        hrs
Flare Week 8 
      :        hrs
Flare Week 10
      :        hrs
Flare Week 12
      :        hrs
Flare Week 14
      :        hrs
a.
Please note the time in military time (e.g., 22:00 hours etc.).

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Appendix E.
Joint Evaluation Worksheet – Sample
JOINT EVALUATION
Subject Right
Subject Left
JOINT
(Tick Correct Answer)
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
Pain/
Tenderness
Swelling
Joint
Pain/
Tenderness
Swelling
Joint
1. Temporomandibular
0
1
0
1
9
NA
0
1
0
1
9
NA
2. Sternoclavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
3. Acromio-clavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
4. Shoulder
0
1
0
1
9
NA
0
1
0
1
9
NA
5. Elbow
0
1
0
1
9
NA
0
1
0
1
9
NA
6. Wrist
0
1
0
1
9
NA
0
1
0
1
9
NA
7. Metacarpophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
8. Metacarpophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
9. Metacarpophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
10. Metacarpophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
11. Metacarpophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
12. Thumb Interphalangeal
0
1
0
1
9
NA
0
1
0
1
9
NA
13. Prox. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
14. Prox. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
15. Prox. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
16. Prox. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
17. Distal Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
18. Distal Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
19. Distal Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
20. Distal Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
21. Hip
0
1
-
-
9
NA
0
1
-
-
9
NA
22. Knee
0
1
0
1
9
NA
0
1
0
1
9
NA
23. Ankle
0
1
0
1
9
NA
0
1
0
1
9
NA
24. Tarsus
0
1
0
1
9
NA
0
1
0
1
9
NA
25. Metatarsophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
26. Metatarsophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
27. Metatarsophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA

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JOINT EVALUATION
Subject Right
Subject Left
JOINT
(Tick Correct Answer)
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
Pain/
Tenderness
Swelling
Joint
Pain/
Tenderness
Swelling
Joint
28. Metatarsophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
29. Metatarsophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
30. Great Toe/Hallux
0
1
0
1
9
NA
0
1
0
1
9
NA
31. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
32. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
33. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
34. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA

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Appendix F.
DAS28 Joint Assessment
Out of the 68 tender and 66 swollen evaluated, the following 28 joints are include in 
DAS28 calculation.  DAS28 will be calculated by the eCRF.
Example of the 28 joints assessed for DAS28:
Left
Right
Swollen
Tender
Swollen
Tender
Shoulder
Elbow
Wrist
MCP
1
2
3
4
5
PIP
1
2
3
4
5
Knee
Subtotal
Total
Swollen
Tender

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Appendix G.
Health Assessment Questionnaire (HAQ-DI) – Sample
In this section we are interested in learning how your illness affects your ability to 
function in daily life.
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
DRESSING AND GROOMING
Are you able to:
Dress yourself, including tying 
shoelaces and doing buttons?
Shampoo your hair?
ARISING
Are you able to:
Stand up from a straight chair?
Get in and out of bed?
EATING
Are you able to:
Cut your own meat?
Lift a full cup or glass to your 
mouth?
Open a new milk carton?
WALKING
Are you able to:
Walk outdoors on flat ground?
Climb up five steps?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
Cane
Devices used for dressing (button hook, 
zipper pull, long-handled shoe horn, etc.)
Walker
Built up or special utensils
Crutches
Special or built up chair
Wheelchair
Other (Specify: __________________)

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Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
Dressing and Grooming
Eating
Arising
Walking
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT 
ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
HYGIENE
Are you able to:
Wash and dry your body?
Take a tub bath?
Get on and off the toilet?
REACH
Are you able to:
Reach and get down a 5-pound 
object (such as a bag of sugar) 
from just above your head?
Bend down to pick up clothing 
from the floor?
GRIP
Are you able to:
Open car doors?
Open jars which have been 
previously opened?
Turn faucets on and off?
ACTIVITIES
Are you able to:
Run errands and shop?
Get in and out of a car?
Do chores such as vacuuming or 
yardwork?

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Please check any AIDS OR DEVICES that you usually use for any of these activities:
Raised toilet seat
Bathtub bar
Bathtub seat
Long-handled appliances for reach
Jar opener (for jars previously opened)
Long-handled appliances in bathroom
Other (Specify: ___________________)
Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
Hygiene
Gripping and opening things
Reach
Errands and chores
HAQ – United States/English
HAQ-DI_AU1.0-eng-USori.doc
© Stanford University

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Appendix H.
FACIT-Fatigue Scale (Version 4) English Version – Sample
Below is a list of statements that other people with your illness have said are important.  
By circling one (1) number per line, please indicate how true each statement has 
been for you during the past 7 days.
Not at 
All
A little 
bit
Some-
what
Quite a 
bit
Very 
much
I feel fatigued
0
1
2
3
4
I feel weak all over
0
1
2
3
4
I feel listless ("washed out")
0
1
2
3
4
I feel tired
0
1
2
3
4
I have trouble starting things because I am tired
0
1
2
3
4
I have trouble finishing things because I am 
tired
0
1
2
3
4
I have energy
0
1
2
3
4
I am able to do my usual activities
0
1
2
3
4
I need to sleep during the day
0
1
2
3
4
I am too tired to eat
0
1
2
3
4
I need help doing my usual activities
0
1
2
3
4
I am frustrated by being too tired to do the 
things I want to do
0
1
2
3
4
I have to limit my social activity because I am 
tired
0
1
2
3
4

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Appendix I.
Treatment Satisfaction Questionnaire for Medication (TSQM) –
Sample
TSQM (Version 1.4)
Treatment Satisfaction Questionnaire for Medication
Instructions:  Please take some time to think about your level of satisfaction or 
dissatisfaction with the medication you are taking in this clinical trial.  We are interested 
in your evaluation of the effectiveness, side effects, and convenience of the medication 
over the last two to three weeks, or since you last used it.  For each question, please place 
a single check mark next to the response that most closely corresponds to your own 
experiences.
1.
How satisfied or dissatisfied are you with the ability of the medication to prevent or 
treat your condition?
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
2.
How satisfied or dissatisfied are you with the way the medication relieves your 
symptoms?
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 

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7 Extremely Satisfied
3.
How satisfied or dissatisfied are you with the amount of time it takes the 
medication to start working? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
4.
As a result of taking this medication, do you experience any side effects at all? 
1 Yes 
0 No (if No, then please skip to Question 9)
5.
How bothersome are the side effects of the medication you take to treat your 
condition? 
1 Extremely Bothersome 
2 Very Bothersome 
3 Somewhat Bothersome 
4 A Little Bothersome 
5 Not at All Bothersome 
6.
To what extent do the side effects interfere with your physical health and ability to 
function (i.e., strength, energy levels, etc.)? 
1 A Great Deal 
2 Quite a Bit 
3 Somewhat
4 Minimally 
5 Not at All 

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7.
To what extent do the side effects interfere with your mental function (i.e., ability 
to think clearly, stay awake, etc.)? 
1 A Great Deal 
2 Quite a Bit 
3 Somewhat 
4 Minimally 
5 Not at All 
8.
To what degree have medication side effects affected your overall satisfaction with 
the medication? 
1 A Great Deal 
2 Quite a Bit 
3 Somewhat 
4 Minimally 
5 Not at All 
9.
How easy or difficult is it to use the medication in its current form? 
1 Extremely Difficult 
2 Very Difficult 
3 Difficult 
4 Somewhat Easy 
5 Easy 
6 Very Easy 
7 Extremely Easy 
10.
How easy or difficult is it to plan when you will use the medication each time? 
1 Extremely Difficult 
2 Very Difficult 
3 Difficult 
4 Somewhat Easy 
5 Easy 

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6 Very Easy 
7 Extremely Easy 
11.
How convenient or inconvenient is it to take the medication as instructed? 
1 Extremely Inconvenient 
2 Very Inconvenient 
3 Inconvenient 
4 Somewhat Convenient 
5 Convenient 
6 Very Convenient 
7 Extremely Convenient 
12.
Overall, how confident are you that taking this medication is a good thing for you? 
1 Not at All Confident 
2 A Little Confident 
3 Somewhat Confident 
4 Very Confident 
5 Extremely Confident 
13.
How certain are you that the good things about your medication outweigh the bad 
things? 
1 Not at All Certain 
2 A Little Certain 
3 Somewhat Certain 
4 Very Certain 
5 Extremely Certain 

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14.
Taking all things into account, how satisfied or dissatisfied are you with this 
medication? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
Quintiles Strategic Research Services© 2004
[Clinical Trial Version]

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Appendix J.
Work Productivity and Activity Impairment (WPAI) – Sample
Rheumatoid Arthritis V2.0 (WPAI:RA)
______________________________________________________________________________________
The following questions ask about the effect of your rheumatoid arthritis on your ability to work and 
perform regular activities.  Please fill in the blanks or circle a number, as indicated.
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.
During the past seven days, how many hours did you miss from work because of problems associated with 
your rheumatoid arthritis?  Include hours you missed on sick days, times you went in late, left early, etc., 
because of your rheumatoid arthritis.  Do not include time you missed to participate in this study.
_____ HOURS
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
During the past seven days, how many hours did you actually work?
_____HOURS (If "0," skip to question 6.)
During the past seven days, how much did your rheumatoid arthritis affect your productivity while you were 
working?  

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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 rheumatoid arthritis 
affected your work only a little, choose a low number.  Choose a high number if rheumatoid arthritis 
affected your work a great deal.
Consider only how much rheumatoid arthritis affected 
productivity while you were working.
Rheumatoid 
arthritis had no 
effect on my work
Rheumatoid arthritis 
completely prevented 
me from working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
During the past seven days, how much did your Rheumatoid arthritis 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 rheumatoid arthritis affected your 
activities only a little, choose a low number.  Choose a high number if rheumatoid arthritis affected your 
activities a great deal.
Consider only how much rheumatoid arthritis affected your ability 
to do your regular daily activities, other than work at a job.
Rheumatoid 
arthritis had no 
effect on my daily 
activities
Rheumatoid arthritis 
completely prevented 
me from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
WPAI:RA  V2.0 (US English)
f:\institut\cultadap\project\3339\study3339\final_versions\wpai-rausaoriq.doc-10/01/2007

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Appendix K.
Short Form-36 (SF-36) Health Survey Questionnaire – Sample
Your Health and Well-Being
SF-36v2® Health Survey © 1992, 1996, 2000, 2010
Medical Outcomes Trust and 
QualityMetric Incorporated.
All Rights Reserved.
SF-36® is a registered trademark of 
Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, 
United States (English))
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 select the one box that best describes your 
answer.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor

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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
The following question is about activities you might do during a typical day.
Does your health now limit you in vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in lifting or carrying groceries?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing several flights of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing one flight of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in bending, kneeling, or stooping? If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking more than a mile?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking several hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in walking one hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in bathing or dressing yourself?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
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?
Cut down on the amount of time you spent on work or other 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

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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?
Accomplished less than you would like 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
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?
Were limited in the kind of work or other 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
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?
Had difficulty performing the work or other activities as a result of your physical 
health (for example, it took extra effort)
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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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?
Cut down on the amount of  time you spent on work or other 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
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?
Accomplished less than you would like 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
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?
Did work or other activities less carefully than usual 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

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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
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
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

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This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel full of life?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks. 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 have you been very nervous?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you felt so down in the dumps that 
nothing could cheer you up?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been 
feeling.  

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How much of the time during the past 4 weeks have you felt calm and peaceful?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you have a lot of energy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you felt downhearted and 
depressed?
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel worn out?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you been happy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel tired?
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, 
etc.)?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
How TRUE or FALSE is the following statement for you?
I seem to get sick a little easier than other people.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
I am as healthy as anybody I know.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false

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How TRUE or FALSE is the following statement for you?  
I expect my health to get worse.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
My health is excellent.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false

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Appendix L.
RAPID-3 Questionnaire/Assessment (in office and at home) –
S
l

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Appendix M.
MRI Assessments and Scoring – Sample
MRI will be performed and assessed following the OMERACT MRI in RA group 
recommendations of a core set of basic MRI sequences, MRI definitions of important RA 
joint pathologies, and an RA MRI scoring system (OMERACT 2002 RAMRIS).
MRI images will be obtained from the most affected by RA wrist and hand (2 nd – 5th
MTP) using high-field and gadolinium contrast acquisition; if both are considered equally 
affected, the dominant wrist and hand will be scanned.
Clinical assessor will be blind for MRI scoring.  Images will be sent for 1 – 2 central 
readers blinded for clinical parameters for assessment of all MRI images.
The pre-requirements for the MRI machines specifications, for the ore set of basic MRI 
sequences acquiring as well as the detailed scoring system for synovitis, bone marrow 
oedema and tenosynovitis will be further detailed in an MRI manual.

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Appendix N.
Ultrasound Assessments and Scoring – Sample
For the sites that will be part of the optional Ultrasound assessment, Grey 
Scale-Ultrasound (GSUS) as well as Power-Doppler Ultrasound (PDUS) will be 
performed to all subjects included in the study at the defined time points of the protocol.
In light of the current evidence, 46-joint validated assessment and 18 tendon/tendon 
compartment assessment will be performed with the inclusion of the following bilateral:
●
Joints:  glenohumeral (i.e., posterior and axillary recesses and biceps sheath), 
elbow (i.e., anterior, posterior and lateral recesses), wrist (i.e., radio-carpal, 
midcarpal, and distal radioulnar joints; dorsal recesses), first through fifth 
metacarpophalangeal (PIP) of the hands (i.e., dorsal and palmar recesses), hip 
(i.e., anterior recess), knee (i.e., anterior and parapatellar recesses) ankle joints 
(i.e., anterior, lateral, and medial recesses of tibiotalar joint; and medial and 
lateral recesses of subtalar joint), and second and fifth metatarsophalangeal 
joints (i.e., dorsal recess).  Joints will be investigated for the presence of 
intra-articular B-mode synovial hypertrophy (SH) and synovial Power Doppler 
(PD) signal.  Ankle SH or synovial PD signal positive will be considered if 
they were detected in either the tibiotalar or the subtalar joints
●
Tendons:  2nd, 4th and 6th extensor compartments at the wrist, 2nd – 5th finger 
flexor tendons, tibialis posterior and peroneal tendons.  Tendons will be 
assessed for GS and Doppler tenosynovitis.
Intra-articular synovial hypertrophy (SH) will be defined according to the Outcome 
Measures in Rheumatology Clinical Trials (OMERACT) as the presence of abnormal 
hypoechoic (relative to subdermal fat) intraarticular tissue that is nondisplaceable and 
poorly compressible.
At each intra-articular synovial recess, B-mode SH will be scored semiquantitatively on a 
scale of 0 – 3 (0, absent; 1, mild; 2, moderate; 3, marked).
Synovial PD signal will be also scored on a semiquantitative scale of 0 – 3 (0, no synovial 
PD signal; 1, mild [≤ 3 PD signals within the SH]; 2, moderate [> 3 PD signals in less 

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than half of the SH area]; 3, marked [PD signals in more than half of the SH area]).  Each 
joint was scored for B-mode SH and synovial PD signal on a scale from 0 to 3.  These 
scores will correspond to the maximum score for SH and PD signal, respectively, 
obtained from any one of the synovial sites evaluated at each joint.  GS and Doppler 
tenosynovitis will be defined and scored according to OMERACT.83,84-86
Technical Requirements:
Different models of ultrasound machines are allowed as long as GS and PD are available.  
It's recommended to use high-end machines as per the training manual which will be 
provided.
US Assessment Conditions:
The US assessments are to be performed during the Screening or Lead-In Period prior to 
dbBaseline Visit by an expert in musculoskeletal ultrasound with verifiable training 
and/or certification and at least 3 years of experience.  Ideally, the Ultrasonographer 
should have prior experience in multicenter study(ies) using ultrasound evaluation in RA 
patients; otherwise training will be provided.  All ultrasound assessors will be provided 
with more details in a US manual.  Ideally the same assessor at each site should perform 
all US evaluations.  The US assessor will be blinded to clinical parameters and the clinical 
assessor will be blinded to US scoring.
B-mode and PD machine settings will be optimized before the study and standardized for 
the whole study.  The US assessment should be performed in a darkened room with 
temperature kept stable.  Patients should have been at least 2 hours resting, and should not 
have drank coffee, alcohol, smoked cigarettes or practiced sport within the prior 8 hours 
or taking NSAIDs within the prior 12 hours.
Further details will be provided in the US manual.

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Appendix O.
ACR 1987 and the ACR/EULAR 2010 Criteria for Classifying RA
The 1987 Criteria for the Classification of RA87
Criterion
Definition
1.  Morning stiffness
Morning stiffness in and around the joints, lasting for at least 
1 hour before maximal improvement
2.  Arthritis of 3 or more joint areas
At least 3 joint areas simultaneously have had soft tissues 
swelling or fluid (not bony overgrowth alone) observed by a 
physician.  The 14 possible joints areas are right or left PIP, 
MCP, wrist, elbow, knee, ankle, and MTP joints
3.  Arthritis of hand joints
At least 1 area swollen (as defined above) in a wrist, MCP or 
PIP joint.
4.  Symmetric arthritis
Simultaneous involvement of the same joint areas (as defined 
in 2) on both sides of the body (bilateral involvement of PIPs, 
MCPs, or MTPs is acceptable without absolute symmetry)
5.  Rheumatoid nodules
Subcutaneous nodules over bony prominences, or extensor 
surfaces, or in juxta-articular regions, observed by a physician
6.  Serum rheumatoid factor
Demonstration of abnormal amounts of serum rheumatoid 
factor by any method for which the result has been positive in 
< 5% of normal control subjects
7.  Radiographic changes
Radiographic changes typical of RA on posteranterior hand 
and wrist radiographs, which must include erosions or 
unequivocal bony decalcification localized in or most marked 
adjacent to the involved joints (osteoarthritis changes alone do 
not qualify)
For classification purposes, a patient is said to have RA if he/she has satisfied at least 4 of 
these 7 criteria.  Criteria 1 through 4 must have been present for at least 6 weeks.  Patients 
with 2 clinical diagnoses are not excluded.  Designation as classic, definite or probable 
RA is not to be made.
The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.88
Target population (Who should be tested?):  Patients who:
1.
Have at least 1 joint with definite clinical synovitis (swelling)*
2.
With the synovitis not better explained by another diseaseâ€

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Classification criteria for RA (score-based algorithm:  add score of categories A – D; a 
score of ≥ 6/10 is needed for classification of a patient as having definite RA)â€¡
Score
A.  Joint involvement Â§
1 large jointÂ¶
0
2 – 10 large joints
1
1 – 3 small joints (with or without involvement of large joints)#
2
4 – 10 small joints (with or without involvement of large joints)
3
> 10 joints (at least 1 small joint)**
5
B.  Serology (at least 1 test result is needed for classification)â€ â€
Negative RF and negative ACPA
0
Low-positive RF or low-positive ACPA
2
High-positive RF or high-positive ACPA
3
C.  Acute-phase reactants (at least 1 test result is needed for classification)â€¡â€¡
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
D.  Duration of symptomsÂ§Â§
< 6 weeks
0
≥ 6 weeks
1
*
The criteria are aimed at classification of newly presenting patients.  In addition, patients with erosive disease 
typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should 
be classified as having RA.  Patients with longstanding disease, including those whose disease is inactive (with 
or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria 
should be classified as having RA.
â€
Differential diagnoses vary among patients with different presentations, but may include conditions such as 
systemic lupus erythematosus, psoriatic arthritis, and gout.  If it is unclear about the relevant differential 
diagnoses to consider, an expert rheumatologist should be consulted.
â€¡
Although patients with a score of < 6/10 are not classifiable as having RA, their status can be reassessed and 
the criteria might be fulfilled cumulatively over time.
Â§
Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging 
evidence of synovitis.  Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal 
joints are excluded from assessment.  Categories of joint distribution are classified according to the location 
and number of involved joints, with placement into the highest category possible based on the pattern of joint 
involvement.
Â¶
"Large joints" refers to shoulders, elbows, hips, knees, and ankles.
#
"Small joints" refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through 
fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
**
In this category, at least 1 of the involved joints must be a small joint; the other joints can include any 
combination of large and additional small joints, as well as other joints not specifically listed elsewhere 
(e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.).

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â€ â€
Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory 
and assay; low-positive refers to IU values that are higher than the ULN but ≤ 3 times the ULN for the 
laboratory and assay; high-positive refers to IU values that are > 3 times the ULN for the laboratory and assay. 
Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be 
scored as low-positive for RF.  ACPA = anti-citrullinated protein antibody.
â€¡â€¡
Normal/abnormal is determined by local laboratory standards.  CRP = C-reactive protein; ESR = erythrocyte 
sedimentation rate.
Â§Â§
Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, 
swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment 
status.

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Appendix P.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor:" previously read:
Sponsor:
For Non-EU Countries:
AbbVie
1 North Waukegan Road 
North Chicago, IL  
60064
For EU Countries:
AbbVie Deutschland 
GmbH & Co. KG 
(AbbVie) 
Knollstrasse 50
67061 Ludwigshafen 
Germany
Has been changed to read:
Sponsor:
For Non-EU Countries:
AbbVie
1 North Waukegan Road 
North Chicago, IL  60064
For EU Countries:
AbbVie Deutschland 
GmbH & Co. KG 
(AbbVie) 
Knollstrasse 50
67061 Ludwigshafen 
Germany
Section 1.1  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-500
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  15 May 2014
Protocol Title:
A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques Drug 
Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical 
Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)

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Objectives:
The primary objective is to investigate the association between residual disease activity at Baseline as 
detected by magnetic resonance imaging (MRI) and the occurrence of flares in RA subjects randomized 
to an adalimumab dose tapering regimen controlled by adalimumab withdrawal.
The Secondary Objectives are:
!
To assess the occurrence and severity of flares and the time to flare in both taper and withdrawal 
arms.
!
To investigate the association between Double-Bind Baseline (dbBaseline) subject demographic 
and disease characteristics and the occurrence of flares.
!
To investigate the association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares.
!
To evaluate the effectiveness of rescue therapy with open-label adalimumab 40 mg every other 
week (eow) over 16 weeks in subjects experiencing a flare. 
!
To assess the change in rheumatoid arthritis MRI scoring system (RAMRIS) scores from 
Baseline to Final visit in the taper, withdrawal and Open-Label Rescue Arms.
!
To describe the course of disease using clinical and patient reported outcomes (PROs) measures 
in the taper, withdrawal and Open-Label Rescue Arms.
!
To assess the rate of anti-adalimumab antibodies (AAA) positive subjects in the taper and 
withdrawal arms.
The study also has the following exploratory objectives:
!
In the subgroup of subjects with a dbBaseline Ultrasound (US) assessment: 
o
To investigate the association between dbBaseline ultrasound scores and the occurrence of 
flares. 
o
To investigate the association between the dbBaseline ultrasound scores and Baseline MRI 
RAMRIS scores.
o
To describe the change in the ultrasound scores from dbBaseline to the time of the 
occurrence of a flare in the taper and withdrawal arms.
!
To investigate the association between biomarker values at dbBaseline (or their change over 
time) and the occurrence of flares.
Investigators:  Investigator information is on file at AbbVie.
Study Sites: Approximately 53 sites
Study Population:
Subjects age ≥ 18 years diagnosed with RA, on a stable dose of adalimumab 40 mg subcutaneously (sc) 
eow (for ≥ 12 months prior to Screening Visit) in combination with methotrexate (MTX) (at stable dose 
for ≥ 12 weeks prior to the Screening Visit) and in documented clinical remission, defined as DAS28 
erythrocyte sedimentation rate (ESR) < 2.6 or DAS28 c-reactive protein (CRP) < 2.6, for ≥ 6 months 
prior to the Screening Visit and DAS28 (ESR) < 2.6 at the Screening Visit.
Number of Subjects to be Enrolled:  Approximately 334

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Methodology:
This is a Phase 4, multicenter, randomized, double-blind, parallel-group study in subjects with RA who 
are in stable clinical remission defined as DAS28 (ESR) or DAS28 (CRP) < 2.6 for at least 6 months 
prior to the Screening Visit.  Though the cut-off for clinical remission of DAS28 (CRP) may not be 
equivalent to the DAS (ESR), in clinical practice both are frequently used to define remission as < 2.6.  
Both will be allowed for the purposes of identifying subjects for Screening; however, throughout the 
study clinical remission will be defined by the more stringent DAS28 (ESR) < 2.6 criteria.  At 
Screening, only subjects with confirmed DAS28 (ESR) < 2.6 will be considered for inclusion in the 
study.
The study activities will start with a Screening Period of up to 21 days to confirm inclusion/exclusion 
criteria including a DAS28 (ESR) assessment of < 2.6.
Subjects who have signed the Informed Consent and who fulfill all Screening criteria will enter the 
study.  Study starts with a 4-week Lead-In Open-Label (OL) Period during which stable DAS28 (ESR) 
clinical remission in 2 assessments 4 weeks apart will be confirmed.  Subjects will receive adalimumab 
40 mg sc eow starting at Week 0 Visit of the Lead-In Period; this will be approximately 2 weeks after 
their last commercial Humira®.
At Week 4, the end of the Lead-In Period, subjects will have a dbBaseline visit.  Subjects must have a 
confirmed DAS28 (ESR) remission at two time points in order to be randomized:
1.
DAS28 (ESR) < 2.6 at the Lead-In Period Week 0
2.
DAS28 (ESR) < 2.6 at the dbBaseline visit Week 4
Subjects who meet the remission criteria will be randomized (5:1) to one of two double-blind arms and 
followed for additional 36 weeks in the Double-Blind Period: 
1.
A reduced frequency of adalimumab 40 mg sc every 3 weeks (q3wks):  taper arm, or
2.
Adalimumab placebo sc q3wks:  withdrawal arm.
All subjects will maintain the required MTX (any dose; oral or sc) at a stable dose for at least 12 weeks 
prior to Screening and throughout the Lead-In and Double-Blind Periods of study. 
Any other allowed RA concomitant medications should also be kept stable throughout the Lead-In and 
Double-Blind Periods of the study; these medications and MTX will be received by local prescriptions. 
During the Double-Blind Period, subjects will be evaluated every 6 weeks for efficacy, including 
detection of flares, PROs, safety and laboratory assessments at scheduled visits on:  Weeks 4, 10, 16, 22, 
28, 34 and 40 (Final visit).
Other unscheduled visits will occur in the suspected event of a flare.  During the interval between 
scheduled visits, subjects will be asked to contact their physicians in case of feeling their disease is 
worsening:  an unscheduled visit will be performed within 2 weeks of contact with the site to assess if 
subjects are experiencing a flare.

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Methodology (Continued):
Subjects with a confirmed flare (defined as an increase from dbBaseline in DAS28 [ESR] of > 0.6 AND 
a DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 
[ESR]) at any time point (at a scheduled or unscheduled visit) will undergo Flare Week 0 visit 
procedures and will be immediately switched to an Open-label rescue arm initiating adalimumab 40 mg 
eow rescue therapy.
In the Open-Label Rescue Arm, subjects will be further evaluated at Flare Weeks 4, 10 and 16 for 
efficacy, PROs, safety and laboratory assessments.
During this period, further treatment escalation/change will be allowed based on the Investigator's 
medical judgment.  Any treatments escalation/change will be documented.  At Flare Week 0, all subjects 
will be requested to initiate weekly at home self-assessment of their RA disease activity by using 
Routine Assessment of Patient Index Data (RAPID)-3 questionnaire until Week 16.
See study schematic below:
A high-field contrast MRI of the most affected or of the dominant hand (2nd to 5th MCP) and wrist (if 
both sides are considered equally affected), will be performed on all subjects during the Lead-In Period 
(prior to the dbBaseline visit) and at Final/Early Termination Visit.
The acquired MRI images will be centrally read and Investigators will be blinded to the results.  Subjects 
should be randomized only when the MRI has been confirmed to be received and complete by Central 
Imaging.

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Methodology (Continued):
In sites that meet pre-specified ultrasound requirements and who wish to participate in the ultrasound 
portion of the study, subjects will undergo US assessment using Gray Scale Ultrasonography (GSUS) 
and Power Doppler Ultrasonography (PDUS) consisting in a systematic longitudinal and transverse 
multiplanar examination of 46 joints and 18 tendon/tendon compartment during Lead-In or at dbBaseline 
Visit prior to randomization and at the Flare Week 0 Visit (if applicable).  US will be performed and 
assessed by local Ultrasonographer independent of the clinical assessor who will be blinded to the US 
scores.
Pharmacokinetics (PK) and immunogenicity will be assessed based on serum adalimumab trough 
concentrations and serum anti-adalimumab antibodies (AAA), respectively.  Blood samples for 
adalimumab concentrations and measurements of AAA will be taken prior to dosing at dbBaseline 
(Week 4), at Weeks 10, 16, 28, 40 and at Early Termination, Flare Weeks 0, 4 and 16 (if applicable).
A panel of inflammatory biomarkers:  matrix metalloproteinase 3 (MMP3), Collagen neo-epitope 
(C1M), Type III collagen neo-epitope (C3M), Matrix metalloproteinase-mediated c-reactive protein 
(CRPM), Matrix metalloproteinase-degraded citrullinated vimentin (VICM), Serum amyloid-associated 
protein (SAA), Interleucin-6 (IL-6), Chemokine (C-X-C motif) ligand 10 CXCL10 and CXCL13 will be 
assessed at dbBaseline (Week 4), Weeks 10, 16, 28, 40 or at Early Termination, Flare Weeks 0, 4 and 
16 (if applicable) on blood samples taken prior to dosing.  At the time of analysis, other potential 
biomarkers identified as adding value to predict flare in this patient population may be included.
Additional optional samples for future biomarker research will be collected.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Male or female subjects ≥ 18 years of age.
2.
Subject has a diagnosis of RA as defined by the 1987 revised ACR classification criteria and/or the 
ACR/EULAR 2010 classification criteria (any duration since diagnosis).
3.
Subject must meet the following criteria:
!
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to Screening Visit;
!
Must be treated with concomitant MTX at a stable dose (oral or sc at any dose) for at least 
12 weeks prior to Screening Visit.
4.
Subject must be in sustained clinical remission based on the following:
!
At least one documented DAS28 (ESR) or DAS28 (CRP) < 2.6 (or calculated based on 
documented components of the DAS28) in the patient chart 6 months or longer prior to the 
Screening Visit;
!
DAS28 (ESR) assessed at Screening < 2.6, with all components including ESR assessed at 
Screening.
5.
If subjects are receiving concomitant conventional synthetic disease-modifying anti-rheumatic 
drugs (csDMARDs) in addition to MTX, the dose must be stable for at least 12 weeks prior to the 
Screening Visit (e.g., chloroquine, hydroxychloroquine, sulfasalazine, gold formulations [including 
auranofin, gold sodium thiomalate, and aurothioglucose] and/or leflunomide).
6.
If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent must be 
< 10 mg/day and the dose must be stable for at least 4 weeks prior to the Screening Visit.
7. 
If subjects are receiving non-steroidal anti-inflammatory drugs (NSAIDs) the dose must be stable 
for at least 4 weeks prior to the Screening Visit.
8.
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Any DAS28 (ESR) or DAS28 (CRP) (or calculated based on documented components of the 
DAS28) assessed within 6 months prior to the Screening Visit ≥ 2.6.
2.
Subject is on an additional concomitant biological disease-modifying anti-rheumatic drug 
(bDMARD) (including but not limited to abatacept, anakinra, certolizumab, etanercept, golimumab, 
infliximab, rituximab or tocilizumab).
3.
Subject has been treated with intra-articular or parenteral corticosteroids within the last 4 weeks 
before Screening.
4.
Subject has undergone joint surgery within 12 weeks of Screening (at joints to be assessed by MRI 
and/or ultrasound).
5.
Subject has a medical condition precluding an MRI (e.g., magnetic activated implanted
devices – cardiac pace-maker, insulin pump, neurostimulators, etc. and metallic devices or 
fragments or clips in the eye, brain or spinal canal and in the hand/wrist undergoing MRI).
6.
Subject has a medical condition precluding a contrast MRI with gadolinium (e.g., nephrogenic 
systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast 
agent, pregnancy or breastfeeding, severe renal insufficiency with an estimated Glomerular 
Filtration Rate [eGFR] below 30 mL/min/1.73 m2 at Screening, hepato-renal syndrome, severe 
chronic liver function impairment).
7.
Subject has been treated with any investigational drug of chemical or biologic nature within a 
minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to the Screening Visit.
Investigational Product:
Adalimumab
Dose:
Lead-In Period:  Adalimumab 40 mg OL eow for 4 weeks
Double-Blind Period:  Adalimumab 40 mg q3wks for 36 weeks
Open-Label Rescue Arm:  Adalimumab 40 mg OL eow for a minimum 
of 16 weeks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe
Reference Therapy:
Placebo for the Double-Blind Period
Dose:
0.8 ml q3wks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe
Duration of Treatment:
The duration of treatment will include a 4-week Lead-In Period (adalimumab 40 mg sc eow) followed by 
a 36-week, randomized, Double-Blind Period with 2 arms:  taper arm (adalimumab 40 mg sc q3wks) 
controlled by matching placebo.  Open-Label Rescue Arm (adalimumab 40 mg sc eow) will be provided 
for 16 weeks (if applicable).  Therefore, the total duration of the study is 40 or 56 weeks (if applicable).

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Criteria for Evaluation:
Efficacy:
Primary Efficacy Variables
!
The primary explanatory variables are the Baseline hand and wrist synovitis and bone marrow 
edema (BME) RAMRIS scores as well as a composite of both and the dependent variable is the 
occurrence of flare up to Week 40 in the tapering arm.
Secondary Variables
!
Time to flare
!
Flare severity
!
Proportion of subjects experiencing a flare
!
Subject demographics and clinical disease characteristics at dbBaseline, including
o
Smoking status, co-morbidities, anti-citrullinated peptide antibody (ACPA) status, Rheumatoid 
Factor (RF) status, disease duration, previous treatment with conventional synthetic Disease 
Modifying Anti-rheumatic Drugs (csDMARDs) or biologic Disease Modifying Anti-rheumatic 
Drugs (bDMARDs) or both, duration of adalimumab therapy, remission duration, disease 
activity, c-reactive protein (CRP) and Health Assessment Questionnaire (HAQ) score
!
Proportion of subjects who regain clinical remission (defined as DAS28 [ESR] < 2.6 and defined as 
DAS28 (ESR) decrease > 1.2 if DAS28 [ESR] was less than 2.6 at flare) in the Open-Label Rescue 
Arm over time
!
Time to regain clinical remission in the Open-Label Rescue Arm
!
Proportion of subjects with low disease activity (defined as DAS28 [ESR] < 3.2)  in the Open-Label 
Rescue Arm over time
!
Change from Baseline in DAS28 (ESR), Clinical Disease Activity Index (CDAI) and Simplified 
Disease Activity Index (SDAI)
!
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI and CDAI:  DAS28 
[ESR] < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8) throughout the study
!
Change from dbBaseline to Week 40 or final Visit in MRI synovitis, BME and erosions RAMRIS 
scores 
!
Change from Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) over time
!
Proportion of subjects with HAQ-DI normal (HAQ-DI ≤ 0.5) at dbBaseline and at Week 40
!
Change from dbBaseline in RAPID 3 scores assessed during Visits
!
Change from Flare Week 0 in RAPID 3 at home assessments
!
Change from dbBaseline in Swollen Joint Count (both 28 and 66 joints)
!
Change from dbBaseline in Tender joint Count (both 28 and 68 joints)
!
Change from dbBaseline  in Patient's Global Assessment of Disease activity 
!
Change from dbBaseline  in Patient's Global Assessment of RA pain 
!
Change from dbBaseline in Physician's Global Assessment of Disease activity
!
Change from dbBaseline in morning stiffness assessment
!
Change from dbBaseline in Sleep disturbance assessment
!
Change from dbBaseline in Treatment Satisfaction Questionnaire for Medication (TSQM)
!
Change from dbBaseline in Work Productivity and Activity Impairment (WPAI)

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Criteria for Evaluation (Continued):
Efficacy(Continued):
Secondary Variables (Continued):
!
Change from dbBaseline in Short Form-36 (SF-36)
!
Change from dbBaseline in Functional Assessment of Chronic Illness Therapy – fatigue 
(FACIT-fatigue)
!
Change from dbBaseline in CRP
!
Change from dbBaseline in ESR
Exploratory Variables
!
dbBaseline and change from dbBaseline to the time of flare in PDUS and GSUS individual and 
composite scores of synovitis, synovial hypertrophy and tenosynovitis 
!
dbBaseline and change from dbBaseline on biomarker values (MMP3, SAA, C1M, C3M, CRPM, 
VICM, IL-6, CXCL10, CXCL13)
Pharmacokinetics:
!
Adalimumab concentrations  measurement dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early 
Termination, Flare Weeks 0, 4 and 16 (if applicable)
!
AAA measurement at dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early Termination, Flare 
Weeks 0, 4, 10 and 16 (if applicable)
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical and 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.
Interim Analysis for Double-Blind Baseline Characteristics:
There are few data describing patient disease characteristics, including markers of residual inflammation 
(such as sensitive imaging assessments and potential biomarkers) and drug levels in patients who are in 
sustained RA clinical remission on a stable treatment with a TNFi and MTX.  An interim analysis will 
be conducted to describe the dbBaseline characteristics of this RA population.  It will be performed after 
the dbBaseline assessments and randomization of the entire study population have been completed.

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Statistical Methods:
Efficacy:
Analysis for Primary Objective:
The association between the occurrence of flares and Baseline MRI RAMRIS scores will be examined 
using logistic regression, which is deemed as the main analysis to address the primary objective.  
Additional analyses will be performed to assess this association using various statistical methods.  
Specifically, descriptive statistics of Baseline MRI RAMRIS scores will be provided for the two groups 
of subjects who flare and who do not flare, and the between-group difference in the mean scores will be 
computed together with a 90% confidence interval (CI).  Linear regression will be used to model the 
relationship between the DAS28 (ESR) at flaring (or at end of study for subjects who do not flare) and 
the Baseline MRI RAMRIS scores.  Receiver operating characteristic (ROC) curve approach will also be 
utilized to investigate the potential flare prediction criteria based on MRI RAMRIS scores.  All model 
based analyses may adjust for dbBaseline clinical patient characteristics including disease duration, 
previous treatment, etc. when appropriate.
Similar analysis will be conducted for RAMRIS synovitis scores, BME scores and the composite of 
both.
Analysis for Secondary Objectives:
Within the analyses to address the secondary objectives the association between dbBaseline disease 
characteristics and the occurrence of flares will be examined using similar analyses as for the primary 
objective.  In addition, characterization of flares, response to rescue therapy in subjects experiencing a 
flare and the clinical and patient reported efficacy outcomes for all trial subjects will be analyzed 
accordingly.
Pharmacokinetic:
Adalimumab trough serum concentrations will be summarized by treatment arm at each time point using 
descriptive statistics.  The association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares will be assessed.  In addition, pharmacokinetic model-based analyses may 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 study arm, and rates of AAA positive subjects will be 
calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), 
and treatment emergent adverse events may be evaluated.
Safety:
Frequency tables and lists of subjects with treatment-emergent AEs by preferred term as in the Medical 
Dictionary for Regulatory Activities (MedDRA) 17.0 dictionary, by system organ class and by causality 
to the study medication as assessed by the Investigator will be provided.  Laboratory test values will be 
summarized over time.

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Determination of Sample Size:
The planned total number of subjects enrolled into the Lead-In Period is approximately 334.
To estimate the odds ratio for the occurrence of flare with baseline MRI score based on historical MRI 
data, an effective sample size of 250 subjects in the dose tapering group will ensure a precision for the 
estimation with the width of 90% CI no more than 0.1 for an odds ratio 1.2, no more than 0.4 for an odds 
ratio 1.5, and no more than 1.0 for an odds ratio 1.8.  Such sample size will also ensure a precision for 
the estimation of a continuous correlation coefficient ρ with the half width of 90% CI of ρ no more than 
0.1 for a mild correlation coefficient 0.2, no more than 0.09 for a moderate correlation coefficient 0.4, 
and no more than 0.07 for a higher correlation with ρ = 0.6.  Assuming a 30% flare rate, this sample size 
will provide the precision that the 2-sided 90% CI of the flare rate has a half width no more than 5%.
Under a 5:1 randomization ratio (dose tapering vs. withdrawal), a total of 300 subjects will be 
randomized.  Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
334 subjects will need to be enrolled into the Lead-In Period.

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Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-500
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  25 February 2016
Protocol Title:
A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques Drug 
Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical 
Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)
Objectives:
The primary objective is to investigate the association between residual disease activity at Baseline as 
detected by magnetic resonance imaging (MRI) and the occurrence of flares in RA subjects randomized 
to an adalimumab dose tapering regimen controlled by adalimumab withdrawal.
The Secondary Objectives are:
!
To assess the occurrence and severity of flares and the time to flare in both taper and withdrawal 
arms.
!
To investigate the association between Double-Blind Baseline (dbBaseline) subject 
demographic and disease characteristics and the occurrence of flares.
!
To investigate the association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares.
!
To evaluate the effectiveness of rescue therapy with open-label adalimumab 40 mg every other 
week (eow) over 16 weeks in subjects experiencing a flare. 
!
To assess the change in rheumatoid arthritis MRI scoring system (RAMRIS) scores from 
Baseline to Final visit in the taper, withdrawal and Open-Label Rescue Arms.
!
To investigate the MRI-flare associations in sub-groups of subjects who meet additional clinical 
remission criteria at dbBaseline including simplified disease activity index (SDAI) ≤ 3.3, 
clinical diseases activity index (CDAI) ≤ 2.8 and ACR/EULAR 2011 boolean-based remission, 
as well as to describe the course of disease and patient reported outcome (PRO) measures in the 
taper, withdrawal and Open-Label Rescue Arms overall and per dbBaseline subgroup.
!
To assess the rate of anti-adalimumab antibodies (AAA) positive subjects in the taper and 
withdrawal arms.
The study also has the following exploratory objectives:
!
In the subgroup of subjects with a Baseline Ultrasound (US) assessment: 
o
To investigate the association between Baseline ultrasound scores and the occurrence of 
flares. 
o
To investigate the association between the Baseline ultrasound scores and Baseline MRI 
RAMRIS scores.
o
To describe the change in the ultrasound scores from Baseline to the time of the occurrence 
of a flare in the taper and withdrawal arms.
!
To investigate the association between biomarker values at dbBaseline (and their change over 
time) and the occurrence of flares.

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Investigators:  Investigator information is on file at AbbVie.
Study Sites: Approximately 72 sites in North America, Europe and Australia
Study Population:
Subjects age ≥ 18 years diagnosed with RA, on a stable dose of adalimumab 40 mg subcutaneously (sc) 
eow (for ≥ 12 months prior to Week 0 Visit) in combination with methotrexate (MTX) (at stable dose for 
≥ 12 weeks prior to Week 0 Visit) or if not on MTX, another allowed conventional synthetic 
disease-modifying anti-rheumatic drugs (csDMARDs) at stable dose or no csDMARDs for ≥ 12 weeks 
prior to Week 0 Visit) and in documented clinical remission, defined as DAS28 erythrocyte 
sedimentation rate (ESR) < 2.6 or DAS28 c-reactive protein (CRP) < 2.6, for ≥ 6 months prior to the 
Screening Visit and DAS28 (ESR) < 2.6 at the Screening Visit.  Patients who are not treated with 
concomitant stable dose of MTX are limited to a maximum of 20% of the study population.
Number of Subjects to be Enrolled:  Approximately 200  
Methodology:
This is a Phase 4, multicenter, randomized, double-blind, parallel-group study in subjects with RA who 
are in stable clinical remission defined as DAS28 (ESR) or DAS28 (CRP) < 2.6 for at least 6 months 
prior to the Screening Visit.  Though the cut-off for clinical remission of DAS28 (CRP) may not be 
equivalent to the DAS (ESR), in clinical practice both are frequently used to define remission as < 2.6.  
Both ESR or CRP and 4 or 3 (when Patient Global Assessment [PGA] is not available) variables DAS28 
will be allowed for the purposes of identifying subjects for Screening; however, throughout the study 
clinical remission will be defined by the more stringent 4 variables DAS28 (ESR) < 2.6 criteria.  At 
Screening, only subjects with confirmed 4 variables DAS28 (ESR) < 2.6 will be considered for inclusion 
in the study.
The study activities will start with a Screening Period of up to 28 days to confirm inclusion/exclusion 
criteria including a DAS28 (ESR) assessment of < 2.6.
Subjects who have signed the Informed Consent and who fulfill all Screening criteria will enter the 
study.  The study starts with a 4-week Lead-In Open-Label (OL) Period during which stable DAS28 
(ESR) clinical remission in 2 assessments 4 weeks apart will be confirmed.  Subjects will receive 
adalimumab 40 mg sc eow starting at the Week 0 Visit of the Lead-In Period; this will be approximately 
2 weeks after their last commercial Humira®.  If needed for study procedures completion or injection 
scheduling adjustment, the lead-in period can be extended for up to 2 more weeks in which case the 
Week 4 Visit study procedures will occur up to 6 weeks after the Week 0 Visit.
At Week 4, the end of the Lead-In Period, subjects will have a dbBaseline visit.  Subjects must have a 
confirmed DAS28 (ESR) remission at two time points in order to be randomized:
1.
DAS28 (ESR) < 2.6 at the Lead-In Period Week 0
2.
DAS28 (ESR) < 2.6 at the dbBaseline visit Week 4
Subjects who meet the remission criteria will be randomized (5:1) to one of two double-blind arms and 
followed for additional 36 weeks in the Double-Blind Period: 
1.
A reduced frequency of adalimumab 40 mg sc every 3 weeks (q3wks):  taper arm, or
2.
Adalimumab placebo sc q3wks:  withdrawal arm.

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Methodology (Continued):
All subjects who are taking concomitant MTX (any dose oral, subcutaneous [sc] or intramuscular [im]) 
and/or other csDMARDs at a stable dose for at least 12 weeks prior to Week 0 Visit will maintain the 
regimen throughout the Lead-In and Double-Blind Periods of study.  Subjects who have not been taking 
any csDMARDs for at least 12 weeks prior to the Week 0 Visit, will also maintain this regimen 
throughout the Lead-In and Double-Blind Periods of study.
Any other allowed RA concomitant medications should also be kept stable throughout the Lead-In and 
Double-Blind Periods of the study; these medications and MTX will be received by local prescriptions. 
During the Double-Blind Period, subjects will be evaluated every 6 weeks for efficacy, including 
detection of flares, PROs, safety and laboratory assessments at scheduled visits on:  Weeks 4, 10, 16, 22, 
28, 34 and 40 (Final visit).
Other unscheduled visits will occur in the suspected event of a flare.  During the interval between 
scheduled visits, subjects will be asked to contact their physicians in case of feeling their disease is 
worsening:  an unscheduled visit will be performed within 2 weeks of contact with the site to assess if 
subjects are experiencing a flare.
Subjects with a confirmed flare (defined as an increase from dbBaseline in DAS28 [ESR] of > 0.6 AND 
a DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 
[ESR]) at any time point (at a scheduled or unscheduled visit) will undergo Flare Week 0 visit 
procedures and will be immediately switched to an Open-label rescue arm initiating adalimumab 40 mg 
eow rescue therapy.
In the Open-Label Rescue Arm, subjects will be further evaluated at Flare Weeks 4, 10 and 16 for 
efficacy, PROs, safety and laboratory assessments.
During this period, further treatment escalation/change will be allowed based on the Investigator's 
medical judgment.  Any treatments escalation/change will be documented.  At Flare Week 0, all subjects 
will be requested to initiate weekly at home self-assessment of their RA disease activity by using 
Routine Assessment of Patient Index Data (RAPID)-3 questionnaires until Week 16.
See study schematic below:

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Methodology (Continued):
A high-field contrast MRI of the most affected hand (2nd to 5th MCP) and wrist will be performed on all 
subjects during the Lead-In Period (prior to the dbBaseline visit) and at Final/Early Termination Visit.  If 
both sides are considered equally affected, the MRI of the dominant hand (2nd to 5th MCP) and wrist will 
be performed.  
The acquired MRI images will be centrally read and Investigators will be blinded to the results.  Subjects 
should be randomized only when the MRI has been confirmed to be received and complete by Central 
Imaging.
In sites that meet pre-specified ultrasound requirements and who wish to participate in the ultrasound 
portion of the study, subjects will undergo US assessment using Gray Scale Ultrasonography (GSUS) 
and Power Doppler Ultrasonography (PDUS) consisting of a systematic longitudinal and transverse 
multiplanar examination of 46 joints and 18 tendon/tendon compartment during Lead-In or at dbBaseline 
Visit prior to randomization and at the Flare Week 0 Visit (if applicable).  US will be performed and 
assessed by local Ultrasonographer independent of the clinical assessor who will be blinded to the US 
scores.
Pharmacokinetics (PK) and immunogenicity will be assessed based on serum adalimumab trough 
concentrations and serum anti-adalimumab antibodies (AAA), respectively.  Blood samples for 
adalimumab concentrations and measurements of AAA will be taken prior to dosing at dbBaseline 
(Week 4), at Weeks 10, 16, 28, 40 and at Early Termination, Flare Weeks 0, 4 and 16 (if applicable).
A panel of inflammatory biomarkers:  matrix metalloproteinase 3 (MMP3), Collagen neo-epitope 
(C1M), Type III collagen neo-epitope (C3M), Matrix metalloproteinase-mediated c-reactive protein 
(CRPM), Matrix metalloproteinase-degraded citrullinated vimentin (VICM), Serum amyloid-associated 
protein (SAA), Interleucin-6 (IL-6), Chemokine (C-X-C motif) ligand 10 CXCL10 and CXCL13 will be 
assessed at dbBaseline (Week 4), Weeks 10, 16, 28, 40 or at Early Termination, Flare Weeks 0, 4 and 
16 (if applicable) on blood samples taken prior to dosing.  At the time of analysis, other potential 
biomarkers identified as adding value to predict flare in this patient population may be included.
Additional optional samples for future biomarker research will be collected.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
!
Male or female subjects ≥ 18 years of age.
!
Subject has a diagnosis of RA as defined by the 1987 revised ACR classification criteria and/or the 
ACR/EULAR 2010 classification criteria (any duration since diagnosis).
!
Subject must meet the following criteria:
o
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to Week 0 Visit;
o
Must be treated with concomitant MTX at a stable dose (oral, sc or im at any dose) for at least 
12 weeks prior to Week 0 Visit or if not on MTX, must be treated with other allowed 
csDMARDs at stable dose for at least 12 weeks prior to Week 0 Visit or if not treated with 
csDMARDs must maintain this regimen for at least 12 weeks prior to Week 0 Visit.
!
Subject must be in sustained clinical remission based on the following:
o
At least one documented 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 
(CRP) < 2.6 (or calculated based on documented components of the DAS28) in the patient chart 
6 months or longer prior to the Screening Visit;
o
4 variables DAS28 (ESR) assessed at Screening < 2.6, with all components including ESR 
assessed at Screening.

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
If subjects are receiving concomitant allowed csDMARDs (in addition or not to MTX) the dose must 
be stable for at least 12 weeks prior to the Week 0 Visit (e.g., chloroquine, hydroxychloroquine, 
sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and aurothioglucose] 
and/or leflunomide).
!
If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent must be 
< 10 mg/day and the dose must be stable for at least 4 weeks prior to the Week 0 Visit.
!
If subjects are receiving concomitant non-steroidal anti-inflammatory drugs (NSAIDs), tramadol or 
other equivalent opioids and/or non-opioid analgesics, the dose and/or therapeutic scheme must be 
stable for at least 4 weeks prior to the Week 0 Visit.
!
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.
Main Exclusion:
!
Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or calculated based 
on documented components of the DAS28) assessed within 6 months prior to the Screening Visit 
≥2.6.
!
Subject is on an additional concomitant biological disease-modifying anti-rheumatic drug 
(bDMARD) (including but not limited to abatacept, anakinra, certolizumab, etanercept, golimumab, 
infliximab, rituximab or tocilizumab).
!
Subject has been treated with intra-articular or parenteral corticosteroids within the last 4 weeks 
before Screening.
!
Subject has undergone joint surgery within 12 weeks of Screening (at joints to be assessed by MRI 
and/or ultrasound).
!
Subject has a medical condition precluding an MRI (e.g., magnetic activated implanted devices –
cardiac pace-maker, insulin pump, neurostimulators, etc. and metallic devices or fragments or clips 
in the eye, brain or spinal canal and in the hand/wrist undergoing MRI).
!
Subject has a medical condition precluding a contrast MRI with gadolinium (e.g., nephrogenic 
systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast 
agent, pregnancy or breastfeeding, severe renal insufficiency with an estimated Glomerular Filtration 
Rate [eGFR] below 30 mL/min/1.73 m2 at Screening, hepato-renal syndrome, severe chronic liver 
function impairment).
!
Subject has been treated with any investigational drug of chemical or biologic nature within a 
minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to the Screening Visit.
Investigational Product:
Adalimumab
Dose:
Lead-In Period:  Adalimumab 40 mg OL eow for 4 weeks
Double-Blind Period:  Adalimumab 40 mg q3wks for 36 weeks
Open-Label Rescue Arm:  Adalimumab 40 mg OL eow for a minimum 
of 16 weeks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe

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Reference Therapy:
Placebo for the Double-Blind Period
Dose:
0.8 ml q3wks
Mode of Administration:
Subcutaneously (SC) pre-filled syringe
Duration of Treatment:
The duration of treatment will include a 4-week Lead-In Period (adalimumab 40 mg sc eow) followed by 
a 36-week, randomized, Double-Blind Period with 2 arms:  taper arm (adalimumab 40 mg sc q3wks) 
controlled by withdrawal matching placebo arm.  Open-Label Rescue Arm (adalimumab 40 mg sc eow) 
will be provided for 16 weeks (if applicable).  Therefore, the total duration of the study is 40 or 56 weeks 
(if applicable).
Criteria for Evaluation:
Efficacy:
Primary Efficacy Variables
!
The primary explanatory variables are the Baseline hand and wrist synovitis and bone marrow 
edema (BME) RAMRIS scores as well as a composite of both and the dependent variable is the 
occurrence of flare up to Week 40 in the tapering arm.
Secondary Variables
!
Time to flare
!
Flare severity
!
Proportion of subjects experiencing a flare
!
Subject demographics and clinical disease characteristics at dbBaseline, including
o
Smoking status, co-morbidities, anti-citrullinated peptide antibody (ACPA) status, Rheumatoid 
Factor (RF) status, disease duration, previous treatment with conventional synthetic Disease 
Modifying Anti-rheumatic Drugs (csDMARDs) or biologic Disease Modifying Anti-rheumatic 
Drugs (bDMARDs) or both, duration of adalimumab therapy, remission duration, disease 
activity, c-reactive protein (CRP) and Health Assessment Questionnaire (HAQ) score
!
Proportion of subjects who regain clinical remission (defined as DAS28 [ESR] < 2.6 and defined as 
DAS28 (ESR) decrease > 1.2 if DAS28 [ESR] was less than 2.6 at flare) in the Open-Label Rescue
Arm over time
!
Time to regain clinical remission in the Open-Label Rescue Arm
!
Proportion of subjects with low disease activity (defined as DAS28 [ESR] < 3.2)  in the Open-Label 
Rescue Arm over time
!
Change from Baseline in DAS28 (ESR), Clinical Disease Activity Index (CDAI) and Simplified 
Disease Activity Index (SDAI)
!
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI and CDAI:  DAS28 
[ESR] < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8) throughout the study
!
Change from dbBaseline to Week 40 or final Visit in MRI synovitis, BME and erosions RAMRIS 
scores
!
Change from Baseline in DAS28 (ESR), Clinical Disease Activity Index (CDAI) and Simplified 
Disease Activity Index (SDAI)
!
Proportion of subjects  maintaining clinical remission (defined by DAS, SDAI and CDAI:  DAS28 
[ESR] < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8) throughout the study

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Secondary Variables (Continued)
!
Change from dbBaseline to Week 40 or final Visit in MRI synovitis, BME and erosions RAMRIS
scores 
!
Change from Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) over time
!
Proportion of subjects with HAQ-DI normal (HAQ-DI ≤ 0.5) at dbBaseline and at Week 40
!
Change from dbBaseline in RAPID 3 scores assessed during Visits
!
Change from Flare Week 0 in RAPID 3 at home assessments
!
Change from dbBaseline in Swollen Joint Count (both 28 and 66 joints)
!
Change from dbBaseline in Tender joint Count (both 28 and 68 joints)
!
Change from dbBaseline  in Patient's Global Assessment of Disease activity 
!
Change from dbBaseline  in Patient's Global Assessment of RA pain 
!
Change from dbBaseline in Physician's Global Assessment of Disease activity
!
Change from dbBaseline in morning stiffness assessment
!
Change from dbBaseline in Sleep disturbance assessment
!
Change from dbBaseline in Treatment Satisfaction Questionnaire for Medication (TSQM)
!
Change from dbBaseline in Work Productivity and Activity Impairment (WPAI)
!
Change from dbBaseline in Short Form-36 (SF-36)
!
Change from dbBaseline in Functional Assessment of Chronic Illness Therapy – fatigue 
(FACIT-fatigue)
!
Change from dbBaseline in CRP
!
Change from dbBaseline in ESR
Exploratory Variables
!
Baseline and change from Baseline to the time of flare in PDUS and GSUS individual and 
composite scores of synovitis, synovial hypertrophy and tenosynovitis
!
dbBaseline and change from dbBaseline on biomarker values (MMP3, SAA, C1M, C3M, CRPM, 
VICM, IL-6, CXCL10, CXCL13)
Pharmacokinetics:
!
Adalimumab concentrations  measurement dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early 
Termination, Flare Weeks 0, 4 and 16 (if applicable)
!
AAA measurement at dbBaseline (Week 4), Week 10, 16, 28, 40 and at Early Termination, Flare 
Weeks 0, 4, 10 and 16 (if applicable)
Interim Analysis for Double-Blind Baseline Characteristics:
There are few data describing patient disease characteristics, including markers of residual inflammation 
(such as sensitive imaging assessments and potential biomarkers) and drug levels in patients who are in 
sustained RA clinical remission on a stable treatment with a TNFi and MTX and/or with other 
csDMARDs(s) or in TNFi monotherapy.  An interim analysis will be conducted to describe the 
dbBaseline characteristics of this RA population.  It will be performed after the dbBaseline assessments 
and randomization of the entire study population have been completed.

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Criteria for Evaluation (Continued):
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical and 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.
Statistical Methods:
Efficacy:
Analysis for Primary Objective:
The association between the occurrence of flares and Baseline MRI RAMRIS scores will be examined 
using logistic regression, which is deemed as the main analysis to address the primary objective.  
Additional analyses will be performed to assess this association using various statistical methods.  
Specifically, descriptive statistics of Baseline MRI RAMRIS scores will be provided for the two groups 
of subjects who flare and who do not flare, and the between-group difference in the mean scores will be 
computed together with a 90% confidence interval (CI).  Linear regression will be used to model the 
relationship between the DAS28 (ESR) at flaring (or at end of study for subjects who do not flare) and 
the Baseline MRI RAMRIS scores.  Receiver operating characteristic (ROC) curve approach will also be 
utilized to investigate the potential flare prediction criteria based on MRI RAMRIS scores.  All model 
based analyses may adjust for dbBaseline clinical patient characteristics including disease duration, 
previous and concomitant treatment, etc. when appropriate.
Similar analysis will be conducted for RAMRIS synovitis scores, BME scores and the composite of 
both.
Analysis for Secondary Objectives:
Within the analyses to address the secondary objectives the association between dbBaseline disease 
characteristics and the occurrence of flares will be examined using similar analyses as for the primary 
objective.  In addition, characterization of flares, response to rescue therapy in subjects experiencing a 
flare and the clinical and patient reported efficacy outcomes for all trial subjects will be analyzed 
accordingly.
Pharmacokinetic:
Adalimumab trough serum concentrations will be summarized by treatment arm at each time point using 
descriptive statistics.  The association between dbBaseline adalimumab trough concentrations and the 
occurrence of flares will be assessed.  In addition, pharmacokinetic model-based analyses may 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 study arm, and rates of AAA positive subjects 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:
Frequency tables and lists of subjects with treatment-emergent AEs by preferred term as in the Medical 
Dictionary for Regulatory Activities (MedDRA) 17.0 dictionary, by system organ class and by causality 
to the study medication as assessed by the Investigator will be provided.  Laboratory test values will be 
summarized over time.
Determination of Sample Size:
The planned total number of subjects enrolled into the Lead-In Period is approximately 200.
To estimate the odds ratio for the occurrence of flare with baseline MRI score based on historical MRI 
data, an effective sample size of 150 subjects in the dose tapering group will ensure a precision for the 
estimation with the width of 90% CI no more than 0.03 for an odds ratio 1.03, no more than 0.07 for an 
odds ratio 1.1, and no more than 0.14 for an odds ratio 1.2.  Such sample size will also ensure a precision 
for the estimation of a correlation coefficient ρ with the width of 90% CI of ρ no more than 0.26 for a 
mild correlation coefficient 0.28, no more than 0.18 for a moderate correlation coefficient 0.55, and no 
more than 0.13 for a higher correlation with ρ = 0.67.  Assuming a 30% flare rate, this sample size will 
provide the precision that the 2-sided 90% CI of the flare rate has a half width no more than 6%.
Under a 5:1 randomization ratio (dose tapering vs. withdrawal), a total of 180 subjects will be 
randomized.  Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
200 subjects will need to be enrolled into the Lead-In Period.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "CI"
CI
Confidence Interval
Section 3.3  Rationale for the Study
Sixth paragraph, last sentence previously read:
Re-institution of normal dose/dosing regimen of TNFi in case of flares effectively 
providing patients the same level of disease control they had before?
Has been changed to read:
Is re-institution of normal dose/dosing regimen of TNFi in case of flares effectively 
providing patients the same level of disease control they had before?

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Section 3.3.1  Additional Considerations on Key Study Parameters
Subsection Clinical Remission Defined by DAS28 < 2.6
Last paragraph previously read:
In this study, clinical remission for subjects inclusion in the study is defined by the 
potentially more stringent DAS28 (ESR) < 2.6; flare will be assessed based on 
DAS28(ESR) evaluation at any time point throughout the study (with ESR measured in 
the same visit).  However, due to the common use of both scores in clinical practice, for 
the purpose of identifying subjects for Screening, both DAS28 (ESR) and (CRP) 
documented as being lower than 2.6 for at least 6 months prior to screening will be 
accepted.  At Screening only, subjects with DAS28 (ESR) < 2.6 may be enrolled.
Has been changed to read:
In clinical practice it's relatively frequent to use the also validated 3 variables DAS2832 or 
instead of the most widely used DAS28 4 variables due to difficulties on getting 
documented patient global assessment (PGA) in a Visual Analogue Scale (VAS).  
Moreover, a recent study has shown that despite the existence of individual patient 
baseline differences prior to treatment with TNFi, after 12 weeks of TNFi and particularly 
for the lower range the 3 and 4 variables DAS28 (CRP).scores were similarly sensitive to 
change, highly correlated and the mean inter-score difference was very small.33  
Accordingly, for the purpose of identifying subjects on stable clinical remission for 
≥6 months for Screening, both DAS28 (ESR) and (CRP) 4 or 3 (when PGA is not 
available) variables documented as being lower than 2.6 for at least 6 months prior to 
screening will be accepted.  However, at Screening, only subjects with 4 variables DAS28 
(ESR) < 2.6 may be enrolled and throughout the study clinical remission is defined by the 
4 variables DAS28 (ESR) < 2.6.  Flare will be assessed based on DAS28 (ESR) 
evaluation at any time point throughout the study (with ESR measured in the same visit).
Concomitant Treatments for RA
The 2013 EULAR recommendations update propose that in RA patients who are in stable 
clinical remission particularly if also treated with concomitant csDMARDs(s) tapering a 

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bDMARD is an option; the updated 2015 ACR guidelines also consider tapering RA 
treatments as an option for such a patient population.  Both treatment recommendations 
acknowledge that more data on tapering is needed as part of a research agenda.
It is the aim of this study to assess, in subjects treated in real life clinical practice 
conditions who have DAS28 < 2.6, if imaging-detected sub-clinical inflammation (and 
disease, patient and treatment patterns as well as adalimumab drug level characteristics) 
brings an additional benefit in predicting and informing clinicians about who has a higher 
risk of flare while treated with a reduced dose of adalimumab.
As this study goal is to include patients as treated in routine clinical practice, the patient 
population must be in line with both treatment recommendations and clinical practice.  
Accumulated data from registries and other real world evidence, such as CORRONA,34
US healthcare insurance claims database, 35 BSRBR,36 RABBIT,37 Nor-DMARD38 and 
ARTIS39 are showing that around 30% – 34% of patients being treated with bDMARDs 
including TNFi are on monotherapy even if at initiation of the bDMARD the vast 
majority of patients were on combination therapy.40  As such this study will include 
mainly patients who are in stable remission for more than 6 months as assessed by DAS28 
< 2.6 and after at least 1 year of treatment with adalimumab with concomitant MTX for at 
least the last 12 weeks prior to inclusion; in order to be in line with the current clinical 
practice up to 20% of the study patient population may be composed of subjects who are 
not treated with concomitant stable MTX but instead are treated with other than MTX 
allowed csDMARDs or not treated with a csDMARD as long as this treatment regimen is 
stable for at least 12 weeks prior to Week 0.
Section 3.6  Benefits and Risks
Third paragraph, last sentence previously read:
All subjects will maintain a stable dose of MTX (any dose; oral or sc) and additional RA 
concomitant medication if deemed necessary before enrollment into the study.

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Has been changed to read:
Subjects will maintain a stable dose of MTX (any dose; oral, sc or im) and/or of any other 
additional concomitant RA medication as taken before enrollment into the study.
Section 4.0  Study Objectives
Second paragraph, sixth bullet previously read:
To describe the course of disease using clinical and patient reported outcomes (PROs) 
measures in the taper, withdrawal and Open-Label Rescue Arms.
Has been changed to read:
To investigate the MRI-flare associations in sub-groups of subjects who meet additional 
clinical remission criteria at dbBaseline including simplified disease activity index 
(SDAI) ≤ 3.3, clinical diseases activity index (CDAI) ≤ 2.8 and ACR/EULAR 2011 
boolean-based remission, as well as to describe the course of disease and patient reported 
outcome (PRO) measures in the taper, withdrawal and Open-Label Rescue Arms overall 
and per dbBaseline subgroup.
Section 4.0  Study Objectives
Last paragraph, bullet list read:
●
In the subgroup of subjects with a dbBaseline Ultrasound (US) assessment:
○
To investigate the association between dbBaseline ultrasound scores and 
the occurrence of RA flares.
○
To investigate the association between the dbBaseline ultrasound scores 
and Baseline MRI RAMRIS scores.
○
To describe the change in the ultrasound scores from dbBaseline to the 
time of RA flare in the taper and withdrawal arms.
○
To investigate the association between biomarker values at dbBaseline (or 
their change over time) and the occurrence of RA flares.

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Has been changed to read:
●
In the subgroup of subjects with a Baseline Ultrasound (US) assessment:
○
To investigate the association between Baseline ultrasound scores and the 
occurrence of RA flares.
○
To investigate the association between the Baseline ultrasound scores and 
Baseline MRI RAMRIS scores.
○
To describe the change in the ultrasound scores from Baseline to the time 
of RA flare in the taper and withdrawal arms.
●
To investigate the association between biomarker values at dbBaseline (or 
their change over time) and the occurrence of flares.
Section 5.1  Overall Study Design and Plan:  Description
First paragraph, last paragraph previously read:
The study duration will include a Screening period of up to 21 days, a 4-week Lead-In 
Period with open-label 40 mg adalimumab eow and a 36-week Double-Blind Period with 
40 mg adalimumab/placebo q3wks; subjects who experience a flare at any time will enter 
a Rescue Arm and will be followed for 16 weeks.
Has been changed to read:
The study duration will include a Screening period of up to 28 days, a 4-week Lead-In 
Period with open-label 40 mg adalimumab eow and a 36-week Double-Blind Period with 
40 mg adalimumab/placebo q3wks; subjects who experience a flare at any time will enter 
a Rescue Arm and will be followed for 16 weeks.

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Figure 1.  Study Design Schematic
Previously read:

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Has been changed to read:
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Subsection title and first and second paragraph previously read:
Screening Period
At the Screening Visit, prior to the Lead-In Period, subjects will receive a full explanation 
of the study design and study procedures, provide a written informed consent, and 
undergo the Screening procedures outlined in Table 1.
The target population for the study consists of RA subjects on adalimumab treatment for 
at least 12 months and in stable clinical remission, as defined by a DAS28 (CRP) or 
DAS28 (ESR) < 2.6 for at least 6 months prior to the Screening Visit, in combination with 
MTX (at a stable dose for ≥ 12 weeks prior to Screening Visit).  Subjects with a 
documented DAS28 (CRP) or (ESR) < 2.6 (or availability of all the components that 

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allow for calculation of a DAS28 score) at least 6 months prior to Screening Visit may be 
screened.  However, for enrollment and throughout the study clinical remission will be 
defined by DAS28 (ESR) < 2.6 criteria.
Has been changed to read:
Screening Period (up to 28 days):
At the Screening Visit, prior to the Lead-In Period, subjects will receive a full explanation 
of the study design and study procedures, provide a written informed consent, and 
undergo the Screening procedures outlined in Table 1.  The Screening period may be 
exceptionally extended beyond 28 days upon justification and further consultation with 
Study Designated Physician.  The target population for the study consists of RA subjects 
on adalimumab treatment for at least 12 months and in stable clinical remission, as 
defined by a 4 or 3 (whenever PGA is not available) variables DAS28 (CRP) or DAS28 
(ESR) < 2.6 for at least 6 months prior to the Screening Visit, in combination with MTX 
(at a stable dose for ≥ 12 weeks prior to Week 0 Visit) or if not on MTX, in other allowed 
csDMARDs at a stable dose or not treated with a csDMARD for ≥ 12 weeks prior to 
Week 0 Visit.  Subjects with a documented DAS28 (CRP) or (ESR) < 2.6 (or availability 
of the 4 or at least 3 components that allow for calculation of a DAS28 score) at least 
6 months prior to Screening Visit may be screened.  However, for enrollment and 
throughout the study clinical remission will be defined by 4 variables DAS28 (ESR) 
< 2.6 criteria.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Third paragraph, last sentence previously read:
Confirmation of a DAS28 (ESR) < 2.6 assessed at the Screening Visit is required prior to 
subject inclusion into the Lead-In Period.

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Has been changed to read:
Confirmation of a DAS28 (ESR) < 2.6 assessed at the Screening and at the Week 0 Visit 
is required prior to subject inclusion into the Lead-In Period.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Last paragraph
Add:  new last sentence
If the re-screening visit is occurring within 4 weeks of last screening some other 
procedures may not be required upon discussion and agreement with Study Designated 
Physician.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Lead-In Period 4 Weeks:
Previously read:
Subjects who fulfill all Screening criteria will enter the study with a 4-week Lead-In OL 
Period:  subjects will receive adalimumab 40 mg sc eow starting at Week 0 of the Lead-In 
Period.  Week 0 will occur 2 weeks after the subject's last dose of commercial Humira®
(± 2 days) to keep in line with eow dosing; the second injection will be given 14 days 
thereafter (± 2 days).  Subjects must undergo an MRI scan of the most affected or of the 
dominant hand (2nd to 5th MCP) and wrist (if both sides are considered equally affected) 
during the 4-week Lead-In Period.
MRI images will be read centrally.  Further details regarding MRI requirements, 
procedures and central reading will be provided in an MRI manual.  The assessors will be 
blinded to the clinical assessments and the clinical Investigator will be blinded to the MRI 
assessments.  The dbBaseline Visit and randomization are not dependent on the results or 
report of the central reader.  Subjects should be randomized only when the MRI has been 
confirmed to be received and complete by Central Imaging. 
Sites will be asked at study-start if they want to participate and if they qualify for the 
optional US assessment, according to requirement described in Appendix N and in the US 

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manual.  Sites that participate in US assessments will need to nominate a qualified 
Ultrasonographer to perform and locally assess the US; there will not be a central reading 
of the US images.  The Ultrasonographer will be blinded to the clinical assessments and 
the clinical Investigator will be blinded to the ultrasound assessments.
Has been changed to read:
Subjects who fulfill all Screening criteria will enter the study with a 4-week Lead-In OL 
Period:  subjects will receive adalimumab 40 mg sc eow starting at Week 0 of the Lead-In 
Period.  Week 0 will occur 2 weeks after the subject's last dose of commercial Humira®
(± 2 days) to keep in line with eow dosing.  At the Week 0 visit subjects will undergo the 
corresponding procedures as outlined in Table 1 including DAS28 (ESR) assessment to 
confirm remission using the ESR result from the same day of the visit.  If the subject 
enrollment is confirmed at the Week 0 visit, the subject will stop commercial Humira®
and initiate adalimumab investigational product open-label sc.  The first sc injection will 
be administered at the site at the end of the visit; the second injection will be given 
14 days thereafter (± 3 days) and every other week (± 3 days) until Week 4 dbBaseline 
Visit.  If needed the subject may be assisted by the study team for the self-injection of the 
syringe.  Subjects must undergo a high-field contrast MRI scan of the most affected hand 
(2nd to 5th MCP) and wrist during the Lead-In Period.  If both sides are considered equally 
affected the MRI of the dominant hand (2nd to 5th MCP) and wrist will be performed.
MRI images will be read centrally.  Further details regarding MRI requirements, 
procedures and central reading will be provided in an MRI manual.  The assessors will be 
blinded to the clinical assessments and the clinical Investigator will be blinded to the MRI 
assessments performed centrally.  A local report for safety reasons on urgent and RA 
inflammation related findings other than RA may be viewed by the investigator.  The 
dbBaseline Visit and randomization are not dependent on the results or report of the 
central reader.  Subjects should be randomized only when the MRI has been 
confirmed to be received and complete by Central Imaging.

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Sites will be asked at study-start if they want to participate and if they qualify for the 
optional US assessment, according to requirement described in Appendix N and in the US 
manual.  Sites that participate in US assessments will need to nominate a qualified 
Ultrasonographer to perform and locally assess the US during the Lead-In period or at the 
dbBaseline Visit; there will not be a central reading of the US images.  The 
Ultrasonographer will be blinded to the clinical assessments and the clinical Investigator 
will be blinded to the ultrasound assessments. 
If needed for procedural compliance (e.g., to allow MRI and its certification, for injection 
scheduling adjustment), the lead-in period can be extended up to 2 more weeks  in which 
case the DAS28 (ESR) assessment and all the dbBaseline Week 4 Visit study procedures 
will occur up to 6 weeks after the Week 0 Visit.  These cases or other exceptions related 
with further extension of the Lead-in period should be discussed with the Study 
Designated Physician.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period:
First paragraph
Add:  new last sentence
At the Week 4 visit, if the subject does not meet the DAS28 (ESR) of < 2.6 or if the 
subject is unable to obtain confirmed and certified MRI scan images, the subject would 
need to be discontinued from the study at an Early Termination visit.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period:
Second paragraph previously read:
Subjects with a confirmed DAS28 (ESR) of < 2.6 at the dbBaseline visit, and as such 
fulfilling confirmed DAS28 (ESR) remission at 2 time points:  Day 1 of Lead-In and 
4 weeks later at the dbBaseline visit, will be randomized in a 5:1 ratio to one of 
two double-blind arms and followed for an additional 36 weeks:

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Has been changed to read:
Subjects with a confirmed DAS28 (ESR) of < 2.6 at the dbBaseline visit, and as such 
fulfilling confirmed DAS28 (ESR) remission at 2 time points:  Day 1 of Lead-In and 
4 weeks later (or, exceptionally later) at the dbBaseline visit, will be randomized in a 
5:1 ratio to one of two double-blind arms and followed for an additional 36 weeks:
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period:
Fourth paragraph previously read:
At each scheduled visit subjects will undergo the corresponding procedures as outlined in 
Table 1.  The initial assessments at each of these visits must include ESR assessment and 
the clinical DAS28 components; if the calculated DAS score meets flare criteria described 
below, the visit then becomes a Flare Week 0 Visit; and the stipulated procedures are 
completed.
Has been changed to read:
At each scheduled visit during the double-blind period subjects will undergo the 
corresponding procedures as outlined in Table 1.  The initial assessments at each of these 
visits must include ESR assessment except if the blood puncture for this procedure is very 
painful (in which case subjects should first fulfill the patient questionnaires); if the 
calculated DAS score meets flare criteria described below, the visit then becomes a Flare 
Week 0 Visit; and the stipulated procedures are completed.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period:
Fifth paragraph, first sentence previously read:
Visits should aim to be scheduled in line with the injection date (± 2 days); in this case, 
subjects should be reminded not to take their injection prior to coming for the visit.  

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Has been changed to read:
Visits, including the dbBaseline Visit should aim to be scheduled in line with the injection 
date (± 3 days); in this case, subjects should be reminded not to take their scheduled 
injection prior to coming for the visit.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Flare at Scheduled Visit:
Last paragraph, first sentence previously read:
At the Flare Week 0 Visit, subjects will undergo further study procedures as described in 
Table 1 under Scheduled/Unscheduled Flare Week 0 Visit and will be switched to 
Open-Label Rescue Arm starting with the first OL injection of adalimumab 40 mg sc at 
the visit.
Has been changed to read:
At the Flare Week 0 Visit, subjects will undergo further study procedures as described in 
Table 1 under Scheduled/Unscheduled Flare Week 0 Visit and will be switched to 
Open-Label Rescue Arm starting with the first OL injection of adalimumab 40 mg sc at 
the end of the visit.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Unscheduled Visit:
First paragraph, second sentence previously read:
If a subject contacts the site due to possible worsening of RA, an unscheduled visit to 
confirm his/her clinical status within 15 days of contact with the site.  
Has been changed to read:
If a subject contacts the site due to possible worsening of RA, an unscheduled visit to 
confirm his/her clinical status within 2 weeks of contact with the site. 

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Flare at Unscheduled Visit:
Previously read:
If during a scheduled visit a flare (defined by DAS28 [ESR] > 2.6 AND an increase from 
dbBaseline in DAS28 [ESR] > 0.6 or increase of DAS28 [ESR] ≥ 1.2 from dbBaseline 
DAS28 [ESR] score irrespective of DAS28 [ESR]) is confirmed, the regular visit will 
then turn into a Flare Week 0 Visit.
Has been changed to read:
At the Flare Week 0 visit subjects will undergo further study procedures as described in 
Table 1 under Scheduled/Unscheduled Flare Week 0 Visit and will be switched to the 
Open Label Rescue Arm starting with the first adalimumab 40 mg sc OL injection at the 
end of the visit if last study drug injection has occurred more than 1 day ago.  If not, OL 
adalimumab 40 mg will be provided for at home sc injection starting the next day.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Rescue Arm
First paragraph
Add:  new last sentence
After the first OL injection, adalimumab 40 mg will be administered sc eow.  Subjects 
will be given RAPID 3 questionnaires (for self-assessment of disease activity) for weekly 
completion to be returned at every visit until the Flare Week 16 Visit.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Rescue Arm
Fourth paragraph, third bullet previously read:
Corticosteroids (a dose up to a maximum of 15 mg oral prednisolone or equivalent/day 
and up to 3 injections intra-articular (i.a.) within the follow-up period of 16 weeks)

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Has been changed to read:
●
Corticosteroids (a dose up to a maximum of 15 mg oral prednisolone or 
equivalent/day and/or up to 3 injections intra-articular (i.a.) within the 
follow-up period of 16 weeks)
●
csDMARDs including MTX (initiation and/or dose or administration mode 
change) and excluding csDMARDs that are not allowed (e.g., azathioprine, 
cyclophosphamide, d-penicilamine)
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Rescue Arm
Fifth paragraph
Add:  new last sentence
Four weeks after an i.a. injection, joints must be again evaluated and included in the 
scores.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Rescue Arm
Last paragraph previously read:
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination Visit.  Subjects 
who prematurely discontinue should complete the procedures outlined for the Early 
Termination Visit in Table 1 as soon as possible after the last dose of study drug and 
preferably prior to the administration of new therapies.  Subjects in the Open-Label 
Rescue Arm (adalimumab 40 mg sc eow) who continue on adalimumab therapy eow after 
the end of study participation will not be contacted for follow-up as any new adverse 
events should be reported through the mechanism used for all postmarketing adverse 
experiences.  All other subjects will be contacted approximately 70 days following study 
drug discontinuation for an assessment of any new or ongoing AEs.

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Has been changed to read:
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination Visit.
Early Termination Visit
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects who prematurely discontinue while on the double blind and/or OL rescue period 
should complete the procedures outlined for the Early Termination/Final Visit in Table 1
as soon as possible after the last dose of study drug and preferably prior to the 
administration of new therapies.
If subjects discontinue the study during the lead-in observational period from Week 0 up 
to Week 4, prior to randomization, a shortened Early Termination visit is required for: 
returning study material and drug, assess any safety/adverse events, collect reason for 
discontinuation.  A 70-day follow-up call/visit will be required; the remainder of full 
Early Termination Visit study procedures can be completed per the investigator's 
discretion.
All subjects discontinuing the study will have a follow-up phone call approximately 
70 days after the last administration of study drug to obtain information on any new or 
ongoing adverse events.
Section 5.2  Selection of Study Population
First paragraph, first and second sentence previously read:
Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
334 subjects will be enrolled into the Lead-In Period.  The study is designed to randomize 
approximately 300 subjects in the Double-Blind Period to meet primary objective 
evaluation without enrolling an undue number of subjects in alignment with ethical 
considerations.  

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Has been changed to read:
Accounting for a 10% discontinuation rate during the Lead-In Period, approximately 
200 subjects will be enrolled into the Lead-In Period.  The study is designed to randomize 
approximately 180 subjects in the Double-Blind Period to meet primary objective 
evaluation without enrolling an undue number of subjects in alignment with ethical 
considerations.
Section 5.2.1  Inclusion Criteria
Criterion 3, 4, 5, 6, 7, and 8 previously read:
3.
Subject must meet the following criteria:
●
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to 
Screening Visit
●
Must be treated with concomitant MTX in a stable dose (oral or sc at any dose) 
for at least 12 weeks prior to Screening Visit
4.
Subject must be in sustained clinical remission based on the following:
●
At least one documented DAS28 (ESR) or DAS28 (CRP) < 2.6 (or calculated 
based on documented components of the DAS28) in the patient chart 6 months 
or longer prior to the Screening Visit;
●
DAS28 (ESR) assessed at Screening < 2.6 (with all components including ESR 
assessed at Screening).
5.
If subjects are receiving concomitant csDMARDs in addition to MTX, the dose 
must be stable for at least 12 weeks prior to the Screening Visit (e.g., chloroquine, 
hydroxychloroquine, sulfasalazine, gold formulations [including auranofin, gold 
sodium thiomalate, and aurothioglucose] and/or leflunomide).
6.
If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent 
must be < 10 mg/day and the dose must be stable for at least 4 weeks prior to the 
Screening visit.
7.
If subjects are receiving NSAIDs, the dose must be stable for at least 4 weeks prior 
to the Screening Visit.

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8.
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 include the following (see local 
informed consent for more detail):
●
Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD);
●
Hormonal contraceptives for 90 days prior to study drug administration;
●
A vasectomized partner.
Has been changed to read:
3. Subject must meet the following criteria:
●
Must be treated with adalimumab 40 mg sc eow for at least 12 months prior to 
Week 0 Visit; 
●
Must be treated with concomitant MTX in a stable dose (oral, sc or im at any 
dose) for at least 12 weeks prior to Week 0 Visit or if not on MTX, must be 
treated with other allowed csDMARDs at stable dose for at least 12 weeks 
prior to Week 0 Visit or if not treated with csDMARDs must maintain this 
regimen for at least 12 weeks prior to Week 0 Visit.
4. Subject must be in sustained clinical remission based on the following:
●
At least one documented 4 or 3 (if PGA is not available) variables DAS28 
(ESR) or DAS28 (CRP) < 2.6 (or calculated based on documented components 
of the DAS28) in the patient chart 6 months or longer prior to the Screening 
Visit;
●
4 variables DAS28 (ESR) assessed at Screening < 2.6 (with all components 
including ESR assessed at Screening).

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5. If subjects are receiving allowed concomitant csDMARDs (in addition or not to MTX) 
the dose must be stable for at least 12 weeks prior to the Week 0 Visit 
(e.g., chloroquine, hydroxychloroquine, sulfasalazine, gold formulations [including 
auranofin, gold sodium thiomalate, and aurothioglucose] and/or leflunomide).
6. If subjects are receiving concomitant oral corticosteroids, prednisone or equivalent 
must be < 10 mg/day and the dose must be stable for at least 4 weeks prior to Week 0 
visit.
7. If subjects are receiving concomitant NSAIDs, tramadol or other equivalent opioids 
and/or non-opioid analgesics the dose and/or therapeutic scheme must be stable for at 
least 4 weeks prior to the Week 0 Visit.
8. 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 include the following (see 
local informed consent for more detail):
●
Oral (except for low-dose progestin-only [lynestrenol and norestisteron]), 
injectable or implanted hormonal contraceptives started for 90 days prior to 
study drug administration;
●
Intrauterine device (IUD);
●
Intrauterine system (for example, progestin-releasing coil);
●
A vasectomized male partner;
●
Abstinence from vaginal intercourse (when in line with preferred and usual 
lifestyle of the subject)

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Section 5.2.1  Inclusion Criteria
Criterion 11 previously read:
If these requirements are not met, subject will have a TB screening assessment:  TB 
screening assessment is negative.  If the subject has evidence of latent TB infection, the 
subject must initiate and complete at least the first 2 weeks (or per local guidelines 
whichever is longer) of TB prophylaxis prior to dbBaseline.
Has been changed to read:
11. Subject has a documented negative TB Screening assessment within 12 months prior 
to Screening Visit or if latent TB infection, subject has had a minimum of 2 weeks (or 
per local guidelines whichever is longer) of TB prophylaxis prior to treatment with 
adalimumab and had or is completing a full course of TB prophylaxis.
If these requirements are not met, subject must perform a TB screening assessment: 
subject has a negative TB screening assessment and if there is a strong suspicion of 
TB exposure the subject must be evaluated by a TB expert (Section 5.3.1.1).  If the 
subject has evidence of latent TB infection, the subject must initiate and complete at 
least the first 2 weeks (or per local guidelines whichever is longer) of TB prophylaxis 
prior to Week 0.
Section 5.2.2  Exclusion Criteria
Criterion 1 previously read:
Any DAS28 (ESR) or DAS28 (CRP) (or calculated based on documented components of 
the DAS28) assessed within 6 months prior to the Screening Visit ≥2.6.
Has been changed to read:
Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or 
calculated based on documented components of the DAS28) assessed within 6 months 
prior to the Screening Visit ≥2.6.

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Section 5.2.2  Exclusion Criteria
Criterion 10 previously read:
Prior exposure to biologics that have a potential or known association with progressive 
multifocal leukoencephalopathy (PML) (i.e., natalizumab [Tysabri®], rituximab 
[Rituxan®], or efalizumab [Raptiva®]) or prior treatment with azathioprine or 
cyclophosphamide.
Has been changed to read:
Prior exposure to biologics that have a potential or known association with progressive 
multifocal leukoencephalopathy (PML) (i.e., natalizumab [Tysabri®], rituximab 
[Rituxan®], or efalizumab [Raptiva®]) or prior treatment with cyclophosphamide.
Section 5.2.3.1  Prior Therapy
Second, third and fourth paragraph previously read:
For each subject that is screened for the study, any other medication (including, but not 
limited to, over-the-counter medicines such as aspirin, antacids, vitamins, mineral 
supplements, and herbal preparations) taken 4 weeks prior to Week 0 Visit and throughout 
the end of the study must be recorded on the appropriate eCRF along with the date(s) of 
administration, reason for use, dosage, route and frequency.
Adalimumab use for ≥ 12 months prior to Screening is required per protocol; date of 
first use, dosage, maximum dosage and reason for use as well as RA disease activity score 
at time of first dose and all subsequent disease activity assessments (if available) should 
be documented and must be recorded on the appropriate eCRF.
MTX use at a stable dose (any dose; oral or sc) for ≥ 12 weeks prior to Screening is 
required per protocol; date of first use, dosage, maximum dosage and reason for use as 
well as RA disease activity score at time of first dose and all subsequent disease activity 
assessments (if available) should be documented and must be recorded on the appropriate 
eCRF.

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Has been changed to read:
For each subject that is screened for the study, any other medication (including, but not 
limited to, over-the-counter medicines such as aspirin, antacids, vitamins, mineral 
supplements, and herbal preparations) taken 4 weeks prior to Week 0 Visit and throughout 
the end of the study must be recorded on the appropriate eCRF along with the date(s) of 
administration, reason for use, dosage, route and frequency.
Adalimumab use for ≥ 12 months prior to Week 0 Visit is required per protocol; date of 
first use, dosage, maximum dosage and reason for use as well as RA disease activity score 
at time of first dose and all subsequent disease activity assessments (if available) should 
be documented and must be recorded on the appropriate eCRF.  A maximum of 
2 non-consecutive adalimumab injections could have been skipped over the last 
12 months but not during the 12 weeks prior to the Week 0 Visit.  Reason(s) for a 
previously missed dose should be documented and cannot be due to an intentional 
tapering of medication (e.g., infection, surgery, lack of medication).  Also there must be 
no evidence of DAS28 ≥ 2.6 during the last 6 months prior to screening as per exclusion 
criteria.  A discussion with Study Designated Physician is recommended.  MTX use at a 
stable dose (any dose; oral, sc or im) for ≥ 12 weeks prior to Week 0 Visit is required for 
at least 80% of subjects recruited; for those subjects on concomitant MTX, date of 
first use, dosage, maximum dosage and reason for use as well as RA disease activity score 
at time of first dose and all subsequent disease activity assessments (if available) should 
be documented and must be recorded on the appropriate eCRF.  A decrease in the dose of 
MTX due to an event of tolerability (or other safety) related with MTX is allowed during 
the 12 weeks period prior to the Week 0 Visit and throughout the study as long as well 
documented.
Subjects who are not taking MTX in a stable dose for ≥ 12 weeks prior to Week 0 can be 
enrolled (up to 20% of overall study population) as long as their allowed csDMARD 
treatment has been stable for at least 12 weeks prior to Week 0 or if not treated with a 
csDMARD this regimen is stable for at least 12 weeks prior to Week 0 Visit.  In these 
cases, csDMARD date of first use, dosage, maximum dosage and reason for use as well as 

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RA disease activity score at time of first dose and all subsequent disease activity 
assessments (if available) should be documented and must be recorded on the appropriate 
eCRF.  A decrease in the dose of csDMARD due to an event of tolerability or other safety 
related is allowed during the 12 weeks period prior to the Week 0 Visit and throughout the 
study as long as well documented.
When no csDMARDs has been used for at least 12 weeks prior to Week 0 Visit, date and 
reasons for stopping previous csDMARDs must be recorded in the eCRF.  The allowed 
RA concomitant medications should be kept stable throughout the Lead-In and 
Double-Blind Periods of the study.
Section 5.2.3.2  Concomitant Therapy 
Subsection Methotrexate:
Previously read:
All subjects must be treated with MTX and maintain a stable dose (any dose; oral or sc are 
allowed) from the 12 weeks prior to Screening and throughout the study.  In the event of
tolerability (or other safety) issues related with MTX, the doses can be decreased and/or 
resumed as needed during the study.
Has been changed to read:
All subjects who were on MTX at inclusion must maintain a stable dose (any dose; oral, 
intra-muscular or sc) from the 12 weeks prior to Week 0 Visit and throughout the study in 
the randomized double-blind arms.  In the event of tolerability (or other safety) issues 
related with MTX, the doses can be decreased and/or resumed as needed during the study 
and these changes documented.
Section 5.2.3.2  Concomitant Therapy 
Subsection Other Disease-Modifying Antirheumatic Drugs (DMARDs), 
Corticosteroids or Other Medications for RA:
First, second, third, fourth and fifth paragraph previously read:
Allowed concomitant csDMARDSs (chloroquine, hydroxychloroquine, sulfasalazine, 
gold formulations [including auranofin, gold sodium thiomalate, and aurothioglucose] and 

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leflunomide) must be a stable dose for at least 12 weeks prior to Screening and at a stable 
dose throughout the study in the randomized double-blind arms.
Concomitant use of oral corticosteroids (< 10 mg/day oral prednisone or equivalent) is 
allowed during the study and should be kept at a stable dose from 4 weeks prior to 
Screening and throughout the study in the randomized double-blind arms.
Concomitant use of oral NSAIDs is allowed during the study and should be kept at a 
stable dose from 4 weeks prior to Screening and throughout the study in the randomized 
double-blind arms.  In the event of tolerability (or other safety) issues, the doses of 
NSAIDs may be skipped, decreased and/or resumed as many times as needed during the 
study.  On the days that subjects are scheduled to be seen in clinic, no regularly scheduled 
NSAIDs should be used within 12 hours of the subject's clinic visit.
Doses of all the RA treatment concomitant medications must remain stable throughout 
study participation (except as medically required due to an AE and in the rescue therapy 
arm; Section 5.3.4.1.2).
Folic acid supplementation during the study treatment period:  All subjects should take a 
dietary supplement of oral folic acid 5 mg once weekly throughout the treatment period.  
Folate should not be administered on the day that MTX study medication is taken, nor on 
the following day.
Has been changed to read:
Allowed other concomitant csDMARDSs (chloroquine, hydroxychloroquine, 
sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and 
aurothioglucose] and leflunomide) must be at a stable dose for at least 12 weeks prior to 
Week 0 Visit and at a stable dose throughout the study in the randomized double-blind 
arms.  In the event of tolerability (or other safety) issues related with the csDMARDs, the 
doses can be decreased and/or resumed as needed during the study and these changes 
documented.

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Concomitant use of oral corticosteroids (< 10 mg/day oral prednisone or equivalent) is 
allowed during the study and should be kept at a stable dose from 4 weeks prior to 
Week 0 Visit and throughout the study in the randomized double-blind arms.
Concomitant use of oral NSAIDs, tramadol or other equivalent opioids and non-opioid 
analgesics is allowed during the study and should be kept at a stable dose and/or 
therapeutic scheme from 4 weeks prior to Week 0 Visit and throughout the study in the 
randomized double-blind arms.  In the event of tolerability (or other safety) issues, the 
doses of NSAIDs may be skipped, decreased and/or resumed as many times as needed 
during the study.  On the days that subjects are scheduled to be seen in clinic, no regularly 
scheduled NSAIDs should be used within 12 hours of the subject's clinic visit.
Doses of all the RA treatment concomitant medications must remain stable throughout 
study participation (except as medically required due to an AE and in the rescue therapy 
arm; Section 5.3.4.1.2).
Folic acid supplementation during the study treatment period:  All subjects treated with 
concomitant MTX should take a dietary supplement of oral folic acid 5 mg once weekly 
or per local guidelines per the investigator's discretion throughout the treatment period.  
Folate should not be administered on the day that MTX study medication is taken, nor on 
the following day.
Section 5.2.3.3  Prohibited Therapy
Sixth bullet previously read:
Opioid analgesics (other than tramadol) or marijuana.
Has been changed to read:
Opioid analgesics (other than tramadol or other equivalent opioid analgesics) or 
marijuana.

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Section 5.2.3.4  Rescue Therapy
Third and fourth bullet previously read:
●
Corticosteroids (in a dose up to > 15 mg prednisolone or equivalent/day and up 
to a maximum of 3 injections i.a. during the 16 weeks)
●
csDMARDs and/or the dose of MTX
Has been changed to read:
●
Corticosteroids (in a dose up to a maximum of 15 mg oral prednisolone or 
equivalent/day and up to 3 injections i.a. within the follow-up period of 
16 weeks)
●
csDMARDs including MTX (initiation and/or dose or administration mode 
change) and excluding not allowed csDMARDs (e.g., azathioprine, 
cyclophosphamide, d-penicilamine)
Section 5.3.1  Efficacy and Safety Measurements Assessed and Flow Chart
First paragraph previously read:
Subjects will be allowed a visit window of ± 7 days for all study visits (with the exception 
of the Screening Period, Lead-In Period and the dbBaseline Visit).  If a subject has an out 
of window visit, the next visit should occur as originally scheduled based on the first date 
of study drug administration (Week 0).
Has been changed to read:
Subjects will be allowed a visit window of ± 7 days for all study visits (with the exception 
of the Screening Period, Lead-In Period and the dbBaseline Visit).  For the lead-in period 
and the dbBaseline period a visit window of ± 3 days is recommended.  For exceptional 
cases, the Study designated Physician should be consulted.  If a subject has an out of 
window visit, the next visit should occur as originally scheduled based on the first date of 
study drug administration (Week 0) between Weeks 0 and 4 Visits.  Once the subject is 
randomized, all doses should be based on the date of randomization (Week 4).

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Table 1.  Study Activities
Header row previously read:
Activity
SCRa
(21 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ET
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Has been changed to read:
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16

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Table 1.  Study Activities
Activity "DAS28 (ESR)" previously read:
Activity
SCRa
(21 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ET
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
DAS28 (ESR)
X
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
Has been changed to read:
Activity
SCRa
(28 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ETd
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
DAS28 (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 1.  Study Activities
Delete:  Activity "Clinical Disease Activity Index (CDAI)/Simplified Disease Activity Index (SDAI)"
Activity
SCRa
(21 Days)
Lead-In 
Period 
(Week 0)
Randomized Double-Blind Period
ESR should be evaluated prior to other study 
procedures to assess DAS28 and check for flare
Open-Label Rescue Arm
When subject has confirmed flare, 
any visit after Double-Blind Baseline 
becomes Flare Week 0
ET
UV
70-Day 
F/U Visit/ 
Call
Week
Flare Week
dbBaseline 
(Week 4)
10
16
22
28
34
40
0p
4
10
16
Clinical Disease 
Activity Index 
(CDAI)/Simplified 
Disease Activity Index 
(SDAI)
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 1.  Study Activities
Table note "d." and "l." previously read:
d.
The ESR from Screening should be used to calculate the DAS28 (ESR) assessment at Day 1.
l.
All females of childbearing potential will have a urine sample collected at dbBaseline prior to study enrollment and 
at study discontinuation/completion.  The samples will be sent to the central laboratory for urine pregnancy testing.  
Monthly pregnancy tests will be performed throughout the study if required by country regulatory authorities.  Any 
subject with a positive urine pregnancy test must have a negative serum test performed at the central laboratory 
prior to enrollment or continuation in the study.
Has been changed to read:
d.
For those subjects who have entered the study at Week 0 but are early terminated before the Week 4 visit, a short 
Early Termination visit is allowed.  This visit would include reason for discontinuation, review of adverse events, 
and investigational product/diary return.  This will be followed by a 70-day follow-up call/visit.  Additional 
assessments are allowed per the Investigator's discretion.
l.
All females of childbearing potential will have a urine sample collected at the Week 0 visit prior to study 
enrollment and at study discontinuation/completion.  The samples will be tested locally by designated study 
personnel.  Monthly pregnancy tests will be performed throughout the study if required by country regulatory 
authorities.  Any subject with a positive urine pregnancy test must have a negative serum test performed at the 
central laboratory prior to enrollment or continuation in the study.  Investigators may conduct more frequent urine 
pregnancy testing as necessary according to their judgment.
Table 1.  Study Activities
Table note "g."
Add:  new last sentence
A CXR may be required for evaluation of active TB.
Section 5.3.1.1  Study Procedures
Subsection Inclusion/Exclusion Criteria
Last paragraph previously read:
At the dbBaseline Visit (Week 4), in order for the subject to be randomized, another 
DAS28 (ESR) must be completed and fulfill the requirement of < 2.6.  The ESR from the 
dbBaseline Visit must be used for this assessment.
Has been changed to read:
At the dbBaseline Visit (Week 4), in order for the subject to be randomized, another 
4 variables DAS28 (ESR) must be completed and fulfill the requirement of < 2.6.  The 

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ESR from the dbBaseline Visit must be used for this assessment.  If the subject does not 
meet the DAS28 (ESR) requirement of < 2.6 at the dbBaseline (Week 4), the subject must 
be discontinued from the trial.  
Section 5.3.1.1  Study Procedures
Subsection DAS28 (CRP) and DAS28 (ESR)
Previously read:
The DAS28 (ESR)29,63 will be completed at all designated study visits listed in Table 1.  
The DAS28 (ESR) should be calculated using all parameters including ESR from the 
current visit.
The DAS28 (ESR) calculation used for study eligibility, enrollment and monitoring will 
be calculated by the eCRF as below:
DAS28(4) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × natural logarithm 
(ln)(ESR#) + 0.014 × Global Health (GH»)
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
#
ESR refers to Erythrocyte Sedimentation Rate evaluated at the site at current visit and expressed in mm/hg 
(1st hour).
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).
DAS28 (CRP)29 maybe calculated based on patient chart review for study Screening as 
below:
DAS28-CRP = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(CRP&+1) + 0.014 × 
GH» + 0.96
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
CRP refers to the c-reactive protein lab value.  CRP unit in the DAS28 (CRP) equation is expressed as mg/L.
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).

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Has been changed to read:
The 4 variables DAS28 (ESR)29,72 will be completed at all designated study visits listed in 
Table 1.  The DAS28 (ESR) should be calculated using all parameters including ESR 
from the current visit.
The 4 variables DAS28 (ESR) calculation used for study eligibility, enrollment and 
monitoring will be calculated by the eCRF as below.  Upon discussion with the SDP, the 
3 variable DAS28 (ESR) can be used during the trial to evaluate flare if the PGA score is 
not available.  For the purpose of chart review for study eligibility and inclusion, the 
3 variable DAS28 (ESR) can be used when the Subject's Global Assessment of Disease 
Activity (PGA) is not available.
4 variables DAS28 (ESR):
DAS28-ESR(4) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × natural logarithm 
(ln)(ESR#) + 0.014 × Global Health (GH»)
3 variables DAS28 (ESR):
DAS28-ESR(3) = [0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × ln(ESR#)] × 1.08 + 
0.16
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
#
ESR refers to Erythrocyte Sedimentation Rate evaluated at the site at current visit and expressed in mm/hr 
(1st hour).
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).
DAS28 (CRP)29 maybe calculated based on patient chart review for study Screening as 
below:
4 variables DAS28 (CRP):

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4 or 3 (if PGA is not available) variables DAS28-CRP (4) = 0.56 × √(TJC28*) + 0.28 × 
√(SJC28**) + 0.36 × ln(CRP&+1) + 0.014 × GH» + 0.96
3 variables DAS28 (CRP):
DAS28-CRP (3) = [0.56 × √ (TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(CRP& + 1)] ×
1.10 + 1.15
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
CRP refers to the c-reactive protein lab value.  CRP unit in the DAS28 (CRP) equation is expressed as mg/L.
»
GH refers to the Subject's Global Assessment of Disease Activity (PGA).
Section 5.3.1.1  Study Procedures
Subsection Clinical Disease Activity Index (CDAI) and Simplified Disease Activity 
Index (SDAI)
First paragraph previously read:
CDAI64 and SDAI64,65 will be completed at visits according to the scheduled in Table 1.  
The SDAI) should be calculated using all parameters including CRP from the same visit 
(and so calculated at next Visit).
Has been changed to read:
CDAI73 and SDAI73,74 will be completed at visits according to the scheduled in Table 1.  
The SDAI and CDAI will be calculated as part of the statistical analysis using all 
parameters including CRP from the same visit (and as such calculated at the next Visit).
Section 5.3.1.1  Study Procedures
Subsection Musculoskeletal Ultrasound (US)
First paragraph, last sentence previously read:
If they decide to and the pre-requirements criteria are met (as per the Ultrasound manual), 
they should perform US for every subject they recruit at time points indicated by the 
protocol.

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Has been changed to read:
If they decide to and the pre-requirements criteria are met (as per the Ultrasound manual), 
they should perform US for every subject they recruit at time points indicated by the 
protocol; exceptions are allowed upon discussion with Study Designated Physician.  For 
sites participating in the ultrasound assessments, all subjects from the site should undergo 
the US scans and assessments as per protocol;
Section 5.3.1.1  Study Procedures
Subsection Musculoskeletal Ultrasound (US)
Second paragraph, fifth sentence previously read:
The assessments and scoring will be locally performed.
Has been changed to read:
The assessments and scoring will be locally performed and afterwards the report of US 
assessments from all subjects will be sent to the central Imaging vendor.  For the 
first subject enrolled and for the first subject with flare assessments further procedures for 
quality assessment are required (as per ultrasound manual).
Section 5.3.1.1  Study Procedures
Subsection Musculoskeletal Ultrasound (US)
Third paragraph previously read:
The optional US will be performed during the Lead-In Period or at the dbBaseline Visit 
prior to randomization and at Flare Week 0 Visit (when applicable) to assess synovial 
hypertrophy, tenosynovitis and erosions through gray scale ultrasonography (GSUS) and 
synovitis/vascularization through Power Doppler Ultrasonography (PDUS).
Has been changed to read:
The optional US will be performed during the Lead-In Period or at the dbBaseline Visit 
prior to randomization and at Flare Week 0 Visit (when applicable and at or up to 7 days 
after the visit) to assess synovial hypertrophy, tenosynovitis and erosions through gray 

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scale ultrasonography (GSUS) and synovitis/vascularization through Power Doppler 
Ultrasonography (PDUS).
Section 5.3.1.1  Study Procedures
Subsection Magnetic Resonance Imaging (MRI)
First paragraph previously read:
An MRI of the most affected or of the dominant hand (2nd to 5th MCP) and wrist (if both 
sides are considered equally affected) will be performed to all subjects during the 
Screening/Lead-In Period (prior to dbBaseline Visit) and the Final/Early Termination 
Visit (if last MRI ≥ 12 weeks before).
Has been changed to read:
An MRI of the most affected or of the dominant hand (2nd to 5th MCP) and wrist (if both 
sides are considered equally affected) will be performed to all subjects during the Lead-In 
Period (prior to dbBaseline Visit) and the Final/Early Termination Visit (if last MRI 
≥12 weeks before).
Section 5.3.1.1  Study Procedures
Subsection TB Screening
First paragraph previously read:
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 locally during the Screening Period for all subjects 
including those with a prior history of Bacille Calmette-Guérin (BCG) administration.  If 
a subject had a negative PPD or IGRA test within 12 months 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 Study Designated Physician.

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Has been changed to read:
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 Bacille Calmette-Guérin (BCG) administration.
Subjects that have a negative PPD or IGRA test and are considered at risk for having 
latent TB (any immunosupressed patient with a strong suspicion of TB exposure and no 
prior vaccination with Bacille Calmette-Guérin) need to be evaluated by a TB expert 
before Week 0.
Subjects at risk for TB exposure are defined as:
●
subjects that have household contact with a person with active TB
●
subjects living in areas with high incidence of TB
●
subjects that frequently visits areas with high prevalence of active TB 
If a subject had a negative PPD or IGRA test within 12 months 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 Study Designated Physician.
Section 5.3.1.1  Study Procedures
Subsection TB Screening
Seventh paragraph previously read:
If the PPD or the IGRA test is positive or the subject has a CXR indicative of latent TB, 
the subject will be required to initiate and have taken at least 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing course of the United States Center for 
Disease Control (CDC) recommended prophylaxis or prophylaxis per local guidelines 
prior to starting study therapy.

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Has been changed to read:
If the PPD or the IGRA test is positive or the subject has a CXR or TB expert opinion 
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 the United 
States Center for Disease Control (CDC) and Prevention recommended prophylaxis or 
prophylaxis per local guidelines prior to starting study therapy.
Section 5.3.1.1  Study Procedures
Subsection TB Screening
Eighth paragraph
Add:  new last sentence
The prophylactic treatment must be maintained during the study until its recommended 
full course is completed.
Section 5.3.1.1  Study Procedures
Subsection TB Screening
Delete:  last paragraph and bullet list
For sites participating in the Czech Republic, the following local requirements will 
also be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure. This information needs to include BCG vaccination, 
cohabitation with individuals who have had TB, and/or reside or work in TB 
endemic locations. The information obtained by the pulmonologist must be 
documented in the subject's source note, dated and signed by the 
pulmonologist. 
●
A pulmonologist must review the results of the PPD skin test or the IGRA test 
and the chest x-ray and has to give 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 Study 
Designated Physician and all such subjects need to receive prophylaxis for 

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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.
Section 5.3.1.1  Study Procedures
Subsection Hepatitis B Testing
First paragraph previously read:
If a subject had a negative hepatitis B virus (HBV) result within 12 months prior to 
Screening and all protocol required documentation is available, these tests repetition are
not required.
Has been changed to read:
If a subject had a negative hepatitis B virus (HBV) result within 12 months prior to 
Screening and all protocol required documentation is available, these tests repetition are 
not required.  At screening subjects must be assessed for high risk of exposure to 
hepatitis B since their last test.  If high risk is suspected, a hepatitis B test should be 
performed.
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Tests
First paragraph previously read:
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential.  At the dbBaseline Visit, subjects of childbearing potential will 
have a urine pregnancy test performed locally by designated study personnel.  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.
Has been changed to read:
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential.  At the Week 0 Visit, subjects of childbearing potential will have a 

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urine pregnancy test performed locally by designated study personnel.  Investigators may 
conduct more frequent urine pregnancy testing as necessary according to their judgment.  
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.
Section 5.3.1.1  Study Procedures
Subsection Adverse Events
Second, third and fourth sentence previously read:
Subjects in the Rescue Arm (adalimumab 40 mg sc eow) who continue on adalimumab 
therapy eow after the end of study participation will not be contacted for follow-up as any 
new adverse events should be reported through the mechanism used for all postmarketing 
adverse experiences.  All other subjects will be contacted approximately 70 days 
following study drug discontinuation for an assessment of any new or ongoing adverse 
events.  In addition, serious adverse events (SAEs) and protocol-related nonserious 
adverse events will be collected from the time the subject signs the study-specific 
informed consent.
Has been changed to read:
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination/Final 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 adverse events.
Section 5.3.1.1  Study Procedures
Subsection Dispense Study Drug
Add:  new second paragraph
Once the limit of 20% of enrolled subjects on other csDMARDs or no csDMARDs is met, 
only subjects on concomitant methotrexate will be allowed into the trial.

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Section 5.4.1  Discontinuation of Individual Subjects
Third paragraph
Add:  new second sentence
If subjects discontinue the study during the lead-in observational period, prior to 
randomization, a short Early Termination visit is required for: returning study material 
and drug, assess any safety/adverse events, collect reason for discontinuation and a 70-day 
follow-up call/visit; the remainder of full Early Termination Visit study procedures can be 
completed per the investigator's discretion.  
Section 5.4.1  Discontinuation of Individual Subjects
Fourth paragraph previously read:
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.
Has been changed to read:
A final phone call will be made to all subjects 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.
Section 5.5.1  Treatments Administered
Last paragraph previously read:
Subjects who meet flare criteria will be entering an Open-Label Rescue Arm and OL 
adalimumab 40 mg will be administered every other week until Week 56 of the trial.
Has been changed to read:
Subjects who meet flare criteria will be entering an Open-Label Rescue Arm and OL 
adalimumab 40 mg will be administered every other week for 16 weeks.

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Section 5.5.5.1  Blinding of Investigational Product
Second paragraph, first sentence previously read:
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 Study 
Designated Physician (Section 7.0) prior to breaking the blind.
Has been changed to read:
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 Study 
Designated Physician (Section 7.0) prior to breaking the blind as long as it does not 
compromise subject safety.
Section 5.6.1  Discussion of Study Design and Choice of Control Groups
First sentence previously read:
This Phase 4 study is designed to investigate the association between residual disease 
activity at baseline, and the occurrence of flares in RA patients on adalimumab in 
combination with methotrexate in sustained clinical remission (DAS28 [ESR] < 2.6) and 
submitted to an adalimumab dose tapering regimen or withdrawal.  
Has been changed to read:
This Phase 4 study is designed to investigate the association between residual disease 
activity at baseline, and the occurrence of flares in RA patients on adalimumab who are in 
sustained clinical remission (DAS28 [ESR] < 2.6) and submitted to an adalimumab dose 
tapering regimen or withdrawal.  
Section 5.6.3  Suitability of Subject Population
First sentence previously read:
Subjects age ≥18 years diagnosed with RA, on a stable dose of adalimumab 40 mg sc 
eow (for ≥ 12 months prior to Screening Visit) in combination with methotrexate (MTX; 
at stable dose for ≥ 12 weeks prior to the Screening Visit.) and in documented clinical 

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remission (DAS28 [ESR] 2.6 or DAS28 [CRP]) for ≥ 6 months prior to the study are 
eligible for this study.  
Has been changed to read:
Subjects age ≥ 18 years diagnosed with RA, on a stable dose of adalimumab 40 mg sc 
eow (for ≥ 12 months prior to Screening Visit) in combination with methotrexate (MTX; 
at stable dose for ≥ 12 weeks prior to the Screening Visit) or if not on MTX in a stable 
other allowed csDMARD or no csDMARD regimen for ≥ 12 weeks prior to Week 0 Visit) 
and in documented clinical remission (DAS28 [ESR] < 2.6 or DAS28 [CRP] 2.6) for 
≥6 months prior to the study are eligible for this study.  Patients who are not on stable 
concomitant MTX will be allowed as per current clinical practice, but limited to 20% of 
the study population.
Section 6.0  Complaints
Add:  new section number and text
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 6.1.5).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2.

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Section 6.0 through 6.7
Section number and title previously read:
6.0
Adverse Events
6.1
Definitions
6.1.1
Adverse Event
6.1.2
Serious Adverse Events
6.2
Adverse Event Severity
6.3
Relationship to Study Drug
6.4
Adverse Event Collection Period
6.5.
Adverse Event Reporting
6.6
Pregnancy
6.7
Toxicity Management
Has been changed to read:
6.0
Complaints
6.1
Medical Complaints
6.1.1
Definitions
6.1.1.1
Adverse Event
6.1.1.2
Serious Adverse Events
6.1.2
Adverse Event Severity
6.1.3
Relationship to Study Drug
6.1.4
Adverse Event Collection Period
6.1.5
Adverse Event Reporting

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6.1.6
Pregnancy
6.1.7
Toxicity Management
Section 6.4  Adverse Event Collection Period
Last paragraph previously read:
Subjects in the Rescue Arm (adalimumab 40 mg sc eow) who continue on adalimumab 
therapy eow after the end of study participation will not be contacted for follow-up as any 
new adverse events should be reported through the mechanism used for all postmarketing 
adverse experiences.  All other subjects will be contacted approximately 70 days 
following study drug discontinuation for an assessment of any new or ongoing AEs.  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.  All SAEs and all ongoing adverse events reported 
during the 70-day follow-up phone call must be captured in the clinical database.
Has been changed to read:
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination/Final 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 adverse events.  
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.
Section 6.5  Adverse Event Reporting
"Immunology Safety Team" building number previously read:
Has been changed to read:

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Section 6.5  Adverse Event Reporting
Add:  new fifth paragraph
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number:
Phone:
Section 6.2  Product Complaint
Add:  new section and text, renumber subsequent sections
6.2
Product Complaint 
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.
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 

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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.
Section 7.0  Protocol Deviations
"Alternate Contact:" previously read:
Alternate Contact:

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Has been changed to read:
Alternate Contact:
Section 8.1.4.1  Analysis for Primary Objective
First paragraph, last sentence previously read:
The 80% and 95% confidence intervals of the odds ratio will also be provided as an 
addition.
Has been changed to read:
The 95% confidence intervals of the odds ratio will also be provided as an addition.
Section 8.1.4.1  Analysis for Primary Objective
Second paragraph, last sentence previously read:
All model based analyses may adjust for dbBaseline clinical patient characteristics 
including age, disease duration, previous treatment, etc., when appropriate.

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Has been changed to read:
All model based analyses may adjust for dbBaseline clinical patient characteristics 
including age, disease duration, previous and concomitant treatment (such as use of MTX, 
use of csDMARD as versus TNFi monotheraphy), etc., when appropriate.
Section 8.1.4.3  Analysis for Exploratory Objectives
Add:  new last paragraph
The occurrence and time to flare from dbBaseline in the concomitant MTX, other 
csDMARDs and no csDMARDs patients will be analyzed for potential differential effect.
Section 8.1.7  Interim Analysis for Double-Blind Baseline Characteristics
First sentence previously read:
There are few data describing patient disease characteristics including markers of residual 
inflammation such as sensitive imaging assessments and potential biomarkers as well as 
drug levels in RA patients who are in sustained clinical remission on a stable treatment 
with a TNFi and MTX.  
Has been changed to read:
There are few data describing patient disease characteristics including markers of residual 
inflammation such as sensitive imaging assessments and potential biomarkers as well as 
drug levels in RA patients who are in sustained clinical remission on a stable treatment 
with a TNFi and MTX and/or with other csDMARDs(s) or in TNFi monotherapy. 
Section 8.2  Determination of Sample Size
Previously read:
The planned total number of subjects enrolled into the Lead-In Period is approximately 
334.
To estimate the odds ratio for the occurrence of flare with dbBaseline MRI score based on 
historical MRI and literature40,75 data, an effective sample size of 250 subjects in the dose 
tapering group will ensure a precision for the estimation with the width of 90% CI no 

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more than 0.1 for an odds ratio 1.2, no more than 0.4 for an odds ratio 1.5, and no more 
than 1.0 for an odds ratio 1.8.  Such sample size will also ensure a precision for the 
estimation of a continuous correlation coefficient ρ with the half width of 90% CI of ρ no 
more than 0.1 for a mild correlation coefficient 0.2, no more than 0.09 for a moderate 
correlation coefficient 0.4, and no more than 0.07 for a higher correlation with ρ = 0.6.  
Assuming a 30% flare rate20-22,24, this sample size will provide the precision that the 
2-sided 90% CI of the flare rate has a half width no more than 5%.
Under a 5:1 randomization ratio (dose tapering versus withdrawal), a total of 300 subjects 
will be randomized.  Accounting for a 10% discontinuation rate during the Lead-In 
Period, approximately 334 subjects will need to be enrolled into the Lead-In Period.
Has been changed to read:
The planned total number of subjects enrolled into the Lead-In Period is approximately 
200. 
A recently published study (DOSERA) showed that 56% (15/27 patients) of patients who 
were previously in low disease activity had treatment failure within 48 weeks after 
reducing the dose of etanercept; the median time to failure was 36 weeks (95% 
CI:15.6-NE).89  The STRASS study, also published in 2015, showed in a similar RA 
patient population, that progressive tapering of TNFi therapy (adalimumab or etanercept) 
was associated with flare in 76.6% (49/64) of patients throughout the study duration; 
importantly, 28.8% of patients flared after the first step of tapering (adalimumab 40 mg  
q3 weeks or etanercept 50 mg q10 days) and the median time to flare was 9 months.90  In 
another tapering study (DRESS) a cumulative incidence of short-lived flares in a 
progressive tapering of TNFi of 55% at 9 months (and 73% at 18 months) was observed.  
Among these studies, the DRESS study had the higher sample size with 121 patients in 
the taper arm but only 43% successfully tapered the TNFi.  None of these studies was 
designed or powered to evaluate predictors of flare neither found definite predictors upon 
further statistical analysis.  A proof of concept study conducted in 44 RA patients in 
clinical remission receiving treatment with a bDMARD has shown that residual synovial 

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inflammation determined by comprehensive ultrasound assessment predicted relapse 
within a short term after discontinuation of the treatment.91
These data provided the rational for assuming a conservative flare rate of 30% and for our 
sample size calculation.
To estimate the odds ratio for the occurrence of flare with baseline MRI score based on 
historical MRI data, an effective sample size of 150 subjects in the dose tapering group 
will ensure a precision for the estimation with the width of 90% CI no more than 0.03 for 
an odds ratio 1.03, no more than 0.07 for an odds ratio 1.1, and no more than 0.14 for an 
odds ratio 1.2.  Such sample size will also ensure a precision for the estimation of a 
correlation coefficient ρ with the width of 90% CI of ρ no more than 0.26 for a mild 
correlation coefficient 0.28, no more than 0.18 for a moderate correlation coefficient 0.55, 
and no more than 0.13 for a higher correlation with ρ = 0.67.  Assuming a 30% flare rate, 
this sample size will provide the precision that the 2-sided 90% CI of the flare rate has a 
half width no more than 6%.
Sensitivity precision levels under various assumptions are presented in Table 4.
Under a 5:1 randomization ratio (dose tapering versus withdrawal), a total of 180 subjects 
will be randomized.  Accounting for a 10% discontinuation rate during the Lead-In 
Period, approximately 200 subjects will need to be enrolled into the Lead-In Period.
Table 4.
Sample Size Assumptions
True Odds 
Ratio
Flare Rate
Sample Size (Dose 
Tapering Arm)
OR from Logistics 
Regression
(90% CI) : CI Width
Correlation
(90% CI) :
CI Width
1.03
30%
150
1.03
(1.02, 1.05) : 0.03
0.28
(0.14, 0.40) : 0.26
1.1
30%
150
1.1
(1.07, 1.14) : 0.07
0.55
(0.46, 0.64) : 0.18
1.2
30%
150
1.21
(1.15, 1.29) : 0.14
0.67
(0.61, 0.73) : 0.13

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Section 10.3  Electronic Patient Reported Outcomes (ePROs)
Add:  new section title and text
10.3
Electronic Patient Reported Outcomes (ePROs)
An electronic patient-recorded outcomes (ePRO) device will be provided to subjects 
during screening and will be completed at all subject visits in the office.  An additional 
device will be given to subjects at their flare Week 0 visit (if applicable) and will be 
completed at home weekly.  Site personnel will provide training on the proper use of the 
e-Diary.  These data will be uploaded to a server, the data on the server will be considered 
source, and maintained and managed by CRF Health.  Patient reported data are completed 
for each subject screened/enrolled in this study.  An ePRO tool called Trialmax, provided 
by the technology vendor CRF Health of Plymouth Meeting, PA, USA, will be used to 
collect this data. The ePRO system is in compliance with Title 21 CFR Part 11.  
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 site investigator, as 
well as delegated personnel.  Such access will be removed from investigator 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 investigator at that time as a 
durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media. 
The electronic device may be programmed to allow data entry for only certain periods of 
time.  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, up until the generation, receipt and confirmation of the study 
archive.

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Section 15.0  Reference List
Add:  new Reference 33 – 40
33. Madsen OR.  Agreement between DAS-CRP with 3 and 4 variables in patients with 
rheumatoid arthritis treated with biological agents in the daily clinic.  J Rheumatol.  
2013;40(4):379-85.
34. Lee SJ, Chang, H, Yazici Y, et al.  Utilization trends of tumor necrosis factor 
inhibitors among patients with rheumatoid arthritis in a United States observational 
cohort study.  J Rheumatol.  2009;36(8):1611–7.
35. Yazici Y, Shi N, John A.  Utilization of biologic agents in rheumatoid arthritis in the 
United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and 
patients new to biologic therapy.  Bull NYU Hosp Jt Dis.  2008;66(2):77–85.
36. Soliman MM, Ashcroft, DM, Watson KD, et al.  Impact of concomitant use of 
DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid 
arthritis: results from the British Society for Rheumatology Biologics Register.  Ann 
Rheum Dis.  2011;70(4):583–9.
37. Listing J, Strangfeld A, Rau R, et al.  Clinical and functional remission: even though 
biologics are superior to conventional DMARDs overall success rates remain low--
results from RABBIT, the German biologics register.  Arthritis Res Ther.  
2006;8(3):R66.  Epub 2006 Apr 5.
38. Heiberg MS, Koldingsnes W, Mikkelsen K, et al.  The comparative one-year 
performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid 
arthritis, psoriatic arthritis, and ankylosing spondylitis:  results from a longitudinal, 
observational, multicenter study.  Arthritis Rheum.  2008;59(2):234–40.
39. Askling J, Fored CM, Brandt L, et al.  Time-dependent increase in risk of 
hospitalisation with infection among Swedish RA patients treated with TNF 
antagonists.  Ann Rheum Dis.  2007;66(10):1339–44.

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40. Manders S, Kievit W, Jansen T, et al.  Significantly better results for TNFI 
combination therapy with MTX than TNFI mono- and combination without MTX 
therapy in patients with RA:  results from the dream registry.  Ann Rheum Dis.  
2013;72:A73-4.
Section 15.0  Reference List
Add:  new Reference 89 – 91
89. van Vollenhoven RF, van der Maas A, Minten MJ, et al.  Disease activity guided dose 
reduction and withdrawal of adalimumab or etanercept compared with usual care in 
rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.  BMJ.  
2015;9;350:h1389.  doi: 10.1136/bmj.h1389.
90. Fautrel B, Pham T, Alfaiate T, et al.  Step-down strategy of spacing TNF-blocker 
injections for established rheumatoid arthritis in remission: results of the multicentre 
non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-
blocker injections in Rheumatoid ArthritiS Study).  Ann Rheum Dis.  2016;75(1):59-
67.
91. Iwamoto T, Ikeda K, Hosokawa J, et al.  Prediction of relapse after discontinuation of 
biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in 
clinical remission: high predictive values of total gray-scale and power Doppler scores 
that represent residual synovial inflammation before discontinuation.  Arthritis Care 
Res (Hoboken).  2014;66(10):1576-81.
Section 15.0  Reference List
Delete:  Reference 75
Peterfy C, Durez P, Haraoui B, et al.  Responses to early rheumatoid arthritis (RA) to 
treatment with adalimumab plus methotrexate vs. Methotrexate alone: magnetic resonance 
imaging results from OPTIMA.  Ann Rheum Dis.  2010;69 Suppl 3:455.

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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Medical Affairs
Statistics
Pharmacokinetics
Medical Affairs
Clinical
Has been changed to read:
Name
Title
Functional Area
Global Medical Affairs
Statistics
Global Medical Affairs
Clinical
Pharmacokinetics
Bioanalytics
Regulatory Affairs
Clinical
Appendix C.  Injection Instructions – Pre-Filled Syringe – Sample
Subsection Study Drug Dosing Schedule
Fourth paragraph, second and third bullet previously read:
●
At Week 4 at the start of the Double-Blind Period, you will receive 3 syringes.  
At the Week 4 Visit, you will administer the injection at the clinic.  You will 
take the other 2 home to be administered at Week 7 and Week 10.  During the 
remainder of the Double-Blind Period (Weeks 10, 16, 22, 28 and 34), you will 
receive 2 syringes at each visit to be taken at Weeks 13, 16, 19, 22, 25, 28, 31, 
34 and 37, respectively.
●
If at any time you have a flare and it is confirmed, you will enter the 
Open-Label Rescue Arm and start a Flare Week 0 Visit.  You will administer 
an injection of open-label adalimumab at the clinic.  You must return all 
double-blind medication at the next visit. 

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○
At the Flare Week 0 Visit, you will also receive 2 additional syringes to 
administer at Flare Weeks 2 and 4. 
○
At the Flare Week 4 Visit, you will receive 3 syringes to be taken at Flare 
Weeks 6, 8 and 10. 
○
At the Flare Week 10 Visit, you will receive 2 additional syringes to be 
taken at Weeks 12 and 14. 
○
If your time of injection falls on a clinic day, you must inject study drug 
after all study procedures are performed (not prior).
Has been changed to read:
●
At Week 4 at the start of the Double-Blind Period, you will receive 2 syringes.  
At the Week 4 Visit, you will administer the injection at the clinic.  You will 
take the other 1 syringe home to be administered at Week 7.  During the 
remainder of the Double-Blind Period (Weeks 10, 16, 22, 28 and 34), you will 
receive 2 syringes at each visit to be taken (one to be administered at the visit 
and the other to be taken at home 3 weeks later) at Weeks 10, 13, 16, 19, 22, 
25, 28, 31, 34 and 37, respectively.
●
If at any time you have a flare and it is confirmed, you will enter the Open 
Label Rescue Arm and start a Flare Week 0 Visit.  You must return all 
double-blind medication at the next visit. 
○
At the Flare Week 0 Visit, you will receive 2 syringes.  One injection of 
open-label adalimumab will be administered at the clinic.  You will take 
the other 1 syringe home to be administered 2 weeks later at Flare Week 2. 
○
At the Flare Week 4 and 10 Visits, you will receive 3 syringes at each visit 
(one to be administered at the visit and the other 2 to be taken separately at 
home every two weeks) to be taken at Flare Weeks 4, 6, 8, 10, 12, 14 
respectively. 
○
If your time of injection falls on a clinic day, you must inject study drug 
after all study procedures are performed (not prior).

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Appendix K  Short Form-36 (SF-36) Health Survey Questionnaire – Sample
Previously read:
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
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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Has been changed to read:
Your Health and Well-Being
SF-36v2® Health Survey © 1992, 1996, 2000, 2010
Medical Outcomes Trust and 
QualityMetric Incorporated.
All Rights Reserved.
SF-36® is a registered trademark of 
Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, 
United States (English))
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 select the one box that best describes your 
answer.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor

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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
The following question is about activities you might do during a typical day.
Does your health now limit you in vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in lifting or carrying groceries?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing several flights of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in climbing one flight of stairs?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in bending, kneeling, or stooping? If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking more than a mile?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in walking several hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all

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The following question is about activities you might do during a typical day.
Does your health now limit you in walking one hundred yards?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
The following question is about activities you might do during a typical day.
Does your health now limit you in bathing or dressing yourself?  If so, how much?
Yes, limited a lot
Yes, limited a little
No, not limited at all
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?
Cut down on the amount of time you spent on work or other 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

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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?
Accomplished less than you would like 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
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?
Were limited in the kind of work or other 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
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?
Had difficulty performing the work or other activities as a result of your physical 
health (for example, it took extra effort)
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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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?
Cut down on the amount of  time you spent on work or other 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
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?
Accomplished less than you would like 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
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?
Did work or other activities less carefully than usual 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

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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
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
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

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This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel full of life?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks. 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 have you been very nervous?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you felt so down in the dumps that 
nothing could cheer you up?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  Please give the one answer that comes closest to the way you have been 
feeling.  

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How much of the time during the past 4 weeks have you felt calm and peaceful?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you have a lot of energy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you felt downhearted and 
depressed?
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel worn out?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 have you been happy?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
This question is about how you feel and how things have been with you during the past 
4 weeks.  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 did you feel tired?
All of the time
Most of the time
Some of the time
A little of the time
None of the time

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During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, 
etc.)?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
How TRUE or FALSE is the following statement for you?
I seem to get sick a little easier than other people.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
I am as healthy as anybody I know.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false

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How TRUE or FALSE is the following statement for you?  
I expect my health to get worse.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false
How TRUE or FALSE is the following statement for you?  
My health is excellent.
Definitely true
Mostly true
Don't know
Mostly false
Definitely false