Clinical trial NCT02814175
Conditions: Psoriatic Arthritis
Keywords: Psoriatic Arthritis
Sponsor: AbbVie
Start date: 2016-08-05; Completion date: 2020-03-19
Enrollment: 246 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An interventional Phase 4 open-label, randomized, controlled, parallel-group, multi-country study in participants with psoriatic arthritis (PsA) consisting of 2 parts: Part 1 (Day 1 up to Week 16) is designed to compare the achievement of minimal disease activity (MDA) between participants randomized to either adalimumab in combination with methotrexate (MTX) or MTX alone escalated to the highest recommended or tolerable dose; Part 2 (Week 16 through Week 32) is designed to evaluate the maintenance or achievement of MDA on 4 different treatment regimens using adalimumab and/or MTX, with participant allocation based on the initial randomized treatment and achievement of MDA in Part 1, and with rescue treatment option.

Detailed description:

Arms: arm 1: Methotrexate (MTX) escalated to 20 - 25 mg or highest tolerable dose every week (ew) arm 2: Adalimumab (ADA) 40 mg every other week (eow) in combination with MTX 15 mg ew arm 3: Participants achieving minimal disease activity (MDA) at Week 16 on MTX escalated to 20 -25 mg or highest tolerable dose ew, continued with the same MTX dose arm 4: Participants not achieving MDA at Week 16 on MTX escalated to 20 - 25 mg or highest tolerable dose ew, received ADA 40 mg eow in combination with MTX 20 - 25 mg or highest tolerable dose ew arm 5: Participants achieving MDA at Week 16 on ADA 40 mg eow plus MTX 15 mg ew, had MTX completely withdrawn at Week 16 and continued receiving ADA as monotherapy arm 6: Participants not achieving MDA at Week 16 on ADA 40 mg eow plus MTX 15 mg ew, had ADA escalated to 40 mg ew in combination with MTX 15 mg ew
Interventions: intervention 1: methotrexate (MTX) intervention 2: adalimumab (ADA)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Adalimumab
M14-496 Protocol Amendment 3
EudraCT 2016-000191-21
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1.0
Title Page
Clinical Study Protocol M14-496
A Phase 4 open-label randomized controlled study 
COmparing the effectiveness of adalimumab 
iNTROduction and methotrexate dose escaLation in 
subjects with Psoriatic Arthritis (CONTROL)
Incorporating Amendment 1, 2, and 3
AbbVie Investigational
  Product:
Adalimumab
Date:
03 June 2019
Development Phase:
4
Study Design:
An interventional Phase 4 open-label, randomized, 
controlled, parallel-group, multi-country study in subjects 
with psoriatic arthritis (PsA) consisting of 2 parts:  Part 1 
is designed to compare the achievement of minimal 
disease activity (MDA) between subjects randomized to 
either adalimumab in combination with methotrexate 
(MTX) or MTX alone escalated to the highest 
recommended or tolerable dose; Part 2 is to evaluate the 
maintenance or achievement of MDA on four different 
treatment regimens using adalimumab and/or MTX, with 
subject allocation based on the initial randomized 
treatment and achievement of MDA in Part 1, and with 
rescue treatment option.
EudraCT Number:
EudraCT 2016-000191-21
Investigator:
Investigator information is on file at AbbVie.
Sponsor:
For Non-EU Countries:
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
For EU Countries:*
AbbVie Deutschland 
GmbH & Co. KG (AbbVie)
Knollstrasse 50
67061 Ludwigshafen
Germany
NCT02814175




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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
28 April 2016
Amendment 1
10 October 2016
Amendment 2
09 March 2018
The purpose of this amendment is to:
●
Update Section 5.5.7, Drug Accountability, to remove requirement for onsite 
monitor confirmation of empty boxes, bottles and returned Sharps containers.
Rationale:  Investigative site staff is responsible for drug accountability and 
destruction per their approved process.  Remote monitoring is conducted to 
ensure information documented is consistent with the investigative site's 
process.
●
Update Section 8.0, Statistical Methods and Determination of Sample Size.
●
To update the pre-specified analysis for the continuous endpoints to be 
MMRM.
Rationale:  MMRM was originally planned as a sensitivity analysis for 
continuous endpoints. Given that MMRM is a more robust statistical method 
in terms of missing data handling as compared to ANCOVA using LOCF, it's 
now elevated to be the primary analysis for continuous endpoints. 
●
To update the sensitivity analysis for the primary endpoint to be CMH test 
based on Observed Cases (OC).
Rationale:  Originally planned sensitivity analysis was logistic regression. 
This is being changed to a CMH test based on OC because this is a more 
appropriate sensitivity analysis for the response rate difference which is how 
the primary analysis is being reported. 
●
To remove pre-specified sensitivity analysis for secondary endpoints.


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Rationale:  Pre-specified sensitivity analyses are deemed not to be necessary 
for non-key secondary endpoints. Additional sensitivity analysis for secondary 
endpoints may be performed post-hoc. 
●
To remove pre-specified treatment group homogeneity analysis and p values 
for demographics and baseline disease characteristics.
Rationale:  Homogeneity analysis and p values for demographics and baseline 
disease characteristics are only meaningful with appropriate sample size 
otherwise a tiny difference which may not be clinically meaningful can have a 
significant p value.  In addition, this is a randomized study, so demographics 
and baseline characteristics are expected to be similar by the study design.  
Further testing using p values are not needed.  Therefore, descriptive statistics 
is used to demonstrate the similarity for the demographics and baseline 
characteristics.  Additional analysis on exploring baseline characteristics may 
be performed post hoc.
●
To remove formal summary of pre- and post-treatment Adverse Event 
analysis.
Rationale:  Pre- and post-adverse events will be provided in the AE listing. 
●
To update the language in the lab change from baseline analysis.
Rationale: Observed values of vital signs and laboratory variables at each 
visit will be summarized for all treated subjects. In addition, the change from 
baseline for lab variables of interest will be provided. 
●
To update the language in Section 8.2 Determination of sample size.
Rationale: For added accuracy.
●
To make editorial changes throughout for clarity
●
The following administrative changes were made:
○
Update Section 1.0, Title Page, to update Sponsor/Emergency contact 
information.
○
Update Section 1.2, Synopsis, to make editorial changes for clarity and to 
align with updates made in Section 8.0, Statistical Methods and 
Determination of Sample Size.
○
Update Section 5.5.2.2, Storage and Disposition of Study Drugs, to clarify 
temperature excursion reporting.


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○
Update Section 6.1.5, Adverse Event Reporting, to provide contact 
information for 
, MD.
○
Update Section 6.0, Complaints, to make editorial changes for clarity.
An itemized list of all changes made to this protocol amendment can be found in 
Appendix K.


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M14-496 Protocol Amendment 3
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-496
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  03 June 2019
Protocol Title:  A Phase 4 open-label randomized controlled study COmparing the effectiveness of 
adalimumab iNTROduction and methotrexate dose escaLation in subjects with Psoriatic Arthritis 
(CONTROL)
Objectives:
Primary Objective
The primary objective is to compare the effectiveness based on the achievement of minimal disease 
activity (MDA) at Week 16 between subjects who had adalimumab introduced and those that had 
methotrexate (MTX) escalated to the highest recommended dose of 20 – 25 mg every week (ew) or 
highest tolerable dose up to 25 mg ew after inadequate disease control on the initial MTX therapy.
Secondary Objectives
•
To compare the effectiveness at Week 16 between subjects who had adalimumab introduced 
and those that had MTX escalated to the highest recommended dose of 20 – 25 mg ew or 
highest tolerable up to 25 mg ew based on the following clinical, functional and quality of life 
measures:
o
Psoriatic Arthritis Disease Activity Score (PASDAS)
o
Disease Activity in Psoriatic Arthritis (DAPSA) score
o
Psoriatic Arthritis Impact of Disease (PsAID) score
o
American College of Rheumatology criteria (ACR) 
o
Disease Activity Score 28 (DAS28)
o
Psoriasis Area and Severity Index (PASI)
o
Health Assessment Questionnaire Disability Index (HAQ-DI)
o
Short Form Health Survey 36 (SF-36) scores:  total, physical component summary (PCS) 
and mental component summary (MCS)
o
Dermatology Life Quality Index (DLQI)
o
Leeds Enthesitis Index (LEI)
o
Tender dactylitic digit count
•
To evaluate the achievement of MDA at Week 32 on each of the four different treatment 
regimens involving adalimumab and/or MTX in Part 2 of the study.
The study also has the following Exploratory Objectives:
•
To evaluate the effectiveness at Week 32 based on the clinical, physical function and quality of 
life measures described under the secondary objectives on each of the four different treatment 
regimens involving adalimumab and/or MTX in the second part of the study.
•
To evaluate ultrasound detected synovitis and enthesitis at joint and enthesis level, and 
treatment effect on each of the study treatment regimens.


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Objectives (Continued):  
Exploratory Objectives (Continued)
•
To assess the pharmacokinetic and immunogenicity of adalimumab with and without 
concomitant MTX.
•
To investigate various biomarkers and their associations with treatment responses and 
outcomes.
Investigators:  Multi-center
Study Sites:  Approximately 60 sites
Study Population:  Approximately 240 adult subjects with active PsA (defined as not in MDA and 
having at least 3 tender and 3 swollen joints) despite having been treated with the first course of MTX at 
the dose of 15 mg ew for ≥ 4 weeks and biologic naive who meet all the inclusion and none of the 
exclusion criteria are planned to be enrolled in the study.
Number of Subjects to be Enrolled:  240 subjects in total, 120 subjects per randomized arm.
Methodology:  This interventional Phase 4 open-label, randomized, controlled, parallel-group, 
multicenter study will be conducted in two (2) parts, each of 16-week duration.
Part 1 (Day 1-Week 16) is designed to compare the achievement of MDA on adalimumab introduced in 
combination with MTX versus MTX alone escalated to the highest recommended dose of 20 – 25 mg ew 
or highest tolerable dose up to 25 mg ew, whatever feasible, in PsA subjects inadequately controlled 
after the initial course of MTX at 15 mg ew.  Part 1 will be open-label, randomized, controlled, parallel 
group.
Part 2 (Week 16-32) is to evaluate the effectiveness of four (4) different treatment regimens consisting 
of adalimumab and/or MTX in maintaining or attaining MDA, as applicable.  Part 2 will be open-label, 
parallel group.  Subjects will be assigned into the four treatment arms based on their MDA status at 
Week 16 and initial randomized treatment.  Starting at Week 24, there will be rescue treatment option 
based on not achieving MDA and investigator's judgment.
Following a maximum 30-day screening period, subjects meeting the selection criteria will be 
randomized in a 1:1 ratio to either of the two (2) arms and treated for 16 weeks in Part 1:
•
Arm 1/Part 1:  Adalimumab 40 mg eow in combination with MTX 15 mg ew (adalimumab 
40 mg eow + MTX 15 mg ew),
•
Arm 2/Part 1:  MTX escalated to 20 – 25 mg or highest tolerable dose ew (MTX 20 – 25 mg or 
highest tolerable dose ew)*
*
MTX will be escalated by increments of 5.0 mg every 2 weeks, starting at 20 mg ew as the 
first MTX dose on or after Day 1, depending on the subject's MTX administration schedule 
prior to the study.  In the case of suspected MTX intolerance or toxicity, the MTX dose 
may be de-escalated by 5 mg and the subject may stay on the highest tolerable MTX dose 
below 20 – 25 mg ew as described per the protocol.  MTX dose should not exceed 25 mg 
ew in this study.


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Methodology (Continued):  
After the assessment of MDA at Week 16 (primary endpoint), subjects will be assigned to one of the 
4 treatment arms based on the achievement of MDA and initial randomized treatment, and treated for 
additional 16 weeks in Part 2 as follows:
•
Arm 1/Part 2:  Subjects achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have MTX completely withdrawn at Week 16 and continue receiving 
adalimumab as monotherapy (adalimumab 40 mg eow),
•
Arm 2/Part 2:  Subjects not achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have adalimumab escalated to 40 mg ew in combination with MTX 15 mg ew 
(adalimumab 40 mg ew plus MTX 15 mg ew),
•
Arm 3/Part 2:  Subjects achieving MDA at Week 16 on MTX escalated to 20 – 25 mg or 
highest tolerable dose ew, will continue with the same MTX dose (MTX 20 – 25 mg or highest 
tolerable dose ew),
•
Arm 4/Part 2:  Subjects not achieving MDA at Week 16 on MTX escalated to 20 – 25 mg or 
highest tolerable dose ew, will receive adalimumab 40 mg eow in combination with MTX 20 –
25 mg or highest tolerable dose ew (adalimumab 40 mg eow plus MTX 20 – 25 mg or highest 
tolerable dose ew).
Subjects in Arms 1-4 of Part 2 of the study will have the option of being rescued, starting at Week 24 
and based on the subject not achieving MDA and the Investigator's judgment.  The selection of the 
rescue treatment regimen will be at the discretion of the Investigator, but should involve adalimumab 
and/or MTX and should not involve prohibited medications per the protocol.  The recommended rescue 
treatment regimens are as follows:
•
Subjects not achieving MDA on adalimumab 40 mg eow (Arm 1) have MTX 15 mg ew added,
•
Subjects not achieving MDA on adalimumab 40 mg ew + MTX 15 mg ew (Arm 2) have MTX 
escalated to 20 – 25 mg ew,
•
Subjects not achieving MDA on MTX 20 – 25 mg or highest tolerable dose ew (Arm 3) have 
adalimumab 40 mg eow added,
•
Subjects not achieving MDA on adalimumab 40 mg eow + MTX 20 – 25 mg or highest 
tolerable dose ew (Arm 4) have adalimumab escalated to 40 mg ew.


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Methodology (Continued):
A schematic of the study design is shown in the following figure:
Both adalimumab and MTX will be provided as study drugs.
MTX will be provided as a study drug for either oral or subcutaneous (sc) administration.  The route of 
MTX administration can be selected at the discretion of the Investigator and may be exchanged between 
oral and sc at any time during the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years of age at Screening
2.
PsA diagnosis established at least 4 weeks prior to the date of the Screening visit and confirmed by 
C1ASsification of Psoriatic Arthritis (CASPAR) criteria at the Screening visit
3.
Not in MDA at the time of screening, defined as not meeting at least 5 of the following 7 criteria:
•
Tender joint count (TJC) ≤ 1 out of 68 assessed
•
Swollen joint count (SJC) ≤ 1 out of 66 assessed
•
PASI ≤ 1 or Body Surface Area (BSA) ≤ 3
•
Patient's assessment of pain visual analogue scale (VAS) ≤ 15


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
•
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
•
HAQ-DI score ≤ 0.5
•
Tender entheseal points ≤ 1 out of 8 assessed
4.
Has active arthritis defined as fulfilling both the below criteria at screening and baseline visits:
•
≥ 3 tender joints (out of 68 assessed)
•
≥ 3 swollen joints (out of 66 assessed)
5.
Treated with MTX 15 mg ew for PsA defined as:
•
Oral or subcutaneous (sc) administration of MTX for at least 4 weeks prior to screening,
•
Change of the MTX administration route (oral or sc) is permitted in this time period if the 
administered dose of MTX 15 mg ew is not changed,
•
This is the first course of MTX the subject has been receiving for the treatment of PsA,
•
Subject has not received a dosage of MTX higher than 15 mg ew prior to the screening visit
•
Subject could have been receiving MTX doses lower than 15 mg ew before reaching the stable 
dose of MTX 15 mg ew defined above,
•
If the subject had been on MTX 15 mg ew for ≥ 12 weeks, temporary MTX discontinuation or 
dose decrease below 15 mg ew for up to 4 weeks is allowed.
6.
If subject is receiving concomitant oral corticosteroids, prednisone or equivalent must be 
≤10 mg/day and the dose must be stable for at least 1 week prior to the baseline visit.
7.
If subject is receiving nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 
(COX) 2 selective inhibitors, paracetamol (up to the maximum recommended dose in the local 
country label), the dose must be stable for at least 1 week prior to the Baseline Visit
8.
If subject is receiving other csDMARDs in addition to MTX (i.e., sulfasalazine), the dose must be 
stable for at least 4 weeks prior to the baseline visit.  If csDMARDs are discontinued before study 
enrollment, the discontinuation must occur at least 4 weeks prior to the baseline Visit.
•
Leflunomide should be discontinued at least 4 weeks prior to the baseline visit.
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Has contraindication(s) to adalimumab therapy and/or known hypersensitivity to adalimumab or its 
excipients (refer to SmPC or prescribing information)
2.
Has history of MTX intolerance/toxicity
3.
Has medical condition(s) precluding MTX dose increase above 15 mg ew
4.
Has had prior exposure to any tumor necrosis factor (TNF) inhibitor, other mechanism of action 
biologic DMARD (bDMARD) or any systemic biologic agent in general


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Investigational Product:
Adalimumab, solution for injection 50 mg/mL (40 mg/0.8 mL) pre-
filled syringe (PFS)
Doses:
40 mg administered eow or ew
Mode of Administration:
Subcutaneous (sc) injection
Reference Therapy:
Methotrexate Tablets:  5 mg 
Methotrexate Pre-filled PEN:
15 mg/0.30 ml
20 mg/0.40 ml
25 mg/0.50 ml
Dose:
Methotrexate ew
Mode of Administration:
Orally or sc
Duration of Treatment:  Up to 32 weeks
Criteria for Evaluation:
Effectiveness:
Primary Endpoint
The proportion of subjects in MDA at Week 16 on adalimumab 40 mg eow plus MTX 15 mg ew as 
compared with subjects on MTX alone escalated to 20-25 mg or highest tolerable dose ew.
Secondary Endpoints
•
The following outcomes after 16 Weeks of treatment with adalimumab 40 mg eow plus MTX 
15 mg ew compared with MTX alone escalated to 20-25 mg or highest tolerable dose ew:
o
Change in PASDAS from baseline
o
Change in DAPSA score from baseline
o
Change in PsAID score from baseline
o
Proportion of subjects achieving ACR 20/50/70 response
o
Change in DAS28-CRP score from baseline
o
Proportion of subjects achieving PASI 75/90/100 response among subjects with BSA ≥ 3%
o
Change in HAQ-DI score from baseline
o
Changes in total SF-36 score, PCS and MCS from baseline
o
Change in DLQI score from baseline
o
Change in Leeds Enthesitis Index (LEI) from baseline
o
Change in tender dactylitic digit count from baseline
•
The proportion of subjects in MDA at Week 32 on each of the four different treatment regimens 
(Arms 1 – 4) in Part 2 of the study.
Exploratory Endpoints:
Clinical Effectiveness 
Clinical effectiveness outcomes listed under the secondary endpoints will be analyzed at Week 32 as 
exploratory endpoints on the 4 different treatment regimens (Arms 1-4) in Part 2 of the study.


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Criteria for Evaluation (Continued):
Ultrasound
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from baseline to 
Week 16 in subjects who had adalimumab introduced compared with those who had MTX 
escalated to 20 – 25 mg or highest tolerable dose ew.
•
The change in OMERACT enthesitis score from baseline to Week 16 in subjects who had 
adalimumab introduced compared with those who had MTX escalated to 20 – 25 mg or highest 
tolerable dose ew.
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from Week 16 – 32 in 
the 4 arms of Part 2 of the study.
•
The change in OMERACT enthesitis score from Week 16 – 32 in the 4 arms of Part 2 of the 
study.
Pharmacokinetic and Immunogenicity:  For subjects receiving adalimumab, blood samples will be 
collected for determination of adalimumab serum concentrations and the presence of anti-adalimumab 
antibodies (AAA).
Exploratory Research Variables and Validation Studies (Optional):  Optional samples may be 
collected to conduct exploratory investigations into known and novel biomarkers.  The types of 
biomarkers to be analyzed may include, but are not limited to:  nucleic acids, proteins, lipids or 
metabolites.
Safety:  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.
Statistical Methods:
Effectiveness:  The primary and secondary efficacy endpoints will be analyzed for the intent-to-treat 
(ITT) population, defined as all subjects who were randomized and received at least one dose of study 
medication.  Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level (2-sided).  A 
Week 16 database lock is planned when all randomized subjects have completed Week 16 (Part 1) of the 
study and statistical comparisons for the primary and secondary efficacy endpoints will be performed at 
Week 16 between the Part 1 treatment groups.  No multiplicity adjustment will be performed for the 
statistical testing.  
To account for missing data for the binary effectiveness endpoints, a non-responder imputation approach 
(NRI) will be used, e.g., subjects who discontinue during Part 1 with missing data will be imputed as a 
non-responder.  For continuous endpoints, the Mixed-effects Model Repeated Measures (MMRM) 
analysis based on all observed data will be used.


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Statistical Methods (Continued):
Effectiveness (Continued):
The response rates for the primary endpoint will be compared between the treatment groups using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factor, the duration of prior MTX 
use of ≤ 3 months or > 3 months. The primary analysis will be based on NRI and the sensitivity analysis 
will be based on OC.  
Binary secondary endpoints in Part 1 will be analyzed using a similar method as the primary endpoint.  
Change from baseline in continuous secondary endpoints will be analyzed using MMRM with treatment, 
stratification factor of duration of prior MTX use, visit, and treatment-by-visit interaction as fixed 
effects, subject as random effect and baseline value as a covariate.
Pharmacokinetic and Immunogenicity:  Adalimumab serum trough concentrations will be 
summarized by treatment arm 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.  In addition, pharmacokinetic model-
based analyses may be performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F).
AAA will be evaluated for each subject receiving adalimumab and each treatment regimen, and rates of 
AAA positivity will be calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, 
efficacy variable(s), and treatment emergent adverse events may be evaluated.
Ultrasound:  For the analysis of ultrasound endpoints in Part 1, similar MMRM model as described for 
the continuous secondary endpoints will be used and baseline weight will be included as an additional 
covariate in the MMRM model.
Safety:  Safety analyses will be carried out using safety population, which includes all subjects that 
received at least one dose of study medication.  Treatment-emergent 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, and up to within 70 days after the last dose of the study medication.  All treatment emergent 
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA®).  The 
number and percent of subjects experiencing AEs will be tabulated by system organ class and preferred 
term.  In addition, a summary of AEs by severity and relationship to study drug will be presented.  AEs, 
which are serious, severe, or life-threatening, which lead to premature study discontinuation will be 
listed and described in detail.  Adverse events of special interest (AESI) will also be tabulated. 


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Statistical Methods (Continued):
Safety:
Observed values of vital signs and laboratory variables at each visit will be summarized for all treated 
subjects, and change from baseline in selected lab variables will be compared between treatment groups 
using a one way ANOVA.  The last evaluation prior to the first dose of study drug will be used as 
Baseline for the analyses in Part 1.  For selected parameters, a listing of all subjects with any laboratory 
determination meeting Common Toxicity Criteria (CTC) (Version 3) of Grade 3 or higher will be 
provided.  Shift tables for changes from Baseline according to the normal range will also be provided for 
laboratory variables.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AAA
Anti-Adalimumab Antibodies
ACR
American College of Rheumatology Criteria
AEs
Adverse events
AESI
Adverse event of special interest
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of Variance
BCG
Bacillus Calmette-Guérin vaccination
bDMARDS
Biologic disease modifying anti-rheumatic drugs 
BSA
Body surface area
CASPAR
ClASsification of Psoriatic Arthritis 
CDC
Center for Disease Control and Prevention
CL/F
Focus on apparent clearance
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
CRP
C-reactive protein
CS
Clinically Significant
csDMARDs
Conventional synthetic disease modifying anti-rheumatic drugs
CTC
Common Toxicity Criteria
CV
Coefficient of variation
CXR
Chest X-ray
DAPSA
Disease Activity in Psoriatic Arthritis Score
DAS28
Disease Activity Score 28
DLQI
Dermatology Life Quality Index
ECG
Electrocardiogram
eCRFs
Electronic case report forms
EDC
Electronic data capture
EMA
European Medicines Agency 
GCP
Good Clinical Practice
HAQ-DI
Health Assessment Questionnaire Disability Index
HBV
Hepatitis B Virus


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HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICH
International Conference of Harmonization
IEC
Independent Ethics Committee 
IgG1
Immunoglobulin G1 sub-class
IGRA
Interferon-Gamma Release Assay
IMP
Investigational Medicinal Product
INH
Isoniazid
IRB
Independent Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LEI
Leeds Enthesitis Index
LOCF
Last Observation Carried Forward
LOQ
Limit of quantification
MCS
Mental Component Summary
MDA
Minimal Disease Activity
MedDRA
Medical Dictionary for Drug Regulatory Activities 
MMRM
Mixed-effects Model Repeated Measures
MTX
Methotrexate
NCS
Not Clinically Significant 
NNMISS
Number of non-missing observations
NRI
Non-responder Imputation
NSAIDS
Non-steroidal anti-inflammatory drugs
OMERACT
Outcome Measures in Rheumatology Clinical Trials
PASDAS
Psoriatic Arthritis Disease Activity Score
PASI
Psoriasis Area and Severity Index
PCS
Physical Component Summary
PD
Premature Discontinuation
PDUS
Power Doppler Ultrasound
PhGA
Physician's Global Assessment of Disease Activity 
PK
Pharmacokinetic 


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PROs 
Patient reported outcomes
PsA
Psoriatic Arthritis
PsAID
Psoriatic Arthritis Impact of Disease Score
PsARC
Psoriatic Arthritis Response Criteria
PtGA
Patient's Global Assessment of Disease Activity
QoL
Quality of Life
RA
Rheumatoid Arthritis
SAP
Statistical Analysis Plan
SAPS
Self-Assessment of Psoriasis Symptoms
SC
Subcutaneous
SF-36
Short Form Health Survey 36
SH
Synovial hypertrophy
SJC
Swollen Joint Count
SmPC
Summary of Product Characteristics 
SpA
Spondyloarthritis
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2T
Treat-to-Target
TA MD
Therapeutic Area Medical Director 
TJC
Tender Joint Count
TNF
Anti-tumor necrosis factor
ULN
Upper limit of normal range
US
Ultrasound
V/F
Volume of distribution
VAS
Visual Analogue Scale
WBC 
White blood count
WHO
World Health Organization


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................15
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................23
3.1
Overview of Disease and its Treatment...................................................23
3.1.1
Methotrexate in Psoriatic Arthritis...........................................................23
3.1.2
Treat-to Target in Psoriatic Arthritis........................................................25
3.1.3
Adalimumab Overview............................................................................26
3.2
Rationale for the Study ............................................................................28
3.3
Differences Statement..............................................................................29
3.4
Benefits and Risks....................................................................................29
3.5
Safety Information ...................................................................................34
4.0
Study Objectives....................................................................35
4.1
Primary Objective ....................................................................................35
4.2
Secondary Objectives...............................................................................35
5.0
Investigational Plan...............................................................36
5.1
Overall Study Design and Plan:  Description ..........................................36
5.1.1
Screening Period ......................................................................................40
5.1.1.1
Rescreening..............................................................................................40
5.1.2
Treatment Period......................................................................................41
5.1.2.1
Part 1 (Randomized Open Label Treatment Period)................................41
5.1.2.2
Part 2 (Open-Label Treatment Period).....................................................42
5.2
Selection of Study Population..................................................................42
5.2.1
Inclusion Criteria .....................................................................................43
5.2.2
Exclusion Criteria ....................................................................................46
5.2.3
Prior and Concomitant Therapy...............................................................49
5.2.3.1
Prior and Concomitant Therapy...............................................................49
5.2.3.2
Prohibited Therapy...................................................................................52
5.2.4
Contraception Recommendations and Pregnancy Testing.......................55


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5.3
Efficacy, Pharmacokinetic, Immunogenicity, Ultrasound and 
Safety Assessments/Variables..................................................................57
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................57
5.3.1.1
Study Procedures .....................................................................................57
5.3.2
Drug Concentration Measurements .........................................................77
5.3.2.1
Handling/Processing of Samples .............................................................77
5.3.2.1.1
Serum Adalimumab Concentration and AAA Analysis ..........................77
5.3.2.2
Disposition of Samples ............................................................................78
5.3.2.3
Measurement Methods.............................................................................78
5.3.3
Efficacy Variables....................................................................................78
5.3.3.1
Primary Variable......................................................................................78
5.3.3.2
Secondary Variables ................................................................................79
5.3.3.3
Exploratory Variables ..............................................................................81
5.3.4
Safety Variables.......................................................................................82
5.3.5
Pharmacokinetic and Immunogenicity Variables ....................................82
5.3.6
Exploratory Research Variables and Validation Studies.........................82
5.4
Removal of Subjects from Therapy or Assessment.................................83
5.4.1
Discontinuation of Individual Subjects....................................................83
5.4.2
Discontinuation of Entire Study...............................................................84
5.5
Treatments................................................................................................85
5.5.1
Treatments Administered.........................................................................85
5.5.1.1
Adalimumab.............................................................................................85
5.5.1.2
Methotrexate ............................................................................................85
5.5.2
Identity of Investigational Product...........................................................87
5.5.2.1
Packaging and Labeling...........................................................................88
5.5.2.2
Storage and Disposition of Study Drugs..................................................89
5.5.3
Method of Assigning Subjects to Treatment Groups...............................89
5.5.4
Selection and Timing of Dose for Each Subject......................................90
5.5.5
Blinding....................................................................................................91
5.5.6
Treatment Compliance.............................................................................91
5.5.7
Drug Accountability.................................................................................91
5.6
Discussion and Justification of Study Design..........................................93
5.6.1
Discussion of Study Design and Choice of Control Groups....................93


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5.6.2
Appropriateness of Measurements...........................................................94
5.6.3
Suitability of Subject Population .............................................................94
5.6.4
Selection of Doses in the Study ...............................................................94
6.0
Complaints .............................................................................95
6.1
Medical Complaints.................................................................................95
6.1.1
Definitions................................................................................................96
6.1.1.1
Adverse Event..........................................................................................96
6.1.1.2
Serious Adverse Events ...........................................................................97
6.1.2
Adverse Event Severity............................................................................98
6.1.3
Relationship to Study Drug......................................................................98
6.1.4
Adverse Event Collection Period.............................................................99
6.1.5
Adverse Event Reporting.......................................................................100
6.1.6
Pregnancy...............................................................................................102
6.1.7
Toxicity Management ............................................................................102
6.2
Product Complaint .................................................................................104
6.2.1
Definition ...............................................................................................104
6.2.2
Reporting................................................................................................104
7.0
Protocol Deviations..............................................................105
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................106
8.1.1
Analysis Population ...............................................................................106
8.1.2
Statistical and Analytical Plan ...............................................................106
8.1.3
Analysis of Demographic Data and Baseline Disease 
Characteristics........................................................................................107
8.1.4
Statistical Analysis of Efficacy..............................................................108
8.1.4.1
Primary Efficacy Variable .....................................................................108
8.1.4.2
Analyses of Secondary Efficacy Variables............................................108
8.1.4.3
Other Exploratory Analyses...................................................................109
8.1.5
Statistical Analyses of Safety.................................................................109
8.1.6
Subject Disposition and Study Drug Exposure......................................110
8.1.7
Pharmacokinetic and Immunogenicity Analyses...................................110
8.2
Determination of Sample Size ...............................................................111
9.0
Ethics.....................................................................................111


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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................111
9.2
Ethical Conduct of the Study.................................................................112
9.3
Subject Information and Consent...........................................................112
10.0
Source Documents and Case Report Form 
Completion ...........................................................................113
10.1
Source Documents .................................................................................113
10.2
Case Report Forms.................................................................................113
11.0
Data Quality Assurance ......................................................114
12.0
Use of Information...............................................................115
13.0
Completion of the Study .....................................................115
14.0
Investigator's Agreement....................................................117
15.0
Reference List ......................................................................118
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................66
Table 2.
Identity of Investigational Product – Adalimumab..................................87
Table 3.
Identity of Investigational Product – MTX..............................................88
List of Figures
Figure 1.
Control Design Scheme ...........................................................................39
Figure 2.
Adverse Event Collection ......................................................................100
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................127
Appendix B.
List of Protocol Signatories....................................................................129
Appendix C.
Study Activities......................................................................................130
Appendix D.
Class VI and Class VII Topical Corticosteroid Examples.....................135
Appendix E.
Tender Joint Count (TJC) and Swollen Joint Count (SJC) 
Assessment.............................................................................................136
Appendix F.
Dactylitis Assessment ............................................................................138


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Appendix G.
Enthesitis Assessment:  Leeds Enthesitis Index and Tenderness at 
the Plantar Fascia ...................................................................................139
Appendix H.
Psoriasis Area and Severity Index (PASI) .............................................140
Appendix I.
Physician's Global Assessment of Disease Activity (PhGA) ................142
Appendix J.
Ultrasound Assessments and Scoring ....................................................143
Appendix K.
Protocol Amendment:  List of Changes.................................................148


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3.0
Introduction 
3.1
Overview of Disease and its Treatment
Psoriatic arthritis (PsA) is an inflammatory progressive arthritis occurring in around 30% 
of patients with psoriasis and an estimated prevalence of 0.1%-0.25% in the general 
population.1-4  PsA entails diverse dermatological, musculoskeletal and extraarticular 
manifestations that often result in impaired physical function, decreased quality of life and 
work disability.5,6  Almost one third of PsA patients may have evident radiographic 
damage at their first presentation to the clinic and around 50% may develop erosions 
within 2 years of the diagnosis.7  The burden of PsA for the patient and society is 
amplified by frequent comorbidities, in particular cardiovascular, resulting in an increased 
and premature mortality.8
Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) remain the 
cornerstone of treating PsA in clinical practice, despite their limited efficacy in reducing 
clinical signs and symptoms and lacking or unproven ability to inhibit radiographic 
progression in this disease9,10  CsDMARDs are also recommended prior to biologic 
DMARDs (bDMARDs) by the international and national PsA management 
recommendations, unless poor prognostic factors, enthesitis, dactylitis or axial 
involvement are present.11-13  In patients that failed csDMARD therapy, bDMARDs have 
demonstrated significant improvements in musculoskeletal and psoriasis outcomes as well 
as potent inhibition of radiographic progression.13,14
3.1.1
Methotrexate in Psoriatic Arthritis
The recommended first choice csDMARD in PsA is methotrexate (MTX).11,12  According 
to the clinical practice insights, MTX may be prescribed in up to 90% of PsA patients 
prior to a biologic agent.15  However, evidence for the efficacy of MTX in PsA is scant 
and data on the efficacious dose conflicting.
A 6-month double-blind randomized placebo controlled trial (MIPA) with a target MTX 
dose of 15 mg/week did not show a superiority of MTX over placebo in controlling PsA 


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arthritis.16  Statistically significant improvements were only observed in patient and 
physician global assessments and mean Psoriasis Area and Severity Index (PASI) score, 
but not in the primary outcome of Psoriatic Arthritis Response Criteria (PsARC), or 
secondary outcomes tender and swollen joint count, composite scores for joint activity 
and improvement, skin improvement, measures of pain and function or laboratory 
inflammatory markers.16  The trial has been criticized for several methodological 
drawbacks, including the low MTX dose capped at 15 mg/week.13,14  By contrast, the 
open-label randomized RESPOND study in relatively early, MTX-naive PsA patients that 
compared infliximab in combination with MTX 15 mg/week with MTX monotherapy at 
the same dose, showed a better effectiveness of the biologic combination, but MTX alone 
provided for high joint and skin responses at Week 16 too.17  In the recent post-hoc 
analysis within TICOPA, the first Treat-to-Target (T2T) trial in PsA, 40.8% and 22.4% of 
early PsA subjects achieved a 20% improvement in the American College of 
Rheumatology Criteria (ACR20) and Minimal Disease Activity (MDA) status, 
respectively, at Week 12 on MTX alone.  Furthermore, 24.7% of subjects in the tight 
control arm received only MTX and remained consistently in MDA until the end of the 
trial at Week 48.  Improvements were also seen in PASI, nail involvement, enthesitis and 
dactylitis.18  Still, the majority of PsA patients will likely be insufficiently controlled on 
MTX alone and inhibition of radiographic progression with MTX remains unproven.9,10
MTX dosing in PsA is mainly based on clinical experience and evidence from trials in 
rheumatoid arthritis (RA).  The recommended target dose is 15-25 mg weekly,11-13 though 
poor tolerance seems to be common at higher MTX doses.19  A vast majority, 91% and 
83% of subjects however reached a MTX dose of at least 20 and 25 mg/week, 
respectively, by Week 12 in the tight control arm of TICOPA trial, following an intense 
MTX escalation scheme.  A trend towards better outcomes with the doses higher than 
15 mg/week was observed, but the differences were not significant.  The interpretation of 
this data is however difficult due to confounding present in the dose escalation.18
Although the mean MTX dose has increased over the past few decades, it was still
16.2 mg/week only in the period between 1994 and 2004 in a Canadian tertiary clinic.20  


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In a more recent large German post-marketing observational study, PsA subjects eligible 
for biologic therapy were on a mean of 15.4 mg/week of MTX at enrolment.15  Likewise, 
the mean MTX dose at baseline in the recent clinical trials with new compounds in PsA 
ranged between 15.8-17.5 mg/week.21-23  This implies that in clinical practice PsA patients 
are insufficiently treated for prolonged periods of time with MTX doses lower than the 
recommended target dose.
It is also unclear whether MTX concomitant to anti-tumor necrosis factor (TNF) therapy 
provides an additional benefit in PsA patients that failed MTX.  No difference in the 
efficacy of anti-TNFs with or without MTX was found for peripheral arthritis in 
randomized controlled trials, though there was some hint that concomitant MTX may 
decrease the progression of structural damage.  The trials were however not designed and 
powered to answer this question.  Data from registries suggest that the use of concomitant 
MTX may prolong drug survival of anti-TNFs, especially monoclonal antibodies, but that 
was not a consistent observation either.24
3.1.2
Treat-to Target in Psoriatic Arthritis
The T2T recommendations for spondyloarthritis (SpA) suggested remission, alternatively 
low disease activity, as the ultimate treatment goal.  It has also been noted that a 
maximum of 6 months for reaching remission or low disease activity seems appropriate, 
but it is advisable to adapt therapy earlier if no significant reduction of disease activity is 
observed within 3 months.25  MDA, which corresponds to the concepts of both remission 
and low disease activity, was suggested as a feasible treatment target in PsA.25,26
The first T2T trial in SpA TICOPA demonstrated that a T2T approach in comparison with 
the standard of care improves long-term joint and skin outcomes in subjects with early 
PsA.27  Per protocol, the tight control arm mandated treatment escalation every 3 months 
if MDA was not achieved, starting with MTX, increasing it up to 25 mg/week within 
3 months, followed by MTX combination with sulphasalazine, before an anti-TNF could 
be introduced.  At 48 weeks (end of the trial), 39% of subjects in the tight control arm 
were on biologics compared with 7% in the standard care arm with no pre-defined 


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treatment protocol.27  It may be speculated that the results of T2T could further be 
improved by an earlier anti-TNF introduction.
3.1.3
Adalimumab Overview
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody 
containing only human peptide sequences.  Adalimumab is produced by recombinant 
DNA technology in a mammalian cell expression system.  It consists of 1330 amino acids 
and has a molecular weight of approximately 148 kilodaltons.  Adalimumab is composed 
of fully human heavy and light chain variable regions, which confer specificity to human 
TNF, and human IgG1 heavy chain and kappa light chain sequences.  Adalimumab binds 
with high affinity and specificity to soluble TNF-α but not to lymphotoxin-α (TNF-β).
TNF is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses.  Elevated levels of TNF play an important role in pathologic 
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.
Adalimumab was first approved for the treatment of patients with RA in the United States 
in December 2002 and in the European Union (EU) in September 2003.  In addition, 
adalimumab is approved for the treatment of patients with early RA, polyarticular juvenile 
idiopathic arthritis (2 years of age and older), PsA, ankylosing spondylitis, Crohn's 
disease (adult and pediatric), ulcerative colitis, plaque psoriasis (adult), hidradenitis 
suppurativa in the EU, US, and the rest of the world.  Adalimumab is also approved for 
the treatment of patients with pediatric enthesitis related arthritis (6 years of age and 
older), pediatric plaque psoriasis (4 years of age and older), and non-radiographic axial 
SpA in the EU and several other countries, as well as for intestinal Behçet's disease in 


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Japan, Argentina, Korea, and Taiwan.  Additional updates regarding approved indications 
can be found in the current edition of the Humira Investigational Drug Brochure.
The efficacy and safety of adalimumab in PsA was originally demonstrated in the ADEPT 
trial (Study M02-518), which was a multicountry, 24-week randomized, double-blind, 
placebo controlled trial that compared adalimumab 40 mg subcutaneously (sc) every other 
week (eow) versus placebo in 313 subjects with moderately to severely active PsA and 
history of inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs).  
Significantly better results in subjects treated with adalimumab compared with placebo 
were seen at Weeks 12 and 24 for joint and skin outcomes, physical function and quality 
of life.28,29  Subjects treated with adalimumab also experienced less radiographic 
progression, including its components joint space narrowing and joint erosions.28  These 
improvements were sustained through the subsequent 120 weeks of open-label 
adalimumab therapy.30-32  The results were confirmed in a smaller, 12-week randomized, 
placebo controlled trial conducted in 100 subjects with active, moderate to severe PsA 
who had failed csDMARD therapy.  Subjects treated with adalimumab 40 mg eow had 
significantly improved joint and skin symptoms, physical function and quality of life 
versus placebo at Week 12.  The improvements were sustained during open-label 
adalimumab therapy until Week 24.33
In a post-hoc analysis of the ADEPT trial, significantly more subjects achieved MDA on 
adalimumab than placebo at Week 24:  39% vs. 7%, respectively.34  ADEPT subanalyses 
also indicated that adalimumab monotherapy provides similar results to adalimumab with 
concurrent MTX.29,30
No published data are currently available on the efficacy of adalimumab escalated to 
40 mg sc every week (ew) in PsA patients that had not achieved sufficient disease control 
on adalimumab at the standard dose of 40 mg sc eow.


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3.2
Rationale for the Study
CsDMARDs are the foundation of PsA treatment, despite their limited efficacy in 
reducing clinical signs and symptoms and lacking or unproven ability to inhibit 
radiographic progression in this disease.  In subjects that failed csDMARD therapy, 
bDMARDs have demonstrated significant improvement in musculoskeletal and psoriasis 
outcomes as well as potent inhibition of radiographic progression.9-14
MTX is the most commonly prescribed csDMARD in PsA, but its recommended dosing 
has been extrapolated from clinical trials in RA and the dose-effect relationship in PsA is 
unclear.13-15,18  Data suggests that even with intense MTX dose escalation to the target 
dose of 25 mg ew in the context of a clinical trial, the majority of PsA subjects do not 
achieve adequate disease control on MTX alone.18,27 In clinical practice, PsA patients 
seem to be insufficiently treated for prolonged periods of time with MTX doses lower 
than the recommended target dose of 20-25 mg ew, and T2T principles are generally not 
followed.15,21-23,25,26
Scientific substantiation that an early introduction of bDMARD therapy substantially 
improves long-term outcomes in subjects with PsA is missing.11-13  A recent post-hoc 
analysis of the PRESTA trial provided some evidence by showing that subjects having 
been treated with etanercept within 2 years of PsA duration experienced greater 
improvements in arthritis related scores and patient reported outcomes (PROs) than those 
with more than 2 years of PsA.35
Treatment strategy trials are clearly needed to define the best timing of bDMARD 
introduction, as highlighted in the recent EULAR research agenda for PsA.11
The present Study M14-496 (CONTROL) primarily aims to assess the effectiveness of 
adalimumab introduction compared with MTX dose escalation to the highest 
recommended dose of 20-25 mg ew11,27 or the highest tolerable dose up to 25 mg ew in 
PsA subjects whose disease activity has been insufficiently controlled after an initial 
course of MTX at 15 mg ew.  The primary effectiveness outcome will be achievement of 


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MDA.  A possible impact of the duration of MTX therapy prior to study enrolment will be 
addressed by stratifying patients at randomization into those having been on MTX 15 mg 
ew for 3 months or less and those more than 3 months on MTX 15 mg ew.
Additionally, the maintenance or attainment of MDA on four different potential treatment 
optimization regimens, using adalimumab and/or MTX will be evaluated in the 
second part of the study.  These treatment regimens include adalimumab monotherapy, 
adalimumab escalation to weekly dosing, delayed introduction of adalimumab and 
continuous treatment with MTX at the highest recommended dose of 20-25 mg or highest 
tolerable dose up to 25 mg ew, depending on the treatment regimen and achievement of 
MDA at the end of the first part of the study.  Such treatment regimens are currently used 
in clinical practice, but lack evidence base.  In subjects not achieving MDA during the 
second part of the study, there will be rescue treatment option in order to allow for their 
improved outcomes by the end of the study. 
CONTROL is a treatment strategy trial in the T2T context with MDA as the major 
outcome of interest.
3.3
Differences Statement
This is the first study in general aiming to assess the effectiveness of bDMARD 
introduction compared with MTX dose escalation to the highest recommended dose of 20-
25 mg ew11,27 or the highest tolerable dose in PsA subjects who have previously been 
treated with MTX.  
3.4
Benefits and Risks
This is a pragmatic study that will address some of the crucial data gaps in the treatment 
of PsA.  Results are expected to inform treatment recommendations and clinical practice.  
The main specific benefit will be provision of data on the effectiveness of bDMARD 
(adalimumab) introduction in combination with MTX compared with prolonging and 
escalating MTX alone to the highest recommended11,27 or tolerable dose.  The other 
benefits will be insights into the effectiveness of different potential treatment optimization 


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regimens consisting of adalimumab and/or MTX in the maintenance or attainment of the 
outcomes in the second part of the study.  These treatment regimens are used in clinical 
practice but lack scientific evidence.
Adalimumab has a well-established safety profile in PsA and other approved indications.  
Adalimumab will be administered in this study at the approved dosing regimen for PsA 
(i.e., 40 mg sc eow).36,37  The only exception will be subjects not achieving MDA on the 
approved adalimumab dosing in combination with MTX, who will be required to escalate 
adalimumab to 40 mg sc ew in combination with MTX.  Adalimumab 40 mg ew has been 
used in ACR20 non-responders in the open-label extension of the ADEPT trial through 
Week 144 with no increased risk of adverse events (AEs) noted.30,31  Adalimumab has 
been approved in the EU for weekly dosing in psoriasis patients with inadequate response 
after 16 weeks of treatment.36  Adalimumab may be used with or without concomitant 
MTX in PsA according to the label.36,37
MTX is an established immunosuppressive drug and has become the most commonly 
used csDMARD in inflammatory arthritides over the past decades.  It is labelled for the 
treatment of RA and severe psoriasis across the world, and also for severe PsA in adults in 
some countries, like the United Kingdom.38,39  MTX is recommended as the first-choice 
csDMARD by the international PsA management recommendations,11 and is also the 
most commonly prescribed csDMARD in PsA.13-15
More than 30,000 subjects participating in hidradenitis suppurativa, polyarticular juvenile 
idiopathic arthritis, pediatric enthesitis related arthritis, Crohn's disease, pediatric Crohn's 
disease, psoriasis, pediatric psoriasis, rheumatoid arthritis, ankylosing spondylitis, non-
radiographic axialspondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis, 
intestinal Behçet's disease, uveitis and ulcerative colitis clinical studies have been treated 
with adalimumab.
The majority of side effects experienced following administration of adalimumab were 
mild to moderate in severity.


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The most commonly reported adverse reactions are infections (such as nasopharyngitis, 
upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, 
haemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for Humira.  TNF-antagonists, such as 
Humira affect the immune system and their use may affect the body's defense against 
infection and cancer.  Fatal and life-threatening infections (including sepsis, opportunistic 
infections and TB), HBV reactivation and various malignancies (including leukaemia, 
lymphoma and HSTCL) have also been reported with use of Humira.
Serious haematological, neurological and autoimmune reactions have also been reported.  
These include rare reports of pancytopenia, aplastic anaemia, central and peripheral 
demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson 
syndrome.
Humira is contraindicated in patients with:
●
Hypersensitivity to the active substance or to any of its excipients;
●
Active tuberculosis or other severe infections such as sepsis, and opportunistic 
infections;
●
Moderate to severe heart failure (NYHA class III/IV).
In its Summary of Product Characteristics, Special warnings and precautions for use for 
Humira are the following:
●
Infections
○
Patients taking TNF-antagonists are more susceptible to serious infections.
○
Impaired lung function may increase the risk for developing infections.
●
Serious infections
○
Serious infections, including sepsis, due to bacterial, mycobacterial, 
invasive fungal, parasitic, viral, or other opportunistic infections such as 
listeriosis, legionellosis and pneumocystis have been reported in patients 
receiving Humira.


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●
Tuberculosis
○
Tuberculosis, including reactivation and new onset of tuberculosis, has 
been reported in patients receiving Humira.  Reports included cases of 
pulmonary and extra-pulmonary (i.e., disseminated) tuberculosis.
●
Other opportunistic infections
○
Opportunistic infections, including invasive fungal infections have been 
observed in patients receiving Humira.  These infections have not 
consistently been recognised in patients taking TNF antagonists and this 
resulted in delays in appropriate treatment, sometimes resulting in fatal 
outcomes.
●
Hepatitis B reactivation
○
Reactivation of hepatitis B has occurred in patients receiving a TNF-
antagonist including Humira, who are chronic carriers of this virus 
(i.e., surface antigen positive).
●
Neurological events
○
TNF-antagonists including Humira have been associated in rare instances 
with new onset or exacerbation of clinical symptoms and/or radiographic 
evidence of central nervous system demyelinating disease including 
multiple sclerosis and optic neuritis, and peripheral demyelinating disease, 
including Guillain-Barré syndrome.
●
Allergic reactions
○
Serious allergic reactions associated with Humira were rare during clinical 
trials.  Non-serious allergic reactions associated with Humira were 
uncommon during clinical trials.  Reports of serious allergic reactions 
including anaphylaxis have been received following Humira 
administration.
●
Immunosuppression
○
In a study of 64 patients with rheumatoid arthritis that were treated with 
Humira, there was no evidence of depression of delayed-type 
hypersensitivity, depression of immunoglobulin levels, or change in 
enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and 
neutrophils.


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●
Malignancies and lymphoproliferative disorders
○
In the controlled portions of clinical trials of TNF-antagonists, more cases 
of malignancies including lymphoma have been observed among patients 
receiving a TNF-antagonist compared with control patients.  However, the 
occurrence was rare.
●
Haematologic reactions
○
Rare reports of pancytopaenia including aplastic anaemia have been 
reported with TNF-antagonists.
○
Adverse events of the haematologic system, including medically 
significant cytopoenia (e.g., thrombocytopaenia, leucopaenia) have been 
reported with Humira.
●
Vaccinations Patients on Humira may receive concurrent vaccinations, except 
for live vaccines.
●
Congestive heart failure
○
In a clinical trial with another TNF-antagonist worsening congestive heart 
failure and increased mortality due to congestive heart failure have been 
observed.  Cases of worsening congestive heart failure have also been 
reported in patients receiving Humira.
●
Autoimmune processes
○
Treatment with Humira may result in the formation of autoimmune 
antibodies.  The impact of long term treatment with Humira on the 
development of autoimmune diseases is unknown.
●
Concurrent administration of biologic DMARDS or TNF-antagonists
○
Concomitant administration of adalimumab with other biologic DMARDS 
(e.g., anakinra and abatacept) or other TNF-antagonists is not 
recommended based upon the possible increased risk for infections, 
including serious infections and other potential pharmacological 
interactions.
●
Elderly patients
○
The frequency of serious infections among Humira treated subjects over 
65 years of age (3.6%) was higher than for those under 65 years of age 
(1.4%).


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○
Some of those had a fatal outcome.  Particular attention regarding the risk 
for infection should be paid when treating the elderly.
●
Surgery
○
There is limited safety experience of surgical procedures in patients treated 
with Humira.
The SmPC states that the long half-life of adalimumab should be taken into consideration 
if a surgical procedure is planned.  A patient who requires surgery while on Humira 
should be closely monitored for infections, and appropriate actions should be taken.
The study will be conducted in subjects previously treated with MTX for PsA at 15 mg 
ew for at least 4 weeks.  Thus, enrolled subjects will have already been exposed to MTX.  
For subjects randomized into the MTX escalation arm, a dose increase up to 20-25 mg ew 
will be required, which is the highest recommended dose in PsA11,27 and also approved 
dose for PsA.38  Rapid MTX dose escalation in subjects with PsA up to 25 mg ew has 
been studied before, though with a different research objective.  The majority, 91% and 
83% of patients were able to reach the MTX dose of at least 20 and 25 mg ew, 
respectively, with no major safety issue.18,27  Further, in the present study subjects are 
allowed to de-escalate to the highest tolerable MTX dose in the case of suspected MTX 
toxicity or intolerance.
3.5
Safety Information
Adalimumab therapy has a well-established and well described safety profile based on 
extensive postmarketing experience and continued clinical trial patient exposure since the 
first approved indication in 2002 for RA.  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.  A detailed discussion of the pre-clinical toxicology, 
metabolism, pharmacology and safety experience with adalimumab can be found in the 
current Summary of Product Characteristics (SmPC) or prescribing information.  AbbVie 


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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 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.
The most relevant undesirable effects of MTX therapy are suppression of the 
haematopoietic system and gastrointestinal disorders.  For a detailed description of the
MTX safety profile, the Investigator should refer to the MTX prescribing information 
provided.
4.0
Study Objectives
4.1
Primary Objective
The primary objective is to compare the effectiveness based on the achievement of MDA 
at Week 16 between subjects who had adalimumab introduced and those that had MTX 
escalated to the highest recommended dose of 20-25 mg ew or highest tolerable dose up to 
25 mg ew after inadequate disease control on the initial MTX therapy.
4.2
Secondary Objectives
The secondary objectives are:
●
To compare the effectiveness at Week 16 between subjects who had 
adalimumab introduced and those that had MTX escalated to the highest 
recommended dose of 20-25 mg ew or highest tolerable up to 25 mg ew based 
on the following clinical, functional and quality of life measures: 
○
Psoriatic Arthritis Disease Activity Score (PASDAS)
○
Disease Activity in Psoriatic Arthritis (DAPSA) score


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○
Psoriatic Arthritis Impact of Disease (PsAID) score
○
American College of Rheumatology criteria (ACR)
○
Disease Activity Score 28 (DAS28) 
○
Psoriasis Area and Severity Index (PASI)
○
Health Assessment Questionnaire Disability Index (HAQ-DI)
○
Short Form Health Survey 36 (SF-36) scores:  total, physical component 
summary (PCS) and mental component summary (MCS)
○
Dermatology Life Quality Index (DLQI)
○
Leeds Enthesitis Index (LEI)
○
Tender dactylitic digit count
●
To evaluate the achievement of MDA at Week 32 on each of the four different 
treatment regimens involving adalimumab and/or MTX in Part 2 of the study.
The study also has the following Exploratory Objectives:
●
To evaluate the effectiveness at Week 32 based on the clinical, functional and 
quality of life measures described under the secondary objectives on each of 
the four different treatment regimens involving adalimumab and/or MTX in 
the second part of the study.
●
To evaluate ultrasound detected synovitis and enthesitis at joint and enthesis 
level, and treatment effect on each of the study treatment regimens.
●
To assess the pharmacokinetic and immunogenicity of adalimumab with and 
without concomitant MTX.
●
To investigate various biomarkers and their associations with treatment 
responses and outcomes.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This interventional Phase 4 open-label, randomized, controlled, parallel-group, 
multicenter study will be conducted in two (2) parts, each of 16-week duration.


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Part 1 (Day 1-Week 16) is designed to compare the achievement of MDA on 
adalimumab introduced in combination with MTX versus MTX alone escalated to the 
highest recommended dose of 20-25 mg ew11,27 or highest tolerable dose up to 25 mg ew, 
whatever feasible, in PsA subjects inadequately controlled after the initial course of MTX 
at 15 mg ew.  Part 1 will be open-label, randomized, controlled, parallel group.
Part 2 (Week 16-32) is to evaluate the effectiveness of four (4) different treatment 
regimens consisting of adalimumab and/or MTX in maintaining or attaining MDA, as 
applicable.  Part 2 will be open-label, parallel group.  Subjects will be assigned into the 
four treatment arms based on their MDA status at Week 16 and initial randomized 
treatment.  Starting at Week 24, there will be rescue treatment option based on not 
achieving MDA and investigator's judgment.
Eligible male and female subjects with PsA will be selected to participate in the study 
according to the selection criteria.
The study will enroll approximately 240 subjects at approximately 60 sites to meet the 
scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  Therefore, if the target number of subjects has 
been enrolled, there is a possibility that additional subjects in screening will not be 
enrolled. 
Following a screening period of up to 30 days, subjects meeting the selection criteria will 
be randomized in a 1:1 ratio to either of the two (2) arms and treated for 16 weeks in 
Part 1:
●
Arm 1/Part 1:  Adalimumab 40 mg eow in combination with MTX 15 mg ew 
(ADA 40 mg eow + MTX 15 mg ew),
●
Arm 2/Part 1:  MTX escalated to 20-25 mg or highest tolerable dose ew (MTX 
20-25 mg or highest tolerable dose ew).*
*
MTX will be escalated by increments of 5.0 mg every 2 weeks, starting at 
20 mg ew as the first MTX dose on or after Day 1, depending on the 
subject's MTX administration schedule prior to the study.  In the case of 


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suspected MTX intolerance or toxicity, the MTX dose may be de-escalated 
by 5 mg and the subject may stay on the highest tolerable MTX dose below 
20-25 mg ew as described per the protocol (see Section 6.1.7, Toxicity 
Management).  The event of MTX toxicity or intolerance must be clearly 
documented in source documents.  MTX dose should not exceed 25 mg ew 
in this study.
After the assessment of MDA at Week 16 (primary endpoint), subjects will be assigned to 
one of the four (4) treatment arms based on the achievement of MDA and initial 
randomized treatment, and treated for additional 16 weeks in Part 2 as follows:
●
Arm 1/Part 2:  Subjects achieving MDA at Week 16 on adalimumab 40 mg 
eow plus MTX 15 mg ew, will have MTX completely withdrawn at Week 16 
and continue receiving adalimumab as monotherapy (ADA 40 mg eow),
●
Arm 2/Part 2:  Subjects not achieving MDA at Week 16 on adalimumab 40 mg 
eow plus MTX 15 mg ew, will have adalimumab escalated to 40 mg ew in 
combination with MTX 15 mg ew (ADA 40 mg ew plus MTX 15 mg ew),
●
Arm 3/Part 2:  Subjects achieving MDA at Week 16 on MTX escalated to 20-
25 mg or highest tolerable dose ew, will continue with the same MTX dose 
(MTX 20-25 mg or highest tolerable dose ew),
●
Arm 4/Part 2:  Subjects not achieving MDA at Week 16 on MTX escalated to 
20-25 mg or highest tolerable dose ew, will receive adalimumab 40 mg eow in 
combination with MTX 20-25 mg or highest tolerable dose ew (ADA 40 mg 
eow plus MTX 20-25 mg or highest tolerable dose ew).
Subjects in Arms 1-4 of Part 2 of the study will have the option of being rescued, starting 
at Week 24 and based on the subject not achieving MDA and the Investigator's judgment.  
The selection of the rescue treatment regimen will be at the discretion of the Investigator, 
but should involve adalimumab and/or MTX and should not involve prohibited 
medications per the protocol.  The recommended rescue treatment regimens are as 
follows: 


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●
Subjects not achieving MDA on adalimumab 40 mg eow (Arm 1) have MTX 
15 mg ew added,
●
Subjects not achieving MDA on adalimumab 40 mg ew + MTX 15 mg ew 
(Arm 2) have MTX escalated to 20-25 mg ew,
●
Subjects not achieving MDA on MTX 20-25 mg or highest tolerable dose ew 
(Arm 3) have adalimumab 40 mg eow added,
●
Subjects not achieving MDA on adalimumab 40 mg eow + MTX 20-25 mg or 
highest tolerable dose ew (Arm 4) have adalimumab escalated to 40 mg ew.
A schematic of the study design is shown below in Figure 1:
Figure 1.
Control Design Scheme
Both adalimumab and MTX will be provided as study drugs.


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MTX will be provided as a study drug for either oral or subcutaneous (sc) administration.  
The route of MTX administration can be selected at the discretion of the Investigator and 
may be exchanged between oral and sc at any time during the study.
5.1.1
Screening Period
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures, will receive a unique subject number via 
Interactive Response Technology (IRT) system and will undergo the study procedures 
identified in Section 5.3.1.1 associated with the Screening Visit.  The investigator will 
evaluate whether the subject meets all of the eligibility criteria specified in Section 5.2.1
and Section 5.2.2 during the period from the Screening Visit through Day 1 prior to 
dosing and record the results of this assessment and the details of the informed consent 
process in the subject's medical records.  Eligible subjects have up to 30 days following 
the Screening Visit to enroll into the study.  The screening period may be extended with 
the approval of the AbbVie TA MD for certain circumstances (e.g., due to delay of 
availability of screening test results, holidays or scheduling/availability issues).
5.1.1.1
Rescreening
●
Subjects that initially screen fail for the study may be permitted to re-screen 
once. There is no minimum period of time a subject must wait to re-screen for 
the study.  All screening procedures with the possible exceptions noted below 
will be repeated.
●
Re-consent is required if there is a newly approved informed consent since the 
original screening visit or if 60 days have passed.
●
If there is one exclusionary laboratory result during screening, a re-test of that 
one particular value is allowed without repeating all other laboratory tests 
provided no more than 30 days have passed since the original screening visit.
●
If the subject had a complete initial Screening visit including the assessment of 
a PPD test (or equivalent), or QuantiFERON-TB Gold test, Chest x-ray (if 
applicable) and ECG, these tests will not be required to be repeated for the re-
screening visit, provided the conditions noted in Section 5.2 are met and no 


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more than 90 days have passed since the original screening visit. Note:  If the 
subject initiated TB treatment and the treatment was completed outside the 
30 day screening window, the screening period may be extended with the 
approval of the AbbVie TA MD.
The subject must meet all inclusion and none of the exclusion criteria at the time of 
enrollment in order to qualify for the study.  As appropriate, sites are encouraged to 
contact the AbbVie Therapeutic Area Medical Director (TA MD) to confirm if subjects 
should or should not be re-screened.
For subjects who do not meet the study eligibility criteria, the site personnel must register 
the subject as a screen failure in both IRT and electronic data capture (EDC) systems.  For 
subjects that re-screen, the Screening number assigned by the IRT at the initial Screening 
visit should be used; a new Screening number should not be requested.
5.1.2
Treatment Period
5.1.2.1
Part 1 (Randomized Open Label Treatment Period)
At the Baseline visit, subjects who meet all the inclusion criteria and none of the 
exclusion criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the 
study and randomized in a 1:1 ratio to Arm 1 or Arm 2 of Part 1 (as described in 
Section 5.1).  During this period of the study, subjects will visit the study site at Week 2, 
Week 4 and then monthly through Week 16 (if local requirements ask for additional 
safety assessments, e.g., due to MTX treatment, respective laboratory tests should be done 
locally).  A ± 2-day window is permitted around scheduled study visits.  
IRT will be utilized to dispense the appropriate study drug (adalimumab and MTX) to 
subjects for administration during the visit or at the regularly scheduled day for MTX.  
Subjects will be given dosing instructions and a dosing diary at the Baseline visit.


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5.1.2.2
Part 2 (Open-Label Treatment Period)
After completing the randomized-open label treatment period at Week 16, subjects will be 
assigned to Arms 1-4 of Part 2 (as described in Section 5.1), based on the achievement of 
MDA and initial randomized treatment, and treated for additional 16 weeks.  Starting at 
Week 24, there will be rescue treatment option based on not achieving MDA and 
investigator's judgment.  During this study period, subjects will visit the study site 
monthly through Week 32.  A ± 2-day window is permitted around scheduled study visits.  
Subjects will be dispensed study drugs at the Week 16 Visit for administration during the 
visit or at the regularly scheduled day for MTX.
No study drug will be administered or injected after the final visit (Week 32 Visit).  
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects who end study participation early will have a Premature Discontinuation (PD) 
Visit and complete the procedures outlined for the PD Visit in Appendix C as soon as 
possible after the last dose of study drug and preferably prior to the administration of any 
new therapies.
Follow-Up Period
Subjects may discontinue their study participation at any time.  Subjects that end study 
participation early will have a PD Visit.  All subjects will have a follow-up phone call 
70 days (± a 7 day window) after the last administration of adalimumab to obtain 
information on any new or ongoing AEs.  For subjects taking only MTX, the follow-up 
phone call will occur 70 days (± 7 day window) after the last administration of MTX.
5.2
Selection of Study Population
Approximately 240 adult subjects with active PsA (defined as not in MDA and having at 
least 3 tender and 3 swollen joints) despite having been treated with the first course of 
MTX at the dose of 15 mg ew for ≥ 4 weeks and biologic naive who meet all the inclusion 
and none of the exclusion criteria are planned to be enrolled in the study at approximately 
60 sites.


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5.2.1
Inclusion Criteria
1.
Adult male or female, ≥ 18 years of age at Screening.
2.
PsA diagnosis established at least 4 weeks prior to the date of the Screening visit 
and confirmed by CASPAR criteria at the Screening visit
3.
Not in Minimal Disease Activity (MDA) at the time of screening, defined as not 
meeting at least 5 of the following 7 criteria:
●
Tender joint count (TJC) ≤ 1 out of 68 assessed
●
Swollen joint count (SJC) ≤ 1 out of 66 assessed
●
PASI ≤ 1 or body surface area (BSA) ≤ 3
●
Patient's assessment of pain visual analogue scale (VAS) ≤ 15
●
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
●
HAQ-DI score ≤ 0.5
●
Tender entheseal points ≤ 1 out of 8 assessed
4.
Has active arthritis defined as fulfilling both the below criteria at screening and 
baseline visits:
●
≥ 3 tender joints (out of 68 assessed)
●
≥ 3 swollen joints (out of 66 assessed)
5.
Treated with MTX 15 mg ew for PsA defined as:
●
Oral or subcutaneous (sc) administration of MTX for at least 4 weeks prior to 
screening,
●
Change of the MTX administration route (oral or sc) is permitted in this time 
period if the administered dose of MTX 15 mg ew is not changed,
●
This is the first course of MTX the subject has been receiving for the treatment 
of PsA,
●
Subject has not received a dosage of MTX higher than 15 mg ew prior to the 
screening visit,
●
Subject could have been receiving MTX doses lower than 15 mg ew before 
reaching the stable dose of MTX 15 mg ew defined above,


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●
If the subject had been on MTX 15 mg ew for ≥ 12 weeks, temporary MTX 
discontinuation or dose decrease below 15 mg ew for up to 4 weeks is allowed.
6.
If subject is receiving concomitant oral corticosteroids, prednisone or equivalent 
must be ≤ 10 mg/day and the dose must be stable for at least 1 week prior to the 
Baseline visit
7.
If subject is receiving nonsteroidal anti-inflammatory drugs (NSAIDs), including 
cyclooxygenase (COX) 2 selective inhibitors, paracetamol (up to the maximum 
recommended dose in the local country label), the dose must be stable for at least 
1 week prior to the Baseline Visit
8.
If subject is receiving other csDMARDs in addition to MTX (i.e., sulfasalazine), 
the dose must be stable for at least 4 weeks prior to the Baseline visit.  If 
csDMARDs are discontinued before study enrollment, the discontinuation must 
occur at least 4 weeks prior to the Baseline Visit
●
Leflunomide should be discontinued at least 4 weeks prior to the Baseline visit
9.
Subject must be able and willing to self-administer sc injections or have a qualified 
person available to administer sc injections
10.
Laboratory values of the following at the Screening visit:
●
Hemoglobin count > 8.5 g/dL
●
White blood count (WBC) > 3.5 × 109/L
●
Platelet count > 100 × 109/L
●
Absolute neutrophil count (ANC) > 1.5 × 109/L
●
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 
must be within 3 times the upper limit of normal range (ULN) for the 
laboratory conducting the test
11.
Subject has a negative TB Screening Assessment.  If the subject has a positive TB 
test or evidence of a latent TB infection, the subject must initiate and complete a 
minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing 


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TB prophylaxis or have documented completion of a full course of TB prophylaxis, 
prior to Baseline.  (See Section 5.3.1.1)
12.
Subject is judged to be in good health as determined by the Investigator based upon 
the results of medical history, laboratory profile, physical examination, chest x-ray 
(CXR), and a 12-lead electrocardiogram (ECG)
13.
A negative serum pregnancy test at the Screening visit and a negative urine 
pregnancy test for women of childbearing potential at the Baseline visit (prior to 
administration of first dose of study drug).  A serum pregnancy test will also be 
taken at the Baseline visit if the urine pregnancy test is positive.  If the serum result 
at the Baseline visit is positive, the subject will be discontinued from the study
14.
If female subject, is either not of childbearing potential (defined as postmenopausal 
for at least 1 year prior to Screening), or surgically sterile (bilateral salpingectomy, 
bilateral oophorectomy and/or hysterectomy), or is of childbearing potential and is 
practicing an approved method of birth control (refer to Section 5.2.4) throughout 
the study and for 180 days after last dose of study drug.
15.
Male subjects who are sexually active with female partner(s) of childbearing 
potential, must agree, from Study Day 1 through 180 days after the last dose of 
study drug to practice the protocol specified contraception (Section 5.2.4).
A condom without spermicide is acceptable in countries where spermicide is not 
available
16.
Subjects must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures
Rationale for the Inclusion Criteria:
1 – 9
To select the adequate subject population for this study 
10 – 12
For the safety of the study subjects


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13 – 15
The impact of adalimumab on pregnancies is unknown.  MTX is 
teratogenic and may be genotoxic
16
In accordance with harmonized GCP
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Has contraindication(s) to adalimumab therapy and/or known hypersensitivity to 
adalimumab or its excipients (refer to SmPC or prescribing information)
2.
Has history of MTX intolerance/toxicity (see MTX prescribing information)
3.
Has medical condition(s) precluding MTX dose increase above 15 mg ew (as per 
Investigator's judgment)
4.
Has had prior exposure to any TNF inhibitor, other mechanism of action bDMARD 
or any systemic biologic agent in general
5.
Had intra-articular or parenteral administration of corticosteroids in the preceding 
4 weeks of the Baseline visit.  Inhaled corticosteroids for stable medical conditions 
are allowed
6.
Was treated with any investigational drug of chemical or biologic nature within a 
minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the 
Baseline visit
7.
Has a history of or currently has active inflammatory articular disease other than 
PsA (e.g., RA, JIA, axial SpA, gout) or systemic autoimmune disease (e.g., mixed 
connective tissue disease, systemic lupus erythematosus, vasculitis) or currently 
has active fibromyalgia.  
●
Subjects with a history of fibromyalgia who are asymptomatic at baseline are 
permitted.


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8.
Had joint surgery at joints to be assessed within this study within the preceding 
60 days of the Baseline visit
9.
Has active skin disease other than psoriasis that would interfere with the 
assessment of psoriasis
10.
Received UVA phototherapy including PUVA or used a tanning booth 4 weeks 
prior to the Baseline visit
11.
Received systemic psoriasis therapy (e.g., oral retinoids) within 4 weeks prior to 
the Baseline visit.  
12.
Received topical psoriasis therapy (e.g., keratolytics, coal tar, anthralin, etc.) within 
2 weeks of the Baseline visit with the exception of the following:
●
Shampoos that contain no corticosteroid
●
Bland (without beta or alpha hydroxy acids) emollients
●
Low potency (Class VI or VII) topical corticosteroids on the palms, soles, face, 
inframammary area and groin only
13.
Permanently wheelchair-bound or bedridden
14.
Currently enrolled in another investigational study.  Concurrent participation in 
non-interventional, epidemiologic or registry trials may be permitted with approval 
from the AbbVie TA MD
15.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study
16.
Received any live/attenuated vaccine within 30 days prior to the Baseline visit, or 
will require vaccination during the study participation including up to 70 days after 
the last dose of study drug
17.
Clinically significant abnormal screening laboratory results as evaluated by the 
Investigator
18.
History of clinically significant drug or alcohol abuse within 1 year preceding the 
Baseline visit


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19.
Known HIV infection, invasive infection (e.g., listeriosis and histoplasmosis) or 
immunodeficiency syndrome
20.
Subjects with any active viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study
21.
Active HBV and HCV defined as: 
●
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity 
on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) 
qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) subjects; 
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab)
22.
Chronic or recurring infections or active TB
23.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline visit or oral anti-infectives within 14 days prior to the 
Baseline visit
24.
Current or history of joint infection within 2 years prior to the Baseline visit
25.
Chronic infection of the upper respiratory tract (e.g., sinusitis), chest 
(e.g., bronchiectasic lung disease), urinary tract or skin (e.g., paronychia, ulcer, 
open wounds)
26.
Evidence of dysplasia or malignancy (including lymphoma and leukemia) other 
than a successfully treated non-metastatic cutaneous squamous cell or basal cell 
carcinoma and/or localized carcinoma in situ of the cervix
27.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease
28.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and any other condition which would put the 
subject at risk by participation in the study


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29.
Has poorly controlled underlying medical condition including cardiac, pulmonary, 
metabolic, renal, neurologic or gastrointestinal conditions, chronic or latent 
infectious diseases or immune deficiency which in the opinion of the investigator 
places the subject at an unacceptable risk for participation in the study
30.
Positive pregnancy test at Screening or Baseline Visit
31.
Female subject who is pregnant, breast-feeding or considering becoming pregnant 
during the study or for approximately 180 days after the last dose of study drug
32.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 180 days after the last dose of study drug.
33.
Received apremilast or JAK inhibitor within 4 weeks of Baseline.
34.
Received tramadol or equivalent opioids and/or non-opioid analgesics 
(e.g., tapentadol, codeine, hydrocodone) or narcotics in fixed combination with 
acetaminophen not at a stable dose for at least 1 week prior to Baseline
Rationale for Exclusion Criteria
1 – 15, 33, 
34
To select the adequate subject population for this study
16 – 29
For the safety of the study subjects
30 – 32
The impact of ADA on pregnancies is unknown.  MTX is teratogenic 
and may be genotoxic.
5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior and Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins and/or 
herbal supplements) that the subject is receiving within 30 days prior to screening or 
receives during the study, must be recorded along with the reason for use, date(s) of 


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administration including start and end dates, and dosage information including dose, route 
and frequency on the appropriate electronic case report form (eCRF).
All prior drug therapies for PsA since the 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.  
MTX use for PsA at a stable dose of 15 mg ew (oral or subcutaneous) for ≥ 4 weeks prior 
to Screening is required per the protocol; dates of use, dosage(s), route of 
administration(s) and reason for use should be documented and must be recorded on the 
appropriate electronic case report form (eCRF).
All subjects receiving MTX in this study are recommended to be on folic or folinic acid 
supplementation with the dose and regimen chosen at the Investigator's discretion.  As per 
general guidance, folic or folinic acid should not be taken on the same day that the MTX 
is administered, but may be taken all other days in the week, beginning 24 hours after the 
MTX dose. 
Oral antiemetic agents are permitted to treat transient gastrointestinal tolerability 
problems possibly caused by MTX dose increase.  The selection of an antiemetic agent 
and duration of antiemetic treatment is at the discretion of the Investigator, but is not 
advised to exceed 2 weeks.
Concomitant csDMARDs (i.e., sulfasalazine ≤ 2 g/day) must be at a stable dose for 
≥4 weeks before the baseline visit and are to remain stable for the duration of the study.  
If csDMARDs (other than MTX) are discontinued before the study, this must be done 
≥4 weeks before the baseline visit.  Leflunomide must be discontinued at least 4 weeks 
prior to the baseline visit and should not be used during the study.
The use of NSAIDs, including COX 2 inhibitors, paracetamol (up to the maximum 
recommended dose in the local country label), are allowed during the study, if subjects are 
receiving stable prescribed doses for ≥ 1 week before the baseline visit.  In the event of 


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tolerability (or other safety) issues, the doses of NSAIDs may be skipped, decreased 
and/or resumed as many times as needed during the study.  If taking any of the above at 
baseline on an as-needed basis, they should continue to use them for the same reason and 
same dose each time.  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.  
In addition, for subjects participating in the US substudy, no NSAIDs should be used 
within 48 hours of the scheduled US examination.
Narcotics other than tramadol or equivalent opioids and/or non opioid analgesics 
(including codeine), are prohibited except in fixed combination with acetaminophen.  
Administration of combined narcotics and acetaminophen and tramadol or equivalent 
opioids and/or non-opioid analgesics should remain at a stable dose and should not occur 
within 24 hours prior to a study visit with joint assessments.
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 for ≥ 1 week prior to baseline 
and remain stable throughout the study.  Inhaled corticosteroids for stable medical 
conditions are allowed.
Doses of all the permitted concomitant medications for PsA must remain stable 
throughout study participation (except as medically required due to an AE 
(Section 6.1.1.1).
For subjects who require isoniazid (INH) for TB prophylaxis, consideration should be 
given to administer pyridoxine (vitamin B6) to prevent peripheral neuropathy.
During the course of the study, subjects may continue treatment with medicated shampoos 
that do not contain corticosteroids, bland (without beta or alpha hydroxy acids) 
emollients, or Class VI or VII low-potency topical corticosteroids on the palms, soles, 
face, inframammary area, and groin only (Appendix D).  Application of these topical 
therapies for psoriasis; however, should not occur within 24 hours of a study visit where 


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psoriasis assessments are collected so as not to interfere with clinical assessments for 
psoriasis.
In addition for subjects aged ≤ 30 with a reported malignancy adverse event, prior 
exposure to or current use of antineoplastics, or other drugs which have a risk of 
malignancy as stated in their label and other relevant documents, 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.
Medications used to treat suspected hypersensitivity reaction or other post-dose systemic 
reaction will be captured as concomitant therapy.
Folic/folinic acid and any other concomitant PsA medications will be received by local 
prescriptions.
The AbbVie TA MD identified in Section 6.1.5 Adverse Event Reporting should be 
contacted if there are any questions regarding concomitant or prior therapies.
5.2.3.2
Prohibited Therapy
The following are prohibited medications during the study:
All bDMARDs (with the exception of adalimumab study drug) and other systemic 
biologic agents with a potential therapeutic impact on the disease being studied, including 
but not limited to the following:
●
Etanercept (Enbrel®)
●
Infliximab (Remicade®)


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●
Abatacept (Orencia®)
●
Anakinra (Kineret®)
●
Rituximab (Rituxan®)
●
Natalizumab (Tysabri®)
●
Tocilizumab (Actemra®)
●
Golimumab (Simponi®)
●
Certolizumab (Cimzia®)
●
Ustekinumab (Stelara®)
●
Belimumab (Benlysta®)
●
Secukinumab (Cosentyx®)
●
Ixekizumab (Taltz®)
The following other medications/therapies:
●
Apremilast
●
JAK inhibitors (examples include but are not limited to:  tofacitinib 
(Xeljanz®), baricitinib (Olumiant®), filgotinib, upadacitinib)
●
Leflunomide
●
Cyclosporine A
●
Corticosteroids administered by local injection or any kind of parenteral route
●
Live/attenuated vaccines (during the study and for 70 days after the last dose 
of study drug)
●
Rifampin/Pyrazinamide combination
●
Anti-retroviral therapy
●
Opioid analgesics (other than tramadol or equivalent opioids and/or non-opioid 
analgesics and narcotics in fixed combination with acetaminophen) or 
marijuana
●
Any investigational drug of chemical or biologic nature
●
UVA phototherapy including PUVA or use of a tanning booth
●
Systemic psoriasis therapy (e.g., oral retinoids) 


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●
Topical psoriasis therapy (e.g., keratolytics, coal tar, anthralin, etc.) with the 
exceptions of medicated shampoos that do not contain corticosteroids, bland 
(without beta or alpha hydroxy acids) emollients, or Class VI or VII low-
potency topical corticosteroids on the palms, soles, face, inframammary area, 
and groin only (Appendix D) 
Medications that may have potential for drug interaction with MTX should be 
administered with caution and careful ongoing monitoring.  Such medications include, but 
are not limited to:
●
Phenytoin, tetracycline, nonsteroidal anti-inflammatory drugs (NSAIDs) and 
salicylates.
●
Trimethoprim/sulfamethoxazole, co-trimoxazole
●
Proton pump inhibitors (such as omeprazole).
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 (see below for subjects participating in the US substudy).  If the site 
determines the subject has taken these medications within 12 hours prior to arrival for a 
study visit, the study visit should be cancelled and rescheduled.
For subjects participating the US substudy, no NSAIDs should be used within 48 hours of 
the scheduled US examination.  If the site determines the subject has taken NSAIDs 
within 48 hours prior to the scheduled US evaluation, the US examination should be 
cancelled and rescheduled.
Subjects may be discontinued from the study if any of the above prohibited medications 
are used during the study.  In addition, joint surgeries should not be performed during the 
study.
Contact the AbbVie TA MD identified in Section 6.1.5 Adverse Event Reporting, if there 
are any questions regarding prohibited therapy(ies).


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5.2.4
Contraception Recommendations and Pregnancy Testing
Contraception Recommendation for Females
If female, subject must be either permanently surgically sterile (bilateral oophorectomy, 
bilateral salpingectomy or hysterectomy) or postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following methods of birth control, on Study Day 1 (or earlier) through at least 180 days 
after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 90 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, excluding low-dose oral gestagens 
(mini-pills containing either lynestrenol or norestisteron) initiated at least 
90 days prior to Study Day 1.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e, Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
women of childbearing potential study participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).


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●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
Contraception Recommendation for Males
If the male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.
If the male subject is sexually active with female partner(s) of childbearing potential, he 
must agree from Study Day 1 through 180 days after the last dose of study drug to 
practice contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing 
potential).
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
Additionally, male subject agrees not to donate sperm from Study Day 1 through 180 days 
after the last dose of study drug.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.


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5.3
Efficacy, Pharmacokinetic, Immunogenicity, Ultrasound and 
Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
Study procedures are discussed in detail in this section, with the exception of drug 
concentration measurements and antibody measurements (discussed in Section 5.3.2 and 
the collection of adverse event (AE) information (discussed in Section 6.0).  All study 
data will be recorded in source documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study specific, Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) approved informed consent form 
before any study procedures are performed or any medications are withheld from the 
subject in order to participate in this study.  Participation in the 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 exploratory 
research/validation studies.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Inclusion/Exclusion Criteria
Subjects will be screened to ensure they meet all inclusion criteria and none of the 
exclusion criteria at the Screening and Baseline visits.
Medical and Surgical History
A complete non-PsA medical and surgical history, including history of alcohol and 
tobacco use will be obtained from each subject at the Screening visit.  Additionally, a list 


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of each subject's specific PsA related medical and surgical history should be recorded at 
Screening.  An updated medical history will be obtained prior to study drug 
administration at Baseline, to ensure the subject is still eligible for enrollment, and the 
medical history will be updated as necessary throughout the study.
A detailed medical history with respect to TB exposure will be documented.  This 
information needs to include Bacillus Calmette-Guérin (BCG) vaccination, cohabitation 
with individuals who had TB, and/or reside or work in TB endemic locations.
Physical Examination
A complete physical examination will be performed at the designated study visits as 
specified in Appendix C.  The physical examination at the baseline visit will serve as the 
baseline physical examination for the entire study.  Physical examination abnormalities 
noted by the Investigator at Baseline prior to the first dose of study drug should be 
recorded in the subject's medical history.  Abnormalities noted after the Baseline visit and 
first dose of study drug should be evaluated and documented by the Investigator as to 
whether or not these are adverse events.  All findings whether related to an adverse event 
or part of each subject's medical history should be captured on the appropriate eCRF page.
A symptom-directed physical examination will be performed when necessary.
Confirmation of PsA Diagnosis
The clinical diagnosis of PsA of at least 4-week duration prior to the screening date 
should be verified at the screening visit against the CASPAR classification criteria (40) 
outlined below.


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CASPAR 
Classification 
Criteria
To meet the criteria of the ClASsification of Psoriatic ARthritis (CASPAR) 
Study Group,* a patient must have inflammatory articular disease (joint, spine, 
or entheseal) with ≥ 3 points from the following 5 categories:
1.
Evidence of current psoriasis, a personal history of psoriasis, or a family 
history of psoriasis.  Current psoriasis is defined as psoriatic skin or scalp 
disease present today as judged by a rheumatologist or dermatologist.†
A personal history of psoriasis is defined as a history of psoriasis that may 
be obtained from a patient, family physician, dermatologist, 
rheumatologist, or other qualified healthcare provider.  A family history of 
psoriasis is defined as a history of psoriasis in a first- or second-degree 
relative according to patient report.
2.
Typical psoriatic nail dystrophy including onycholysis, pitting, and 
hyperkeratosis observed on current physical examination.
3.
A negative test result for the presence of rheumatoid factor by any method 
except latex but preferably by enzyme-linked immuosorbent assay or 
nephelometry, according to the local laboratory reference range.
4.
Either current dactylitis, defined as swelling of an entire digit, or a history 
of dactylitis recorded by a rheumatologist.  
5.
Radiographic evidence of juxtaarticular new bone formation, appearing as 
ill-defined ossification near joint margins (but excluding osteophyte 
formation) on plain radiographs of the hand or foot.
*
Taylor W, Gladman D, Helliwell P, et al; the CASPAR Study Group.  Classification criteria for psoriatic arthritis.  
Arthritis Rheum.  2006;54:2665-73.40
†
Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.
The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, body weight, and body temperature will be obtained at each visit, as 
noted in Appendix C.  Blood pressure, pulse rate and respiratory rate should be performed 
before blood draws are performed.  Height will be measured at the Screening Visit only 
and weight will be measured at the Screening visit and Week 32 or the premature 
discontinuation visit (with shoes off).  All measurements will be recorded in metric units 
where applicable.


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12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Appendix C.  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 site monitor and kept with the subject's 
source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided all protocol required documentation is available.  
If there are other findings that are clinically significant, the Investigator must contact the 
AbbVie TA MD before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the Investigator.
Chest X-Ray (CXR)
All subjects will undergo a standard CXR (posterior-anterior [PA] and lateral views) at 
the Screening visit to rule out the presence of TB or other clinically relevant findings.  
The CXR will not be required if the subject had a previous normal chest x-ray within 
90 days of Screening, provided all protocol required documentation is available at the site 
(as outlined below) and provided nothing has changed in the subject's medical history to 
warrant a repeat test.
Subjects can have a repeat CXR at any time during the study as warranted based on the 
opinion of the Investigator.
A radiologist must perform an assessment of the CXR.  The Investigator will indicate the 
clinical significance of any findings and will sign and date the report.  In the assessment 
of the chest x-ray, the Investigator or their delegate must indicate the presence or absence 
of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  If 


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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 Investigator must contact the AbbVie TA MD before enrolling the subject.
TB Screening
For subjects treated with corticosteroids (equivalent to Prednisone 5 mg or above – with 
ongoing treatment or treatment within 1 month prior to TB screening), an Interferon-
Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test) must be performed 
during the Screening Period for all subjects including those with a prior history of Bacille 
Calmette-Guérin (BCG) administration.
For subjects NOT treated with corticosteroids (equivalent to Prednisone 5 mg or above –
with ongoing treatment or treatment within 1 month prior to TB screening), a PPD skin 
test (alternatively, also known as tuberculin skin test) must be placed, or an 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.
If a subject had a negative PPD or QuantiFERON-TB Gold test (or IGRA equivalent such 
as T-SPOT TB test) within 90 days prior to Screening, and all protocol required 
documentation is available, this test does not need to be repeated, provided nothing has 
changed in the subject's medical history to warrant a repeat test.  All cases where the 
Investigator feels a repeat test is not needed must be discussed with the AbbVie TA MD 
prior to subject enrollment.
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 


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negative.  The absence of induration should be recorded as "0 mm," not 
"negative."  (If required by specific countries a two-step test may be performed 
per local guidelines.  The result of the second test should be recorded.  An 
induration of 5 mm or greater will be considered as PPD positive.)
Subjects who have had an ulcerating reaction to a PPD skin test in the past should 
not be re-exposed and should not be tested at Screening but will be considered 
PPD positive.
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.
If the PPD or the QuantiFERON-TB Gold test is positive or the subject has a CXR 
indicative of latent TB, the subject will be required to initiate and have taken at least 
2 weeks (or per local guidelines, whichever is longer) of an ongoing course of Center for 
Disease Control (CDC) recommended prophylaxis or prophylaxis per local guidelines 
prior to starting study therapy.
Subjects with a prior history of latent TB that have a documented completion of the CDC 
recommended or local guideline recommended prophylaxis may be permitted to enroll.  If 
the subject has a prior history of latent TB, but has not completed or received prophylaxis, 
prophylaxis must be initiated for at least 2 weeks (or per local guidelines, whichever is 
longer) prior to starting study therapy.
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.  In the event both a PPD test and a 
QuantiFERON-TB Gold test are performed, the result of the QuantiFERON-TB Gold test 
will supersede the result of the PPD test.  However, only one test is required.  If the 
QuantiFERON-TB Gold test is indeterminate, the site should repeat the test with another 


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blood sample or perform a PPD test.  If the second QuantiFERON-TB Gold 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.
Hepatitis B Testing
All subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  
A positive result for the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and 
core antibodies HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab 
Total (+) require PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that 
meets or exceeds detection sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below, do not require 
HBV DNA PCR qualitative testing. 
●
HBc Ab Total (–) and HBs Ab (–)
●
HBc Ab Total (–) and HBs Ab (+) 
●
HBc Ab Total (+) and HBs Ab (+)
Hepatitis C Testing:
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation if test results indicate active Hepatitis C (HCV 
RNA detectable in any subject with anti HCV Ab).
Pregnancy Test
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential.  At the Baseline Visit, subjects of childbearing potential will have 
a urine pregnancy test performed locally by designated study personnel.  A serum 


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pregnancy test will also be taken on Day 1 if the urine pregnancy test is positive.  If the 
serum result at Day 1 is positive, the subject is considered a screen failure.  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.
Starting at baseline, all women of childbearing potential will have a urine pregnancy test 
performed locally by designated study personnel at each visit, including at the last dose 
and PD visit, if applicable (see Appendix C). 
Clinical Laboratory Tests
Blood and urine samples will be obtained for clinical laboratory tests.  Samples will be 
obtained at the designated study visits as specified in Appendix C.  Samples will be 
obtained for the laboratory tests listed in Table 1.
All Screening laboratory results must be reviewed, signed and dated by the Investigator 
for review and signature prior to the randomization of a subject.  Subjects will not be 
randomized into the study if laboratory or other Screening result abnormalities are 
deemed clinically significant by the Investigator.
When blood draws are performed as part of a clinic visit, the draws should be performed 
after all clinical assessments and 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 required by country regulatory authorities or considered warranted by the Investigator 
to confirm eligibility, subjects will be tested for antibodies to the Human 


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Immunodeficiency Virus (HIV) at Screening and documented that the test has been 
performed.  This testing is to be done at a local lab.  A subject will not be eligible for 
study participation if test results indicate a positive HIV infection.  AbbVie will not 
receive results from the testing and not be made aware of any positive result.
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.  Laboratory abnormalities are 
considered to be adverse events only if they result in discontinuation from the study, 
necessitate therapeutic medical intervention, and/or if the Investigator considers them to 
be an adverse event.


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Table 1.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Other Laboratory Tests
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
Chloride
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Sodium bicarbonate
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Leukocytes
Nitrites
Serum pregnancy test
Urine pregnancy test
HIV, if applicable (testing to 
be conducted at local lab)
HBsAg
HBsAb
HBcAb
HBV PCR
HCVAb
HCV PCR
PPD or the QuantiFERON-
TB Gold test 
hs-CRP
FSH*
*
If applicable.
Assessment of Peripheral Joints
Tender Joint Count (TJC) and Swollen Joint Count 
(SJC)
TJC68 and SJC66, including the DIP joints of the hands and excluding hips for swelling, 
will be performed as recommended for clinical trials in PsA.41  Additionally, the TJC28 
and SJC28 required for the calculation of DAS28 will be extracted from the 
corresponding TJC68 and SJC66, respectively.  The TJC/SJC assessments will be 
performed at the visits specified in Appendix C. 


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Tender Joint Count (TJC)
An assessment of 68 joints (TJC68; Appendix E) will be done for tenderness by pressure 
manipulation on physical examination.  Joint pain/tenderness will be classified as either 
present ("1"), absent ("0"), replaced ("9") or no assessment ("NA").
Swollen Joint Count (SJC)
An assessment of 66 joints (SJC66; Appendix E) will be done by physical examination.  
The joints to be examined for swelling are the same as those examined for tenderness, 
except the hip joints excluded.  Joint swelling will be classified as present ("1"), absent 
("0"), replaced ("9") or no assessment ("NA").
If possible, the TJC and SJC should be performed by an independent joint assessor who 
should not perform any other study related procedures, as much as possible.  In order to 
minimize variability, the same joint assessor should evaluate a subject at each visit 
throughout the duration of the trial.  A back-up independent assessor, who is trained and 
competent in performing such assessments, should be identified.  It is the responsibility of 
the Principal Investigator to ensure all assessors are qualified to perform joint 
assessments.  If the independent assessor is not available, the pre-identified back-up 
assessor will perform such assessments.
Dactylitis Assessment
Dactylitis will be assessed as dactylitic digit count and tender dactylitic digit count. 
Hands and feet bilaterally will be assessed for the presence/absence of dactylitis and 
associated tenderness.  The score for each dactylitic count and tender dactylitic count can 
range 0-20 (Appendix F).  The dactylitis assessments will be performed at the visits 
specified in Appendix C.


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Enthesitis Assessment
Leeds Enthesitis Index (LEI)
The LEI42 is an enthesitis measure developed specifically for PsA and assesses the 
presence or absence of tenderness at the following 3 bilateral enthesial sites:  medial 
femoral condyles, lateral epicondyles of the humerus, and Achilles tendon insertions.  
Tenderness on examination is recorded as either present (1) or absent (0) for each of the 
6 sites, for an overall score range of 0-6 (Appendix G).  The LEI assessments will be 
performed at the visits specified in Appendix C.
Tenderness at the Plantar Fascia
Tenderness at the plantar fascia as an additional typical PsA enthesitis site27 will be 
assessed as present (1) or absent (0) (Appendix G).  The tenderness at the plantar fascia 
assessment will be performed at the visits specified in Appendix C.
Psoriasis Evaluation
Psoriasis Area and Severity Index (PASI)
The PASI provides quantitative assessment of psoriasis lesional burden based on the 
amount of body surface area involved and degree of severity of erythema, induration, and 
scale, weighted by body part.43,44  A qualified Investigator or designee who has been 
trained by the sponsor/designee, if necessary, will perform the PASI assessment 
(Appendix H).  The site should make every attempt to have the same qualified 
Investigator or designee perform all PASI assessments on a given subject throughout the 
study as specified in Appendix C.
Body Surface Area (BSA)
BSA affected by psoriasis will be measured.  The subject's right or left hand will be 
selected as the measuring device.  For purposes of clinical estimation, the total surface of 
the palm plus five digits will be assumed to be approximately equivalent to 1% of BSA.45  
Measurement of the total area of involvement by the Investigator or delegated site staff is 


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aided by imagining if scattered plaques were moved so that they were next to each other 
and then estimating the total area involved.  BSA will be measured as specified in 
Appendix C. 
Physician's Global Assessment of Disease Activity (PhGA)
PhGA will be evaluated on a 0-100 mm horizontal visual analogue scale (VAS) with a 
question referring to both musculoskeletal and skin disease activity currently46
(Appendix I).  The PhGA is to be performed at the visits described in Appendix C.
Patient Reported Outcomes (PROs)
The subject should complete these questionnaires before site personnel perform any 
clinical assessments and before any interaction with site personnel has occurred to avoid 
biasing the subject's responses.  Subjects will be instructed to follow the instructions 
provided with each instrument and to provide the best possible response to each item.  
Site personnel shall not provide interpretation or assistance to subjects other than 
encouragement to complete the tasks.  Subjects will complete the following 
questionnaires at the visits specified in Appendix C.
Patient's Global Assessment of Disease Activity (PtGA)
PtGA will be evaluated on a 100 mm horizontal VAS with a question referring to both 
arthritis and psoriasis disease activity over the past week.46  The VAS is anchored by the 
opposite adjectives of "excellent" and "poor."
Patient's Global Assessment of Arthritis
Patient's Global Assessment of Arthritis will be performed on a 100 mm horizontal VAS 
with a question referring to arthritis disease activity over the past week.46  The VAS is 
anchored by the opposite adjectives of "excellent" and "poor."


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Patient's Assessment of Pain
Patient's Assessment of Pain will be performed on a 100 mm horizontal VAS with a 
question referring to pain over the past week.46  The VAS anchors are "no pain" and "pain 
as bad as it could be."
Psoriatic Arthritis Impact of Disease (PsAID)
PsAID is a validated patient self-reported tool to assess the impact of PsA on patient's life.  
Two versions of the questionnaire were developed by an European League Against 
Rheumatism (EULAR) initiative:  one for clinical practice (PsAID-12) and one for 
clinical trials (PsAID-9).  Both contain physical and psychological domains.  The PsAID-
9 version will be used in this study.47
Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI is a standardized measure of physical function in arthritis.  The HAQ-DI 
questionnaire contains 20 items divided into 8 domains that measure:  dressing and 
grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities.48
Short Form 36 Health Survey (SF-36)
SF-36 is a generic measure to assess patients' general health and well-being (i.e., health 
related quality of life).  The short version 2 (SF-36v2) consisting of 36 questions will be 
used.49,50
Dermatology Life Quality Index (DLQI)
DLQI is a measure of subject's quality of life (QoL) related to skin disease.  The DLQI 
questionnaire consists of 10 questions concerning subjects' perception of the impact of 
skin diseases on different aspects of their health related quality of life over the last week.  
The items of the DLQI encompass aspects such as symptoms and feelings, daily activities, 
leisure, work or school, personal relationships and the side effects of treatment.51


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Self-Assessment Psoriasis Symptoms (SAPS) v.3.0
The subject will rate his/her psoriasis symptoms within the past 24 hours utilizing an 11-
item questionnaire.52
Musculoskeletal Ultrasound (US) 
Investigators will at study start indicate if they want to participate in the optional US 
assessments or not.  If they decide to participate, they should, if possible, perform an US 
evaluation for every subject they enroll at visits indicated in Appendix C.
For the sites participating in the optional US assessment, high-end ultrasound equipment 
is recommended.  The US must be performed by an expert sonographer (rheumatologist 
or radiologist) with verifiable training and/or certification in ultrasonography, 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 should be blinded for subject characteristics 
and treatment arm; he/she should be the same person throughout the study, and a back-up 
with the same qualifications should be appointed.  
The assessments and scoring will be locally performed.  US should be performed the same 
day as the clinical examination, or the day before the visit if not possible, and prior to 
injecting study medication.  The subjects undergoing US evaluation should not take 
NSAIDs for the last 48 hours prior to the US assessment.  (See Section 5.2.3.2 Prohibited 
Therapy).
The ultrasound evaluation will comprise a comprehensive assessment of joints, entheses 
and tendons. 
For the joint evaluation, the following 23 pairs of joints will be scanned: 
●
Metacarpophalangeal (MCP) joints 1 to 5, 
●
Proximal interphalangeal (PIP) joints 1 to 5,
●
Distal interphalangeal (DIP) joints 2 to 5,


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●
Metatarsophalangeal (MTP) joints 1 to 5,
●
Wrist, elbow, knee, ankle (tibiotalar).
The US assessment of synovitis will consist of an evaluation of hypoechoic synovial 
hyperplasia (SH) using Grayscale (or B mode) and synovial vascularization using Power 
Doppler (PDUS).  The pre-specified set of 23 paired joints will be scanned in longitudinal 
and transverse scan from the dorsal aspect with the joint in a neutral position, except for 
the knee, which will also be examined in a flexed position (30°).
The presence of synovitis (i.e., SH and Power Doppler) will be scored according to the 
OMERACT-EULAR PDUS composite semi-quantitative scale (0 to 3).53
For the entheses evaluation, the following 5 pairs of entheses will be scanned:
1.
Common extensor tendon insertion at the lateral humeral epicondyle,
2.
Quadriceps tendon insertion at the superior pole of the patella,
3.
Patellar tendon proximal insertion at the inferior pole of the patella,
4.
Patellar tendon distal insertion at the tibia tuberosity,
5.
Achilles tendon insertion at the calcaneus; plantar aponeuroses insertion at the 
calcaneus.
Each evaluated enthesis will be scored in terms of inflammatory (i.e., presence of Doppler 
signal within 2 mm from the cortical bony insertion and hypoechogenicity of the tendon 
insertion with or without increase of its thickness) and structural lesions (i.e., cortical 
abnormalities erosions and enthesophytes, and calcifications) according to the 
OMERACT enthesitis composite semi quantitative scale (0 to 3).55
Finally, the presence of tenosynovitis will be also recorded.  The following 28 bilateral 
tendons will be assessed for Grayscale and Doppler tenosynovitis:
●
Extensor compartments at the wrist (from 1-6),


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●
2nd-5th finger flexor tendons, 
●
Tibialis posterior, flexor hallux longus, flexor digitorum common and peroneal 
tendons.  
Evaluation and scoring will be performed according to the OMERACT definition and 
scoring system.56
Note:  All the specified 46 joints and 10 entheses should be evaluated at every visit 
indicated in Appendix C.  Only affected tendons will be assessed after Day 1 (Baseline).  
Standardized evaluation scans and examples of synovitis, enthesitis and tenosynovitis 
grading for each site examined will be available in an Atlas.
Details of US evaluation are presented in Appendix J.
Dispense Study Drug, Dosing and Compliance
Adalimumab and MTX
Study medication(s), dosing instructions and a dosing diary will be dispensed to subjects 
beginning at Baseline (Day 1) and as specified in Appendix C.  Investigators will be 
provided with additional MTX product information from the manufacturer.  The first dose 
of study drug(s) will be administered after all other Baseline (Day 1) procedures are 
completed. 
MTX will be provided for either oral or subcutaneous (sc) administration as requested by 
the Investigator.  ADA and sc MTX 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.
Subjects or a designated family member or friend will be trained to administer study 
medication(s), if needed or considered appropriate, during the first visit or several times.  
This training must be documented in the subject's source document.


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Subjects or a trained designated family member or friend or a health care professional will 
administer the injections of the study medication(s) in the subject's home or in the clinic 
during the weeks the subjects are not in the office for scheduled study visits.
For subjects that cannot/will not self-administer study medication(s) or do not have 
adequate support (friend, family member or healthcare professional) at home, 
administration will occur in the clinic.
On those days that a study visit takes place, study medication is to be administered after 
all clinical assessments including questionnaires, ultrasound evaluation (if applicable) and 
vital sign determination.
Adalimumab should be administered sc at approximately the same time of the day eow or 
ew, as per study protocol (with the exception of office visits).  At all office visits, subjects 
should be observed after study drug administration until judged clinically stable by the 
study personnel.  Study drug should be administered after all clinical assessments 
including questionnaires and vital sign determination.  If an anaphylactic reaction or other 
serious allergic reaction occurs, administration of study medication should be 
discontinued immediately and appropriate therapy initiated.  When dosing at home, 
subjects should be instructed to contact the site immediately with any signs or symptoms 
of a reaction.  (See Section 6.1.7 for toxicity management).
MTX should be administered orally or sc at approximately the same time of the day ew.  
During the study subjects should continue with their regular MTX administration 
schedule prior to the study enrolment.  If MTX is not routinely taken on the day of the 
study visit, the MTX will be dispensed to the subject and the subject will take the 
medication home and administer it at their regular schedule.  There is no relation between 
the adalimumab and MTX administration schedule defined per this study protocol, but 
generally adalimumab and MTX are not recommended to be administered on the same 
day.  See Section 5.5.1 Treatments Administered for additional information on MTX 
administration and dose escalation of MTX.


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For subjects who deviate from the dosing schedule, every effort should be made to bring 
the subject back to the study Part 1 or 2 dosing schedule as soon as possible.
Subjects will maintain a dosing diary for all study drug administered outside of the study 
visit (i.e., at home) to capture dosing dates and times.  The subject must be instructed to 
return study drug and diaries at each clinic visit for the purpose of compliance assessment 
and drug accountability as detailed in Section 5.5.7.  At visits specified in Appendix C, 
the site personnel will review and retain a copy of the dosing diary, returned study drug 
kits, and empty study drug packaging to verify compliance.  Additionally, any discernible 
departure from the protocol regarding study drug administration will be documented 
appropriately.
Randomization and Assignment of Subject Numbers
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria at Baseline and are willing to continue in the study.
Serum Adalimumab Concentrations
Samples will be obtained for serum adalimumab concentrations at the designated study 
visits as indicated in Appendix C and described in more detail under Section 5.3.2 only 
for subjects receiving adalimumab.
Anti-Adalimumab Antibodies (AAA)
Samples will be obtained for AAA at the designated study visits as indicated in 
Appendix C and described in more detail under Section 5.3.2 only for subjects receiving 
adalimumab.
Optional Samples for Exploratory Research and Validation Studies
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the main study even if they decide not to 
participate in this optional exploratory research/validation studies.  The procedure for 


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obtaining and documenting informed consent for exploratory research samples is 
discussed in Section 9.3.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which subjects would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor PsA by assessing associations between disease 
characteristics, outcomes data and biomarkers of interests. 
Validation studies, including those related to the development of potential in-vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research/validation studies samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on adalimumab (or 
drugs of this class) or this disease and related conditions continues, but for no longer than 
20 years after study completion.  Instructions for the preparation and shipment of the 
samples will be provided in a laboratory manual.  
The following optional samples will be collected at the visits indicated in Appendix C. 
●
A single whole blood sample for pharmacogenetic analysis will be collected at 
Day 1 or any subsequent visit (if not obtained on Day 1)
●
Whole blood for epigenetic analysis
●
Whole blood for transcriptomic 
●
Serum and Plasma Samples for systemic analyses, including but not limited to 
proteomic and metabolomic


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5.3.2
Drug Concentration Measurements
Blood samples for the pharmacokinetic (PK) measurement of serum ADA levels and anti-
ADA antibody (AAA) concentrations will be taken at the designated visits, as specified in 
Appendix C only for subjects receiving adalimumab.
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 6 mL evacuated serum collection tubes 
without gel separator.  Sufficient blood will be collected to provide approximately 2.4 mL 
serum for the adalimumab and AAA assays.  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).
5.3.2.1
Handling/Processing of Samples
The blood samples for adalimumab and AAA will be handled/processed as outlined 
below.  
5.3.2.1.1
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 four aliquots, all 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 Split 1, PK Split 2, AAA Split 1, AAA Split 2).  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 


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access to a –20°C or colder freezer will need to ship the samples the day they are 
collected.
Additional detailed instructions for the handling and processing of samples will be 
provided from the central laboratory.
5.3.2.2
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 
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.
5.3.2.3
Measurement Methods
Serum concentrations of adalimumab and AAA will be determined using validated ligand 
binding methods under the supervision of the Drug Analysis Department at AbbVie.  Any 
additional analytes may be analyzed using non-validated methods.  The residual serum 
volume of the samples may be used for future exploratory assay development and 
validation.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variable
The proportion of subjects in MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew as compared with subjects on MTX alone escalated to 20- 25 mg or highest 
tolerable dose ew.
Minimal Disease Activity (MDA)
MDA in PsA is defined as fulfilling at least 5 of the 7 following criteria:57,58
●
TJC ≤ 1 (out of TJC68 assessed in this study)


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●
SJC ≤ 1 (out of SJC66 assessed in this study)
●
PASI ≤ 1 or BSA ≤ 3
●
Patient's assessment of pain VAS ≤ 15
●
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
●
HAQ-DI score ≤ 0.5
●
Tender entheseal points ≤ 1 (out of 8 assessed in this study)
5.3.3.2
Secondary Variables
●
The following outcomes after 16 Weeks of treatment with adalimumab 40 mg 
eow plus MTX 15 mg ew compared with MTX alone escalated to 20-25 mg or 
highest tolerable dose ew:
○
Change in PASDAS from baseline
○
Change in DAPSA score from baseline
○
Change in PsAID score from baseline
○
Proportion of subjects achieving ACR 20/50/70 response
○
Change in DAS28-CRP score from baseline
○
Proportion of subjects achieving PASI 75/90/100 response among subjects 
with BSA ≥ 3%
○
Change in HAQ-DI score from baseline
○
Changes in total SF-36 score, PCS and MCS from baseline
○
Change in DLQI score from baseline
○
Change in Leeds Enthesitis Index (LEI) from baseline
○
Change in tender dactylitic digit count from baseline
●
The proportion of subjects in MDA at Week 32 on each of the four different 
treatment regimens (Arms 1-4) in Part 2 of the study.


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Psoriatic Arthritis Disease Activity Score (PASDAS)
PASDAS is a weighted disease activity measure developed specifically for PsA.  It 
includes PhGA, PtGA, SF-36 PCS, SJC, TJC, Leeds enthesitis count, tender dactylitic 
count and CRP.
PASDAS score is calculated by the following equation:59
Disease Activity in Psoriatic Arthritis (DAPSA)
DAPSA is a PsA disease activity measure, calculated by summing SJC66 + TJC68 + 
Patient's assessment of pain + PtGA + CRP.60-62
American College of Rheumatology Criteria (ACR)
The ACR is a standard criteria originally developed to measure the effectiveness of 
various arthritis medications or treatments in clinical trials for RA, but is also widely used 
in PsA.  The ACR measures improvement in TJC or SJC, and improvement in at least 3 of 
the following 5 parameters:  Patient's assessment of pain, PtGA, PhGA, physical function 
(HAQ-DI) and acute phase reactant (CRP).  ACR 20/50/70 response is achieved if 
≥20%/≥ 50%/≥ 70% improvement in TJC or SJC as well as a ≥ 20%/≥ 50%/≥ 70% 
improvement in ≥ 3 of the other 5 parameters.63
Due to the specific of PsA (skin activity included in PtGA), ACR responses will be 
calculated both using PtGA and Patient's global assessment of arthritis in this study.


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Disease Activity Score-28 (DAS28)
DAS28 is a weighted measure of disease activity originally developed for RA, but is also 
used in PsA clinical trials.  DAS-28 includes TJC, SJC, PtGA and acute phase reactant 
(CRP in this study) and is calculated by the following equation:64,65
DAS28-CRP = 0.56 × √TJ + 0.28 × √SJ + 0.36 × ln(CRP* + 1) + 0.014 × PtGA + 0.96
*
CRP unit in the DAS28-CRP equation is expressed as mg/L.
Due to the specific of PsA (skin activity included in PtGA), DAS28-CRP will be 
calculated both using PtGA and Patient's global assessment of arthritis in this study.
Psoriasis Area and Severity Index (PASI) 75/90/100
PASI 75/90/100 denotes ≥ 75%/≥ 90%/100% improvement in PASI score.43,44
5.3.3.3
Exploratory Variables
Clinical Effectiveness Variables
Clinical effectiveness outcomes listed under the secondary variables at Week 32 on the 
4 different treatment regimens (Arms 1-4) in Part 2 of the study.
Ultrasound Variables
●
The change in Global OMERACT-EULAR synovitis score (GLOESS) from 
baseline to Week 16 in subjects who had adalimumab introduced in 
combination with MTX compared with those who had MTX escalated to 20-
25 mg ew or highest tolerable dose.
●
The change in OMERACT enthesitis score from baseline to Week 16 in 
subjects who had adalimumab introduced in combination with MTX compared 
with those who had MTX escalated to 20-25 mg ew or highest tolerable dose.
●
The change in Global OMERACT-EULAR synovitis score (GLOESS) from 
Week 16-32 in the 4 arms of Part 2 of the study. 


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●
The change in OMERACT enthesitis score from Week 16-32 in the 4 arms of 
Part 2 of the study. 
5.3.4
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.
5.3.5
Pharmacokinetic and Immunogenicity Variables
For subjects receiving adalimumab, blood samples will be collected for determination of 
adalimumab serum concentrations and the presence of anti-ADA antibodies (AAA) as 
specified in Appendix C. 
5.3.6
Exploratory Research Variables and Validation Studies
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to: nucleic acids, proteins, lipids or metabolites. 
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of PsA or related conditions and/or adalimumab or drugs of 
similar classes.  The results from these analyses are exploratory in nature and may not be 
included with the study report.
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be banked for future use.  
Samples may then be used to validate putative biomarker signatures obtained from a 
prospective study, leading to the development of diagnostic tests. 


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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 if any of the following occur:
●
Clinically significant abnormal laboratory result(s) or adverse event(s), as 
determined by the Investigator in consultation with the AbbVie TA MD.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie TA MD.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie TA 
MD.
●
Joint surgery
●
The subject becomes pregnant while on study medication.
●
Subject has known dysplasia of the gastrointestinal tract or 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 non-compliant with TB prophylaxis.
●
The subject develops tuberculosis, or any other significant or opportunistic 
infections.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial in consultation with 
the AbbVie TA MD.


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If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the PD visit must be completed within 2 weeks 
of the last dose of study drug, and preferably prior to the initiation of another therapy.  
However, these procedures should not interfere with the initiation of any new treatments 
or therapeutic modalities that the Investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of the study drug, the subject will be treated in 
accordance with the Investigator's best clinical judgment.
A final phone call will be made to the subject approximately 70 days (± 7 day window) 
after the last dose of study drug to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs (as described in Section 5.1.2.2).  The information will 
be recorded on the appropriate eCRF page.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.
For subjects who are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation.
Subjects who discontinue the study prematurely will not be replaced.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 


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notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
5.5.1.1
Adalimumab
Adalimumab will be administered in this study open-label and at the standard dosing 
regimen 40 mg sc eow except in one arm of Part 2 as described below.
●
Subjects randomized to Arm 1/Part 1 or assigned to Arms 1 and 4 of Part 2 at 
Week 16 (as described in Section 5.1 and Table 2), will receive adalimumab 
40 mg eow.  Starting at the Baseline (Day 1) visit, subjects who are eligible for 
randomization will receive the first dose of study drug:  adalimumab 
40 mg/0.8 mL.
●
Subjects assigned to Arm 2/Part 2 (as described in Section 5.1 and Table 2), 
will receive adalimumab 40 mg ew beginning at the Week 16 visit.
●
Subjects entering the rescue arm at or after Week 24 will have adalimumab 
introduced or escalated at the Investigator's discretion.  For the recommended 
rescue treatment regimens see Section 5.1 Overall Study Design and Plan:  
Description.
5.5.1.2
Methotrexate
MTX will be administered open-label either orally as tablets or subcutaneously by pre-
filled pens (sc) as outlined below.
●
Subjects randomized to Arm 1/Part 1 will continue at the stable dose of MTX 
15 mg ew (as described in Section 5.1 and Table 3). 
●
Subjects randomized to Arm 2/Part 1 will increase MTX dose to 20-25 mg or 
highest tolerable dose ew as described below (see also Section 5.1 and 
Table 3).


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●
Subjects assigned to Arm 1/Part 2 will discontinue MTX at Week 16 
(Section 5.1 and Table 3).  MTX should be discontinued immediately and 
completely at the Week 16 Visit (subjects will not taper-off MTX).
●
Subjects assigned to Arm 2/Part 2 will continue at the stable dose of MTX 
15 mg ew after the Week 16 visit (see also Section 5.1 and Table 3).
●
Subjects assigned to Arm 3/Part 2 will continue MTX at 20-25 mg or highest 
tolerable dose ew after the Week 16 Visit (as described in Section 5.1 and 
Table 3).
●
Subjects assigned to Arm 4/Part 2 will continue MTX at 20-25 mg or highest 
tolerable dose ew after the Week 16 Visit (as described in Section 5.1 and 
Table 3).
●
Subjects entering the rescue arm at or after Week 24 will have MTX 
introduced or escalated at the Investigator's discretion.  For the recommended 
rescue treatment regimens see Section 5.1 Overall Study Design and Plan:  
Description.
During the study subjects should remain on their regular MTX administration schedule as 
prior to the study and MTX should be taken on the same day and approximately the same 
time of day ew.
The escalation of MTX dose in Arm 2/Part 1 should be in the increments of 5 mg every 
two weeks until the MTX dose of 20-25 mg ew is reached.27,66,67  The dose escalation 
begins on Day 1, starting with MTX 20 mg ew as the first MTX dose at or after Day 1, as 
applicable according to the MTX administration schedule prior to study enrolment.  The 
dose of MTX should only be escalated providing there are no clinical and/or laboratory 
signs of MTX intolerance or toxicity.  
In the case of clinical and/or laboratory signs of MTX intolerance/toxicity, MTX dose 
may be de-escalated by 5 mg, including during the MTX escalation period.67,68  The 
subject may stay on the highest tolerable MTX dose which is lower than 20-25 mg ew if 
MTX intolerance/toxicity occurred, see Section 6.1.7 for additional information.  MTX 
dose should not exceed 25 mg ew in this study.


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Change in the route of MTX administration (between oral and sc) is allowed at any time 
as deemed necessary by the Investigator.  Switching from oral to sc administration may 
improve MTX bioavailability and/or decrease MTX intolerance/toxicity, particularly at 
MTX doses ≥ 20 mg ew.69
The tolerability of oral MTX at doses ≥ 20 mg ew may also be improved by dividing the 
total dose of MTX into two administrations on the same day, but not exceeding the total 
daily dose of MTX to be taken in the week.
All subjects receiving MTX in this study are recommended to be on folic or folinic acid 
supplementation with the dose and regimen chosen at the Investigator's discretion (see 
Section 5.2.3.1 Prior and Concomitant Therapy).
There is no required timely relationship between MTX and adalimumab administration 
per this protocol, but in general MTX and adalimumab are not advised to be administered 
on the same day.
5.5.2
Identity of Investigational Product
Information about the adalimumab formulation to be used in this study is presented in 
Table 2.
Table 2.
Identity of Investigational Product – Adalimumab
Investigational Product
Adalimumab Solution for Injection,
50 mg/mL (40 mg/0.8 mL) Pre-Filled Syringe
Dosage Form
Solution for injection in pre-filled syringe
Formulation
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
Strength (mg)
40 mg/0.8 mL
Mode of Administration
Subcutaneous injection
Manufacturer 
AbbVie Deutschland GmbH & Co. KG


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Mode of administration for adalimumab is subcutaneous injection.
Adalimumab, solution for injection, 50 mg/mL (40 mg/0.8 mL) do not require 
reconstitution before use.
Information about the MTX formulation to be used in this study is presented in Table 3.
Table 3.
Identity of Investigational Product – MTX
Investigational Product
MTX Tablets
MTX Pre-Filled Pen
Dosage Form
Tablet
Solution for injection in pre-filled pen
Strength (mg)
5mg
15 mg/0.30 ml
20 mg/0.40 ml 
25 mg/0.50 ml
Mode of Administration
Orally
Subcutaneous injection
Manufacturer
Teva/Hexal
Medac
5.5.2.1
Packaging and Labeling
Adalimumab, solution for injection, 50 mg/mL (40 mg/0.8 mL) will be packaged in 
cartons containing 2 pre-filled syringes.  Each pre-filled syringe and carton will be labeled 
as required per country requirements.  Labels must remain affixed to the syringe and 
carton.  Each kit label will contain a unique kit number.  The type and amount of kits 
dispensed will be managed by the IRT.
Subjects will receive blister cartons or bottles containing MTX tablets.  Each blister 
carton or bottle will contain 30 tablets of MTX 5 mg.  Each drug will be labeled as per 
country requirements.  Labels must remain affixed to the supplies.  Each kit label will 
contain a unique kit number.  The type and amount of kits dispensed will be managed by 
the IRT.  MTX for injection will be provided as 15 mg/0.30 ml, 20 mg/0.40 ml and 
25 mg/0.50 ml solution for injection in pre-filled pens, packaged in cartons.  Each pen and 
carton will be labeled as required per local requirements.  Each label must remain affixed 
to the supplies.  Each kit label will contain a unique kit number.  The type and amount of 
kits dispensed will be managed by the IRT.


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5.5.2.2
Storage and Disposition of Study Drugs
Adalimumab pre-filled syringes are to be stored protected from light at 2° to 8°C/36° to 
46°F.  Study 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 and
temperature excursions 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.
MTX tablets must be stored at 15° to 25°C, protected from light.
MTX prefilled pens for injection must be stored at 15° to 25°C, protected from light and 
must not be frozen.
All clinical supplies must be stored and locked in a secure place and stored under the 
conditions specified on the label until they are dispensed for subject use or are returned to 
AbbVie.
Investigational products are for investigational use only and are to be used only within the 
context of this study.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally randomized using IRT.  Before the study is initiated, IRT 
directions will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
visit.  Subjects who meet the inclusion and exclusion criteria defined in Section 5.2.1 and 
Section 5.2.2 will be centrally randomized in a 1:1 ratio to adalimumab + MTX or MTX 
alone on Day 1 (Baseline).  Using IRT, subjects will be first stratified by the duration of 
MTX treatment at 15 mg ew into two strata:  ≤ 3 months and > 3 months.  Then within 
each stratum, the IRT will assign a randomization number that will encode the subject's 


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treatment group assignment according to the randomization schedule generated by the 
Statistics Department at AbbVie.
After the assessment of MDA at Week 16, subjects will be assigned to one of the 
four treatment arms of Part 2 (Arms 1-4) as described in Section 5.1 for an additional 
16 weeks using IRT.  Additionally, IRT will be used to dispense study medication if a 
subject changes the mode of MTX administration (i.e., oral to sc or sc to oral) and if 
applicable decreases the dose of MTX (e.g., change from 25 mg sc to 20 mg sc or change 
from 20 mg sc to 15 mg sc).  The sites will register changes in dose and mode of 
administration into IRT.
IRT will provide the appropriate medication kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Appendix C.  
Returned study medication should not be re-dispensed to any subject.
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 study medication (adalimumab or MTX) on 
their regularly scheduled dosing date, they should take the forgotten medication 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 for adalimumab and MTX separately on the Subject-Dosing 
Diary. 
Doses of adalimumab or MTX not administered (e.g., not taken before next dose is 
scheduled), should be recorded as not taken in the source and Subject-Dosing Diary.  The 
remaining extra study drug should be returned to the study site full.  For subjects who 


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deviate from the dosing schedule, every effort should be made to bring the subject back to 
their Part 1 or 2 dosing schedule as soon as possible.
5.5.5
Blinding
This study is open-label study.  Blinding is not applicable.
5.5.6
Treatment Compliance
The Investigator or his/her designated representatives will dispense study drugs 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 Subject-Dosing Diary 
for adalimumab and MTX to record all dosing dates and times.  Compliance information 
will be documented on the appropriate eCRF.  Subjects will be counseled on missed doses 
of medication and it should be documented in the subjects' source.  If the subject does not 
return the dosing diary, IP boxes and sharp containers (when applicable), the site should 
question the subject and obtain as much information as possible as to the dosing of the 
study drug.
The information should be documented on the source documents as per "best recollection" 
and when possible, re-verified and documented in the source 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 and in the correct amounts.  For adalimumab, in the US/Puerto 
Rico adequate temperature is cool to the touch, for non-US sites, temperature recording 
devices (temptales) are provided in the shipments.  This will be accomplished by 
documenting the condition of the shipment, verifying the kit numbers in the package 


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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 IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, Kit number(s), date dispensed, 
subject number and identification of person dispensing the drug.
All empty IP boxes (tablets, pen, prefilled syringes) and the status of each bottle, number 
of tablets remaining in each one returned, will be inventoried by the site.  Each subject 
will be given their own sharps disposal container to store used adalimumab pre-filled 
syringes and/or methotrexate pre-filled pens, if necessary.  Empty IP boxes, empty bottles, 
any unused study drug and Sharps containers should be returned by the subject at each 
visit for accountability and compliance purposes and new containers issued as necessary.  
Site staff will complete study medication accountability in IRT, using source documents, 
subject dosing diaries, empty IP boxes, bottles and by visually inspecting the syringes 
and/or pens in the Sharps container whenever possible.  Used Sharps containers should 
never be opened.  The site monitor will verify drug accountability either at the site or 
during remote monitoring and will complete the reconciliation in IRT.  The site staff will 
document that the used pre-filled syringes and/or pens have been destroyed, using 
appropriate biohazard precautions, when appropriate.  All study drug unit doses must be 
inventoried, accounted for, and returned to AbbVie or destroyed per instructions from 
AbbVie and according to local regulations.  For IRT accountability/reconciliation, lost 
status does not apply to empty boxes and bottles not returned.  If a subject returns to a site 
for a visit with proof of taking all doses (verbal and/or dosing diary) the IP is documented 
as used.  In all cases, comments should be documented in source and IRT (e.g., 'subject 
lost to follow-up, no medication returned; study drug verified, subject did not return 
empty boxes').


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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is an open-label, randomized, controlled, parallel-group, multi-country study in 
subjects with PsA consisting of 2 parts:  Part 1 is designed to compare the achievement of 
MDA between subjects randomized to either adalimumab introduced in combination with 
MTX or MTX alone escalated to the highest recommended or tolerable dose; Part 2 is to 
compare the maintenance or achievement of MDA between four different treatment 
regimens using adalimumab and/or MTX, with subject allocation based on the initial 
randomized treatment and achievement of MDA in Part 1.
An open label design was chosen to be able to allow for the subcutaneous and not solely 
oral MTX use.  Although oral MTX is the usual way of using MTX in PsA, some patients 
may be switched to parenteral MTX in the case of gastrointestinal intolerance or 
insufficient effectiveness in clinical practice.  This is a pragmatic study, aiming to reflect 
and inform clinical practice.
Subjects eligible for the study are required to have prior MTX therapy at 15 mg ew for at 
least 4 weeks.  The MTX dose of 15 mg ew was selected as the currently recommended 
starting MTX dose.66,67  Additionally, 15 mg ew or slightly higher is also the average 
MTX dose seen in clinical practice.15,20-23  Four weeks is considered to be the minimum 
period to establish therapeutic effect of MTX.38  The treatment regimens investigated in 
Part 2 of the study are used in clinical practice but lack scientific evidence.
MDA was selected as the primary effectiveness variable for the following reasons:  it is a 
composite disease activity measure encompassing all crucial domains of PsA, including 
patient perspective, and has been well validated in PsA; corresponds to the status of 
remission or low disease activity; has been shown to be associated with long-term patient 
benefits in terms of less radiographic progression and improvements in PROs, has been 
recommended as the treatment target in PsA; was shown to be able to discriminate 
between active treatment and placebo as well as different treatment regimens (T2T 
approach and standard of care).11,25-27,34,53,55,70-72


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5.6.2
Appropriateness of Measurements
All effectiveness measurements in this study are standard and validated.41  All clinical and 
laboratory procedures in this study are standard and generally accepted.
5.6.3
Suitability of Subject Population
This is a pragmatic study designed to assess the effectiveness of adalimumab introduced 
in combination with MTX compared with MTX alone escalated to the highest 
recommended11,27 or tolerable dose.
The study will enroll adult male and female subjects with active PsA (defined as not in 
MDA and having ≥ 3 tender and ≥ 3 swollen joints) despite treatment with MTX at 15 mg 
ew for at least 4 weeks who have not been receiving a prior biologic for PsA.  At 
enrollment, the study subjects will have been treated for a relatively short period of time 
with 15 mg MTX ew, and will require treatment modification/adjustment due to 
inadequate disease control.  It is estimated that by not being in MDA and having 
≥3 tender and ≥ 3 swollen joints, the subjects will have a sufficient level of PsA disease 
activity to compare the effectiveness of adalimumab in combination with stable dose of 
MTX and escalated MTX.  The subjects need to be bDMARD naive at enrolment in order 
to be able to assess the effectiveness of bDMARD introduction.
5.6.4
Selection of Doses in the Study
Adalimumab will be administered in this study at the approved dosing regimen for PsA 
(i.e., 40 mg sc eow).36,37  The only exception will be subjects not achieving MDA on the 
approved adalimumab dosing in combination with MTX, who will be required to escalate 
adalimumab to 40 mg sc ew in combination with MTX (Arm 2/Part 2).  Adalimumab 
40 mg ew has been used in ACR20 non-responders in the open-label extension of the 
ADEPT trial up to Week 144 with no increased risk of adverse events.30,31  Adalimumab 
has been approved in the EU for weekly dosing in psoriasis patients with inadequate 
response after 16 weeks of treatment.36  Adalimumab may be used with or without 
concomitant methotrexate in PsA according to the label.36,37


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The highest recommended MTX dose of 20-25 mg ew in this study is in line with the 
international recommendations for the management of PsA.11  This dose, along with the 
MTX dose escalation scheme required in this study, has been studied in subjects with PsA 
before,18,27 though with a different research objective.  The dosing of MTX is also in line 
with the MTX prescribing information for PsA.38
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 compounds and
●
Device components (pre-filled syringe and pen).
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events (AEs), please refer to 
Sections 6.1 through 6.1.7.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide another cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 


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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 
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.


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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
Assessment of adverse event relationship to the study medications(s) will be made with 
respect to adalimumab and MTX.  The investigator will use the following definitions to 
assess the relationship of the adverse event to the use of study drug:


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Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 70 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events 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 will be contacted 70 days (± 7 day window) following study drug discontinuation 
for an assessment of any new or ongoing AEs.  All SAEs and all ongoing adverse events 
reported during the 70-day follow-up phone call must be captured in the clinical database.
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any non-serious event of 
malignancy in subjects 30 years of age and younger, whether related to study drug or not, 
the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the event by entering the serious adverse event or non-serious event of 
malignancy in subjects 30 years of age and younger data into the RAVE® electronic data 
capture (EDC) system.  Serious adverse events and non-serious events of malignancy in 
subjects 30 years of age and younger, that occur prior to the site having access to the 
RAVE® system or if RAVE® is not operable should be documented on the SAE Non-CRF 
forms and emailed (preferred route) or faxed to Clinical Pharmacovigilance within 
24 hours of being made aware of the serious adverse event.
Email:  
FAX to:  




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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 for adalimumab will be the most current version of SmPC (prescribing 
information).  The reference document used for SUSAR reporting in the EU countries for 
MTX will be the MTX prescribing information provided to the investigator.
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).  Pregnancies in study 
subjects and their partners will be collected from the date of the first dose through 
180 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 
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
Adalimumab
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.  


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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.
Methotrexate
The definition of MTX intolerance and/or toxicity is based on MTX intolerance and 
toxicity as described in the MTX prescribing information provided to the investigator.  An 
event of intolerance or toxicity is to be recorded as AE.  The decision for treatment 
adjustment is at the investigator's discretion.
MTX will be escalated by 5.0 mg every 2 weeks.  If MTX intolerance/toxicity is 
suspected, MTX dose reduction by 5 mg, including during the escalation period, may be 
performed.  Any subject who cannot tolerate the highest recommended dose specified in 
the protocol (20-25 mg ew) due to toxicity or intolerance, is permitted to continue on the 
highest tolerable dose.
Temporary MTX discontinuation followed by re-introduction/re-escalation of MTX is 
allowed if the issue resolves within 4 weeks.  The TA MD must be consulted if the 
Investigator would like to temporarily discontinue MTX more than one time.
If the investigator would like to decrease the MTX dose for any reasons other than MTX 
intolerance/toxicity, the AbbVie TA MD must be contacted first.


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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 subject 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 AEs will be reported in the study summary.  All other 
complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days.  If returns cannot be 


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accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Contacts:
Primary Contact:
1 North Waukegan Road
North Chicago, IL  60064
USA
Office:
Fax:
Alternate Contact:
94528 Rungis Cedex
France
Office:
Fax:
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


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●
Subject who received wrong treatment or incorrect dose
●
Subject who received excluded or prohibited concomitant treatment
8.0
Statistical Methods and Determination of Sample 
Size
8.1.1
Analysis Population
The primary and secondary efficacy endpoints will be analyzed for the intent-to-treat 
(ITT) population, defined as all subjects who were randomized and received at least 
one dose of study medication.  Subjects in the ITT population will be analyzed according 
to the treatment group they were randomized to.  In order to evaluate the impact of major 
protocol violations on the results of the trial, additional analysis of the primary efficacy 
endpoint may be conducted on the per protocol population if deemed necessary.  The Per 
Protocol population consists of all ITT subjects who entered the randomized period of the 
study and did not meet any major protocol violation during the Part 1 of the study.
The safety population consists of all subjects who received at least one dose of study 
medication.
8.1.2
Statistical and Analytical Plan
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 tests will be conducted at α = 0.05 level (2-sided).  
Descriptive statistics will be provided including but not limited to the number of 
observations, mean, standard deviation, median, minimum and maximum for continuous 
endpoints; and counts and percentages for binary endpoints.  


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A Week 16 database lock is planned when all randomized subjects have completed 
Week 16 (Part 1) of the study.  The Week 16 study results (through Week 16) will be 
based on this database lock.  Statistical comparisons for the primary and secondary 
efficacy endpoints will be performed at Week 16 between the Part 1 treatment groups.  No 
multiplicity adjustment will be performed for the statistical tests since there is only 
one primary endpoint. 
Data from the subsequent period (Part 2) will be reported at the completion of the study 
by Part 2 treatment groups.  
The last available pre-treatment values recorded on or before Day 1 (the first dose of 
Part 1) will be considered as the Baseline value for efficacy analysis.  All subsequent 
study visits will be determined in reference to the baseline. 
To account for missing data for the binary efficacy endpoints, a non-responder imputation 
approach (NRI) will be used, i.e., subjects who discontinue during Part 1 with missing 
data will be imputed as a non-responder.  For continuous endpoints, the Mixed-effects 
Model Repeated Measures (MMRM) analysis based on all observed data will be used.  
The rescued patients' last observation on or before the rescued visit will be included in the 
analysis of Part 2 treatments.  The efficacy and safety after the rescue will be summarized 
separately for the rescued patients.
8.1.3
Analysis of Demographic Data and Baseline Disease 
Characteristics
Demographic and Baseline characteristics will be summarized by treatment groups.  The 
number of observations, mean, standard deviation, median, minimum and maximum will 
be summarized for continuous variables; Binary endpoints will be summarized via counts 
and percentages.


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Duration of study treatment will be summarized.  Medical History will be summarized by 
body system and diagnosis.  Prior and concomitant medication will be summarized using 
the World Health Organization (WHO) Drug Dictionary. 
8.1.4
Statistical Analysis of Efficacy
8.1.4.1
Primary Efficacy Variable
The primary endpoint is the proportion of subjects achieving MDA at Week 16 on 
adalimumab 40 mg eow plus MTX 15 mg ew as compared with subjects on MTX alone 
escalated to 20-25 mg or highest tolerable dose ew.
The null hypothesis is that there is no difference in response rates between the 
adalimumab + MTX and MTX groups; the alternative hypothesis is that the response rates 
between the treatment groups are different.  The response rates will be tested using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factor of the duration 
of prior (to screening) use of MTX at 15 mg ew.  The stratification factor is defined as the 
duration of prior MTX 15 mg ew use of ≤ 3 months or > 3 months.
Sensitivity analyses will be conducted using the same method described above using 
observed cases (OC).
8.1.4.2
Analyses of Secondary Efficacy Variables
A complete list of secondary efficacy endpoints is provided in Section 5.3.3.2.  Binary 
secondary endpoints in Part 1 will be summarized using count and percentages and will be 
compared between treatment groups using CMH test adjusting for the stratification factor 
of the duration of prior use of MTX.
MDA at Week 32 is a Part 2 endpoint and it will be summarized by four treatment 
regimens.  No statistical testing will be performed. 
For the continuous secondary endpoints, the change from baseline at Week 16 will be 
analyzed using MMRM with treatment, stratification factor of prior MTX use, visit, and 


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treatment-by-visit interaction as fixed effects, subject as random effect and baseline value 
as a covariate.  The MMRM analysis is based on all observed data.  The LS mean, 95% CI 
and standard error for each randomized treatment group, the LS mean of the treatment 
difference and its associated 95% CI and p-value from the MMRM model will be 
presented.
8.1.4.3
Other Exploratory Analyses
Analysis for other efficacy endpoints referenced in (Section 5.3.3.3) will be performed 
using similar methods to those described in Section 8.1.4.2.
For ultrasound assessment in Part 1, baseline weight will also be included as additional 
covariate in MMRM.
8.1.5
Statistical Analyses of Safety
Safety analyses will be carried out using safety population, which includes all subjects 
that received at least one dose of study medication.  Treatment-emergent 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, and up to within 70 days after the last dose of the study medication.  
All treatment emergent AEs will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®).  The number and percent of subjects experiencing 
AEs will be tabulated by system organ class and preferred term.  In addition, a summary 
of AEs by severity and relationship to study drug will be presented.  AEs, which are 
serious, severe, or life-threatening, which lead to premature study discontinuation will be 
listed and described in detail.  Adverse event of special interest (AESI) will also be 
tabulated. 
Observed values of vital signs and laboratory variables at each visit will be summarized 
for all treated subjects, and change from baseline in selected lab variables will be 
compared between treatment groups using a one way ANOVA.  The last evaluation prior 


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to the first dose of study drug will be used as Baseline for the analyses in Part 1.  For 
selected parameters, a listing of all subjects with any laboratory determination meeting 
Common Toxicity Criteria (CTC) (Version 3) of Grade 3 or higher will be provided.  
Shift tables for changes from Baseline according to the normal range will also be provided 
for laboratory variable.
8.1.6
Subject Disposition and Study Drug Exposure
The number of subjects will be tabulated overall for the following categories:  
randomized, ITT population, completed (e.g., Part 1), and discontinued for each treatment 
group and for the total sample as appropriate.  The reasons for discontinuation will also be 
summarized per CRF categories. 
Treatment compliance will be summarized for adalimumab and MTX respectively for 
Part 1 and Part 2, as appropriate.  Adalimumab 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%).  
MTX compliance will be calculated as the number of tablets/injections actually received 
divided by the number of tablets/injections expected during the participation in the study.  
Compliance will be summarized for the ITT population. 
8.1.7
Pharmacokinetic and Immunogenicity Analyses
Adalimumab serum trough concentrations will be summarized by treatment arm 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.  In addition, pharmacokinetic model-based analyses may be performed with the 
focus on apparent clearance (CL/F) and apparent volume of distribution (V/F).


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AAA will be evaluated for each subject receiving adalimumab and each treatment 
regimen, and rates of AAA positivity will be calculated.  As appropriate, the effect of 
AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment emergent 
adverse events may be evaluated.
8.2
Determination of Sample Size
The study is powered to detect the difference in MDA response rates at Week 16 between 
adalimumab + MTX 15 mg and MTX escalated dose groups.  Assuming an MDA 
response rate of 40% in the adalimumab + MTX group and 20% in the escalated MTX 
group, a total sample size of 240 subjects, 120 subjects per arm, will provide at least 90% 
statistical power to detect the difference between the two treatment groups with a 
significance level of 0.05, allowing approximately 10% dropout.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Following local regulation, substantial amendments may also be reviewed and approved 
by the national competent authority.
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.


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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.  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.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional exploratory research/validation studies.  The 


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nature of the testing should be explained and the subject given an opportunity to ask 
questions.  The informed consent must be signed before the samples are collected and any 
testing is performed.  If the subject does not consent to provide samples for the optional 
exploratory research/validation studies, it will not impact their participation in the study.
In the event a subject withdraws consent to participate from the study, stored exploratory 
research/validation studies samples will continue to be used for research and analysis.  In 
the event that a subject would like to withdraw consent for research using these samples, 
the subject may request that their samples be withdrawn.  Once AbbVie receives the 
request, remaining exploratory research/validation studies samples will be destroyed.  If 
the subject changes his/her consent, and the samples have already been tested, those 
results will still remain as part of the overall research data.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (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 


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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 
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.
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.


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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 exploratory research/validation studies that 
may be done using the samples from this study will be experimental in nature and the 
results will not be suitable for clinical decision making or patient management, hence, 
neither the investigator, the subject, nor the subject's physician (if different from the 
investigator) will be informed of individual subject results, should analyses be performed, 
nor will anyone not directly involved in this research.  Correspondingly, researchers will 
have no access to subject identifiers.  Individual results will not be reported to anyone not 
directly involved in this research other than for regulatory purposes.  Aggregate data from 
exploratory research/validation studies from this study may be used in scientific 
publications or presented at medical conventions.  Exploratory research/validation studies 
data will be published or presented only in a way that does not identify any individual 
subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.


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AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Medicines Evaluation Agency (EMA) Guidance on 
Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit 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 SmPC or prescribing information for adalimumab 
and the product labeling for adalimumab and methotrexate.
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 open-label randomized controlled study COmparing the 
effectiveness of adaLimumab iNTROduction with methotrexate 
dose escaLation in subjects with Psoriatic Arthritis (CONTROL)
Protocol Date:
03 June 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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Villani AP, Rouzaud M, Sevrain M, et al.  Prevalence of undiagnosed psoriatic 
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Madland TM, Apalset EM, Johannessen AE, et al.  Prevalence, disease 
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10.
Acosta Felquer ML, Coates LC, Soriano ER, et al.  Drug therapies for peripheral 
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Gossec L, Smolen JS, Ramiro S, et al.  European League Against Rheumatism 
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Soriano ER, Acosta-Felquer ML, Luong P, et al.  Pharmacologic treatment of 
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Mease PJ, Armstrong AW.  Effective management of psoriasis and psoriatic 
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Behrens F, Koehm M, Arndt U, et al.  Does concomitant methrotrexate with 
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Kingsley GH, Kowalczk A, Taylor H, et al.  A randomized placebo-controlled trial 
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Baranauskaite A, Raffayová H, Kungurov NV, et al.  Infliximab plus methotrexate 
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Coates LC, Helliwell PS.  Methotrexate efficacy in the tight control in psoriatic 
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Nikiphorou E, Negoescu A, Fitzpatrick, JD, et al.  Indispensable or intolerable?  
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Chandran V, Schentag CT, Gladmann DD.  Reappraisal of the effectiveness of 
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Ritchlin C, Rahman P, Kavanaugh A, et al.  Efficacy and safety of the anti-
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Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al.  Treatment of psoriatic arthritis in 
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Mease PJ.  Measures of psoriatic arthritis.  Arthritis Care Res (Hoboken).  
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46.
Cauli A, Gladman DD, Mathieu A, et al.  Patient global assessment in psoriatic 
arthritis:  a multicenter GRAPPA and OMERACT study.  J Rheumatol.  
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including definitions for ultrasonographic pathology.  J Rheumatol.  
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55.
Terslev L, Naredo E, Iagnocco A, et al.  Defining enthesitis in spondyloarthritis by 
ultrasound: results of a Delphi process and of a reliability reading exercise.  
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ultrasound score for tenosynovitis in rheumatoid arthritis.  Ann Rheum Dis.  
2013;72:1328-34.
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Helliwell PS, Fitzgerald O, Fransen J, et al.  The development of candidate
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Smolen JS, Schoels M, Aletaha D.  Disease activity and response assessment in 
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A brief review.  Clin Exp Rheumatol.  2015;33 (Suppl 93):S48-50.
61.
Schoels MM, Aletaha D, Alasti F, et al.  Disease activity in psoriatic arthritis 
(PsA): defining remission and treatment success using the DAPSA score.  Ann 
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64.
Van der Heijde DMFM, van't Hof MA, van Riel PLCM, et al.  Judging disease 
activity in clinical practice in rheumatoid arthritis: first step in the development of a 
disease activity score.  Ann Rheum Dis.  1990;49:916-20.
65.
Prevoo MLL, van 't Hof MA, Kuper HH, et al.  Modified disease activity scores 
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Visser K, van der Heijde D.  Optimal dosage and route of administration of 
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Molina JT, Garcia FJB, Alen JC, et al.  Recommendations for the use of 
methotrexate in rheumatoid arthritis: up and down scaling of the dose and 
administration routes.  Rheumatol Clin.  2015;11:3-8.
68.
Burmester G-R, Kivitz AJ, Kupper H, et al.  Efficacy and safety of ascending 
methotrexate dose in combination with adalimumab: the randomized CONCERTO 
trial.  Ann Rheum Dis.  2015;74:1037-44.
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Goodman SM, Cronstein BN, Bykerk VP.  Outcomes related to methotrexate dose 
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Coates LC, Cook R, Lee K, et al.  Frequency, predictors, and prognosis of 
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Coates LC, Helliwell PS.  Validation of minimal disease activity criteria for
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Kavanaugh A, van der Heijde D, Beutler A, et al.  Patients with psoriatic arthritis 
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randomized, placebo-controlled, GO-REVEAL study.  Arthritis Care Res 
(Hoboken).  2016;68(2):267-74.


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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/competent authority 
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
Global Medical Affairs
Clinical Pharmacology & 
Pharmacometrics
Statistics
Bioanalysis
Clinical Program Development
Statistics


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Appendix C.
Study Activities
Activity
Screeninga
Day 1
Baseline
Week
2
Week
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week
28
Week
32/PD
70 Day
F/U 
Visit/Call
Informed Consent
X
Inclusion/Exclusion Criteria
X
Xb
Confirm PsA diagnosis
X
Medical/Surgical History 
X
Xc
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examd
X
X
Vital Signs/Weight/Heighte
X
X
X
X
X
X
X
X
X
X
X
12 Lead ECG
Xf
Chest X-Ray
Xg
Central lab QuantiFERON-TB 
Gold teste (and/or local PPD 
skin test)
Xh
Hematology
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
X
X
X
X
X
X
CRP 
X
X
X
X
X
X
X
X
X
X
HIVj
X
HBV and HCV Screening
X
Urine Pregnancy Test
X
X
X
X
X
X
X
X
X
X


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Activity
Screeninga
Day 1
Baseline
Week
2
Week
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week
28
Week
32/PD
70 Day
F/U 
Visit/Call
Serum Pregnancy Testk
X
Blood samples for PKl
X
X
X
X
X
X
X
X
X
Blood samples for AAAl
X
X
X
X
X
X
X
X
X
66 – Swollen Joint Count 
(SJC66)
X
X
X
X
X
X
X
X
X
X
X
68 – Tender Joint Count (TJC68)
X
X
X
X
X
X
X
X
X
X
X
Physician's global assessment of 
disease activity (PhGA)
X
X
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
X
X
X
Body surface area (BSA)
X
X
X
X
X
X
X
X
X
X
X
Leeds Enthesitis Index
X
X
X
X
X
X
X
X
X
X
X
Tenderness at the plantar fascia
X
X
X
X
X
X
X
X
X
X
X
Dactylitis
X
X
X
X
X
X
X
X
X
X
Psoriatic Arthritis Impact of 
Disease (PsAID) 
X
X
X
X
X
X
X
X
X
X
Patient's assessment of pain
X
X
X
X
X
X
X
X
X
X
X
Patient's global assessment of 
disease activity (PtGA)
X
X
X
X
X
X
X
X
X
X
X
Patients' global assessment of 
arthritis
X
X
X
X
X
X
X
X
X
X
X


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Activity
Screeninga
Day 1
Baseline
Week
2
Week
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week
28
Week
32/PD
70 Day
F/U 
Visit/Call
Health Assessment 
Questionnaire – Disability Index 
(HAQ-DI)
X
X
X
X
X
X
X
X
X
X
X
Short Form-36 (SF 36)
X
X
X
X
X
X
Self-Assessment of Psoriasis 
Symptoms (SAPS)
X
X
X
X
X
X
X
X
X
X
Dermatology Life Quality Index 
(DLQI)
X
X
X
X
X
X
Ultrasound (if applicable)m
X
X
X
X
Randomization
X
Dispense Study Drug(s) 
X
X
X
X
X
X
X
X
X
Dispense Dosing Instructions
X
Xn
Dispense Dosing Diary
X
Xn
Review and copy subject dosing 
diary, monitor compliance and 
perform drug Reconciliation
X
X
X
X
X
X
X
X
X
Monitor Adverse Events
Xo
X
X
X
X
X
X
X
X
X
X
X
Optional Exploratory Research:  
Pharmacogenetic sampleso
X
Optional Exploratory Research:  
Epigenetic sampleso
X
X
X
X
X


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Activity
Screeninga
Day 1
Baseline
Week
2
Week
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week
28
Week
32/PD
70 Day
F/U 
Visit/Call
Optional Exploratory Research:  
Transcriptomic sampleso
X
X
X
X
X
Optional Exploratory Research: 
Samples for proteomic and 
targeted protein investigations 
(Plasma)p
X
X
X
X
X
Optional Exploratory Research: 
Samples for proteomic and 
targeted protein investigations 
(Serum)p
X
X
X
X
X
PD = Premature discontinuation; F/U = Follow-Up
a.
Perform within 30 days prior to study drug administration.
b.
Before study drug administration, all inclusion and exclusion criteria should be re-confirmed based on assessments completed during the Screening period.
c.
Update history.
d.
A symptom directed physical exam should be performed when necessary and if needed for physician assessments/questionnaires.
e.
Height will be measured at Screening only and weight will be measured at the Screening and Week 32/PD.
f.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required.
g.
Chest x-ray not required at Screening if subject had a previous normal chest x-ray within 90 days of Screening.
h.
Subjects treated with corticosteroids (equivalent to Prednisone 5 mg or above – with ongoing treatment or treatment within 1 month to TB screeening) must be screened with 
a QuantiFERON-TB Gold In-tube test or equivalent (central lab).  Subjects NOT treated with corticosteroids can be screened with a PPD skin test (alternatively, also known 
as tuberculin skin test) locally or an Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test or T-SPOT TB test) centrally.
i.
Dipstick urinalysis will be completed by the central lab at all required visits.  A microscopic analysis will be performed at Screening and in the event the dipstick results show 
protein, ketones or blood greater than negative or glucose greater than normal.


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j.
If required by country regulatory authorities or deemed warranted by the Investigator to confirm eligibility, subjects will be tested for HIV and documented that the test has 
been performed.  This testing is to be done at a local laboratory.  A subject will not be eligible for study participation if test results indicate a positive HIV infection.  AbbVie 
will not receive results from the testing and not be made aware of any positive result.
k.
All females of childbearing potential will have a serum pregnancy test at Screening. In addition to the screening serum pregnancy test, 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.
l.
PK and AAA samples will be collected only for subjects receiving adalimumab.
m.
Ultrasound will be performed on all subjects at sites that participate in the US assessment.
n.
Subjects assigned to Part 2, Arm 4, will be given an adalimumab dosing diary and instruction at Week 16.
o.
Collect serious adverse events and protocol-related nonserious AEs that occur after a subject signs the informed consent, prior to the first dose of study drug.
p.
Optional samples:  Subject will sign additional consent forms; if the additional consent forms are not signed, no optional samples will be collected.


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Appendix D.
Class VI and Class VII Topical Corticosteroid Examples
Class
Generic Name or Local Equivalent
%
VI
Prednicarbate
0.05
Triamcinolone acetonide
0.025
Desonide
0.05
Fluocinolone acetonide
0.01
Triamcinolone acetonide
0.025
Flumethasone pivalate
0.03
Fluocinolone acetonide
0.01
Desonide
0.05
Triamcinolone acetonide
0.025
Betamethasone valerate
0.01
VII
Betamethasone valerate
0.2
Hydrocortisone acetate
1.0
Hydrocortisone
1.0, 2.5
Methylprednisolone
0.25
Fluorometholone
0.025
Hydrocortisone
1.0, 2.5


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Appendix E.
Tender Joint Count (TJC) and Swollen Joint Count (SJC) 
Assessment
Joint Evaluation
Subject Right
Subject Left
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
JOINT
(Circle Correct Answer)
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


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Joint Evaluation
Subject Right
Subject Left
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced
NA = No 
Assessment
JOINT
(Circle Correct Answer)
Pain/
Tenderness
Swelling
Joint
Pain/
Tenderness
Swelling
Joint
27. Metatarsophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
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.
Dactylitis Assessment
Please indicate which DIGITS are SWOLLEN ONLY or SWOLLEN & PAINFUL
with a tick.
Left Hand
Right Hand
Digit
5
4
3
2
Thumb
Thumb
2
3
4
5
Swollen only
Swollen & painful
Left Foot
Right Foot
Digit
5
4
3
2
Hallux
Hallux
2
3
4
5
Swollen only
Swollen & painful
Dactylitic count = Number of swollen digits (range 0-20).
Tender dactylitic count = Number of swollen and painful digits (range 0-20).


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Appendix G.
Enthesitis Assessment:  Leeds Enthesitis Index and Tenderness at 
the Plantar Fascia
Leeds Enthesitis Index (LEI)
Please tick for each tender enthesis
Tender Right
Tender Left
Medial condyle femur
܆
܆
Lateral epicondyle humerus
܆
܆
Achilles tendon insertion
܆
܆
LEI = Number of tender entheses (0-6)
Tenderness at the Plantar Fascia
Please tick for tender enthesis
Tender Right
Tender Left
Insertion of plantar fascia to the calcaneus
܆
܆
Total number of enthesitis sites = LEI + number of tender plantar fascias (range 0-8).


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Appendix H.
Psoriasis Area and Severity Index (PASI)
Four anatomic sites – head, upper extremities, trunk, and lower extremities – are assessed 
for erythema, induration and desquamation using a 5-point scale:
●
0 = no symptoms
●
1 = slight
●
2 = moderate
●
3 = marked
●
4 = very marked
Based on the extent of lesions in a given anatomic site, the area affected is assigned a 
numerical value:
●
1 = < 10%
●
2 = 10%-29%
●
3 = 30%-49%
●
4 = 50%-69%
●
5 = 70%-89%
●
6 = 90%-100%
Since the head, upper extremities, trunk and lower extremities correspond to 
approximately 10%, 20%, 30% and 40% of body surface area, respectively; the PASI 
score is calculated using the formula:
PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + Iu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il + Dl)Al
where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, 
and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, 
respectively.  PASI scores range from 0.0 to 72.0 with the highest score representing 
complete erythroderma of the severest possible degree.  Typically scores of 3 or less 


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represent mild disease, scores over 3 and up and including 15 represent moderate disease 
and scores over 15 are considered to be associated with severe disease.


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Appendix I.
Physician's Global Assessment of Disease Activity (PhGA)
VAS will be used to assess the physician's global assessment of disease activity.  The 
VAS consists of a horizontal 100 mm line anchored at either end by opposite adjectives 
reflecting the spectrum/severity of the parameters assessed.
Please mark the line below to indicate patient's current disease activity considering both 
musculoskeletal and skin disease activity.
0
100
Disease not 
active at all
Disease extremely
active


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Appendix J.
Ultrasound Assessments and Scoring 
For the sites that will be part of the optional ultrasound assessment, Grey Scale (GS) and 
Power-Doppler Ultrasound (PDUS) will be performed to all subjects included in the study 
at the defined time points of the protocol (Appendix C).
PDUS evaluation will be performed at 46 joints, 10 entheses and 28 tendons/tendon 
synovial compartments (see also Ultrasound evaluation in Section 5.3.1.1 Study 
Procedures).
Joints Evaluation
Twenty-three (23) pairs of joints will be scanned at each time point:
●
Metacarpophalangeal (MCP) joints 1 to 5,
●
Proximal interphalangeal (PIP) joints 1 to 5,
●
Distal interphalangeal (DIP) 2 to 5,
●
Metatarsophalangeal (MTP) joints 1 to 5,
●
Wrist, elbow, knee and ankle (tibiotalar).
The pre specified set of 23 paired joints will be scanned in longitudinal and transverse 
scan from the dorsal aspect with the joint in a neutral position, except for the knee, which 
will also be examined in a flexed position (30°). 
The US assessment will consist of an evaluation of hypoechoic synovial hyperplasia (SH) 
using Grayscale (or B mode) and synovial vascularization using PDUS.  The presence of 
synovitis (i.e., SH and Power Doppler signal) will be scored according to the OMERACT-
EULAR PDUS composite semi-quantitative scale (0 to 3).53


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Table.  Ultrasound Scoring Systems of Synovitis at Joint and Patient Levels.53
Joint level (for individual joints)
A) Single components
Greyscale inflammatory (hypoechoic) synovial hyperplasia
●
Grade 0: No hypoechoic synovial hyperplasia
●
Grade 1: Minimal hypoechoic synovial hyperplasia (filling the angle between 
the periarticular bones, without bulging over the line linking tops of the bones)
●
Grade 2: Hypoechoic synovial hyperplasia bulging over the line linking tops 
of the periarticular bones but without extension along the bone diaphysis
●
Grade 3: Hypoechoic synovial hyperplasia bulging over the line linking tops 
of the periarticular bones and with extension to at least one of the bone 
diaphysis
Power Doppler Signal
●
Grade 0: No flow in the hypoechoic synovial hyperplasia
●
Grade 1: Up to 3 single spots signals or up to 2 confluent spots or 1 confluent 
spot plus up to 2 single spots
●
Grade 2: Vessel signals in less than half of the area of the synovium (< 50%)
●
Grade 3: Vessel signals in more than half of the area of the synovium (> 50%)
B) Composite Score
OMERACT-EULAR composite PDUS synovitis score
●
Grade 0 (normal joint): No greyscale-detected synovial hyperplasia and no PD 
signal
●
Grade 1 (minimal synovitis):  Grade 1 synovial hyperplasia and ≤ Grade 1 PD 
signal
●
Grade 2 (moderate synovitis):  Grade 2 synovial hyperplasia and ≤ Grade 2 PD 
signal; OR Grade 1 synovial hyperplasia and a Grade 2 PD signal
●
Grade 3 (severe synovitis):  Grade 3 synovial hyperplasia and ≤ Grade 3 PD 
signal; OR Grade 1 or 2 synovial hyperplasia and a Grade 3 PD signal
Patient Level
Global OMERACT-EULAR Synovitis Score (GLOESS)
●
Sum of composite PDUS scores for all joints assessed


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Entheses Evaluation
The following 5 entheses will be evaluated bilaterally:
1.
Common extensor tendon insertion at the lateral humeral epicondyle,
2.
Quadriceps tendon insertion at the superior pole of the patella,
3.
Patellar tendon proximal insertion at the inferior pole of the patella,
4.
Patellar tendon distal insertion at the tibia tuberosity,
5.
Achilles tendon insertion and plantar aponeuroses insertion at the calcaneus.
For the enthesis evaluation, US will be initially performed in B mode to detect 
morphologic abnormalities, and subsequently with power Doppler to detect abnormal 
vascularization at bony insertion.  For each enthesis the following elementary lesions will 
be recorded within 2 mm from the cortical bone, according to the OMERACT definition 
of enthesitis:55
●
Presence of Doppler signal, 
●
Hypoechogenicity of the tendon insertion, 
●
Thickening of tendon insertion,
●
Erosions,
●
Enthesophytes,
●
Calcifications.
Except for the presence of Doppler signal, each elementary lesion will be scored binary as 
present or absent.  The presence of Doppler signal will be scored semiquantitative as 0 
(absent) to 3 (severe), according to the following semi-quantitative grade:
●
0 = absent
●
1 = maximum 3 Doppler spots, 
●
2 = more than 3 and less than 50% of the enthesis area
●
3 = more than 50% of the enthesis area


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Tenosynovitis Evaluation
The following 14 tendon compartments will be assessed bilaterally for the presence of GS 
and Doppler tenosynovitis:
●
Extensor compartments at the wrist (1 to 6),
●
2nd-5th finger flexor tendons, 
●
Tibialis posterior, flexor hallux longus, flexor digitorum common and peroneal 
tendons. 
Presence and grading of tenosynovitis will be defined and performed according to the 
OMERACT definition and scoring system.56
Note:  Standardized evaluation scans and examples of synovitis, enthesitis and 
tenosynovitis grading for each site examined will be available in an Atlas. 
Technical Requirements:
Different models of ultrasound machines are allowed as long as B-mode (Greyscale) and 
high quality Doppler modules are available.  It is recommended to use high-end machines 
as per the training Atlas which will be provided.  B-mode and Doppler machine settings 
will be optimized before the study and standardized for the whole study.  
US Assessment Conditions:
The US assessments must be performed by an expert in musculoskeletal US with 
verifiable training and/or certification and at least 3 years of experience.  Ideally, the 
ultrasonographer should have prior experience in multicenter study(ies); otherwise 
training will be provided.  The Ultrasonographer must be independent of the clinical 
Investigator and should be blinded for subject characteristics and treatment arm; he/she 
should be the same person throughout the study, and a back-up with the same 
qualifications should be appointed.  The clinical assessor will be blinded to the US 
scoring. 


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The US assessment should be performed in a darkened room with temperature kept stable.  
Subjects are recommended to stop NSAIDs intake, if present, within the prior 48 hours of 
each US evaluation.
Further details about probe position will be provided in the US Atlas.






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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-496
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  09 March 2018
Protocol Title:  A Phase 4 open-label randomized controlled study COmparing the effectiveness of 
adalimumab iNTROduction and methotrexate dose escaLation in subjects with Psoriatic Arthritis 
(CONTROL)
Objectives:
Primary Objective
The primary objective is to compare the effectiveness based on the achievement of minimal disease 
activity (MDA) at Week 16 between subjects who had adalimumab introduced and those that had 
methotrexate (MTX) escalated to the highest recommended dose of 20-25 mg every week (ew) or 
highest tolerable dose up to 25 mg ew after inadequate disease control on the initial MTX therapy.
Secondary Objectives
•
To compare the effectiveness at Week 16 between subjects who had adalimumab introduced 
and those that had MTX escalated to the highest recommended dose of 20-25 mg ew or highest 
tolerable up to 25 mg ew based on the following clinical, functional and quality of life 
measures:
o
Psoriatic Arthritis Disease Activity Score (PASDAS)
o
Disease Activity in Psoriatic Arthritis (DAPSA) score
o
Psoriatic Arthritis Impact of Disease (PsAID) score
o
American College of Rheumatology criteria (ACR) 
o
Disease Activity Score 28 (DAS28)
o
Psoriasis Area and Severity Index (PASI)
o
Health Assessment Questionnaire Disability Index (HAQ-DI)
o
Short Form Health Survey 36 (SF-36) scores:  total, physical component summary (PCS) 
and mental component summary (MCS)
o
Dermatology Life Quality Index (DLQI)
o
Leeds Enthesitis Index (LEI)
o
Tender dactylitic digit count
•
To evaluate the achievement of MDA at Week 32 on each of the four different treatment 
regimens involving adalimumab and/or MTX in Part 2 of the study.
The study also has the following Exploratory Objectives:
•
To evaluate the effectiveness at Week 32 based on the clinical, physical function and quality of 
life measures described under the secondary objectives on each of the four different treatment 
regimens involving adalimumab and/or MTX in the second part of the study.
•
To evaluate ultrasound detected synovitis and enthesitis at joint and enthesis level, and 
treatment effect on each of the study treatment regimens.


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Objectives (Continued):  
Exploratory Objectives (Continued)
•
To assess the pharmacokinetic and immunogenicity of adalimumab with and without 
concomitant MTX.
•
To investigate various biomarkers and their associations with treatment responses and 
outcomes.
Investigators:  Multi-center
Study Sites:  Approximately 60 sites
Study Population:  Approximately 240 adult subjects with active PsA (defined as not in MDA and 
having at least 3 tender and 3 swollen joints) despite having been treated with the first course of MTX at 
the dose of 15 mg ew for ≥ 4 weeks and biologic naive who meet all the inclusion and none of the 
exclusion criteria are planned to be enrolled in the study.
Number of Subjects to be Enrolled:  240 subjects in total, 120 subjects per randomized arm.
Methodology:  This interventional Phase 4 open-label, randomized, controlled, parallel-group, 
multicenter study will be conducted in two (2) parts, each of 16-week duration.
Part 1 (Day 1-Week 16) is designed to compare the achievement of MDA on adalimumab introduced in 
combination with MTX versus MTX alone escalated to the highest recommended dose of 20-25 mg ew 
or highest tolerable dose up to 25 mg ew, whatever feasible, in PsA subjects inadequately controlled 
after the initial course of MTX at 15 mg ew.  Part 1 will be open-label, randomized, controlled, parallel 
group.
Part 2 (Week 16-32) is to evaluate the effectiveness of four (4) different treatment regimens consisting 
of adalimumab and/or MTX in maintaining or attaining MDA, as applicable.  Part 2 will be open-label, 
parallel group.  Subjects will be assigned into the four treatment arms based on their MDA status at 
Week 16 and initial randomized treatment.  Starting at Week 24, there will be rescue treatment option 
based on not achieving MDA and investigator's judgment.
Following a maximum 30-day screening period, subjects meeting the selection criteria will be 
randomized in a 1:1 ratio to either of the two (2) arms and treated for 16 weeks in Part 1:
•
Arm 1/Part 1:  Adalimumab 40 mg eow in combination with MTX 15 mg ew (adalimumab 
40 mg eow + MTX 15 mg ew),
•
Arm 2/Part 1:  MTX escalated to 20-25 mg or highest tolerable dose ew (MTX 20-25 mg or 
highest tolerable dose ew)*
*
MTX will be escalated by increments of 5.0 mg every 2 weeks, starting at 20 mg ew as the 
first MTX dose on or after Day 1, depending on the subject's MTX administration schedule 
prior to the study.  In the case of suspected MTX intolerance or toxicity, the MTX dose 
may be de-escalated by 5 mg and the subject may stay on the highest tolerable MTX dose 
below 20-25 mg ew as described per the protocol.  MTX dose should not exceed 25 mg ew 
in this study.


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Methodology (Continued):  
After the assessment of MDA at Week 16 (primary endpoint), subjects will be assigned to one of the 
4 treatment arms based on the achievement of MDA and initial randomized treatment, and treated for 
additional 16 weeks in Part 2 as follows:
•
Arm 1/Part 2:  Subjects achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have MTX completely withdrawn at Week 16 and continue receiving 
adalimumab as monotherapy (adalimumab 40 mg eow),
•
Arm 2/Part 2:  Subjects not achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have adalimumab escalated to 40 mg ew in combination with MTX 15 mg ew 
(adalimumab 40 mg ew plus MTX 15 mg ew),
•
Arm 3/Part 2:  Subjects achieving MDA at Week 16 on MTX escalated to 20-25 mg or highest 
tolerable dose ew, will continue with the same MTX dose (MTX 20-25 mg or highest tolerable 
dose ew),
•
Arm 4/Part 2:  Subjects not achieving MDA at Week 16 on MTX escalated to 20-25 mg or 
highest tolerable dose ew, will receive adalimumab 40 mg eow in combination with MTX 20-
25 mg or highest tolerable dose ew (adalimumab 40 mg eow plus MTX 20-25 mg or highest 
tolerable dose ew).
Subjects in Arms 1-4 of Part 2 of the study will have the option of being rescued, starting at Week 24 
and based on the subject not achieving MDA and the Investigator's judgment.  The selection of the 
rescue treatment regimen will be at the discretion of the Investigator, but should involve adalimumab 
and/or MTX and should not involve prohibited medications per the protocol.  The recommended rescue 
treatment regimens are as follows:
•
Subjects not achieving MDA on adalimumab 40 mg eow (Arm 1) have MTX 15 mg ew added,
•
Subjects not achieving MDA on adalimumab 40 mg ew + MTX 15 mg ew (Arm 2) have MTX 
escalated to 20-25 mg ew,
•
Subjects not achieving MDA on MTX 20-25 mg or highest tolerable dose ew (Arm 3) have 
adalimumab 40 mg eow added,
•
Subjects not achieving MDA on adalimumab 40 mg eow + MTX 20-25 mg or highest tolerable 
dose ew (Arm 4) have adalimumab escalated to 40 mg ew.


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Methodology (Continued):
A schematic of the study design is shown in the following figure:
Both adalimumab and MTX will be provided as study drugs.
MTX will be provided as a study drug for either oral or subcutaneous (sc) administration.  The route of 
MTX administration can be selected at the discretion of the Investigator and may be exchanged between 
oral and sc at any time during the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years of age at Screening
2.
PsA diagnosis established at least 4 weeks prior to the date of the Screening visit and confirmed by 
C1ASsification of Psoriatic Arthritis (CASPAR) criteria at the Screening visit
3.
Not in MDA at the time of screening, defined as not meeting at least 5 of the following 7 criteria:
•
Tender joint count (TJC) ≤ 1 out of 68 assessed
•
Swollen joint count (SJC) ≤ 1 out of 66 assessed
•
PASI ≤ 1 or Body Surface Area (BSA) ≤ 3
•
Patient's assessment of pain visual analogue scale (VAS) ≤ 15


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
•
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
•
HAQ-DI score ≤ 0.5
•
Tender entheseal points ≤ 1 out of 8 assessed
4.
Has active arthritis defined as fulfilling both the below criteria at screening and baseline visits:
•
≥ 3 tender joints (out of 68 assessed)
•
≥ 3 swollen joints (out of 66 assessed)
5.
Treated with MTX 15 mg ew for PsA defined as:
•
Oral or subcutaneous (sc) administration of MTX for at least 4 weeks prior to screening,
•
Change of the MTX administration route (oral or sc) is permitted in this time period if the 
administered dose of MTX 15 mg ew is not changed,
•
This is the first course of MTX the subject has been receiving for the treatment of PsA,
•
Subject has not received a dosage of MTX higher than 15 mg ew prior to the screening visit
•
Subject could have been receiving MTX doses lower than 15 mg ew before reaching the stable 
dose of MTX 15 mg ew defined above,
•
If the subject had been on MTX 15 mg ew for ≥ 12 weeks, temporary MTX discontinuation or 
dose decrease below 15 mg ew for up to 4 weeks is allowed.
6.
If subject is receiving concomitant oral corticosteroids, prednisone or equivalent must be 
≤10 mg/day and the dose must be stable for at least 1 week prior to the baseline visit.
7.
If subject is receiving nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 
(COX) 2 selective inhibitors, paracetamol (up to the maximum recommended dose in the local 
country label), the dose must be stable for at least 1 week prior to the Baseline Visit
8.
If subject is receiving other csDMARDs in addition to MTX (i.e., sulfasalazine), the dose must be 
stable for at least 4 weeks prior to the baseline visit.  If csDMARDs are discontinued before study 
enrollment, the discontinuation must occur at least 4 weeks prior to the baseline Visit.
•
Leflunomide should be discontinued at least 4 weeks prior to the baseline visit.
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Has contraindication(s) to adalimumab therapy and/or known hypersensitivity to adalimumab or its 
excipients (refer to SmPC or prescribing information)
2.
Has history of MTX intolerance/toxicity
3.
Has medical condition(s) precluding MTX dose increase above 15 mg ew
4.
Has had prior exposure to any tumor necrosis factor (TNF) inhibitor, other mechanism of action 
biologic DMARD (bDMARD) or any systemic biologic agent in general


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Investigational Product:
Adalimumab, solution for injection 50 mg/mL (40 mg/0.8 mL) pre-
filled syringe (PFS)
Doses:
40 mg administered eow or ew
Mode of Administration:
Subcutaneous (sc) injection
Reference Therapy:
Methotrexate Tablets:  5 mg 
Methotrexate Pre-filled PEN:
15 mg/0.30 ml
20 mg/0.40 ml
25 mg/0.50 ml
Dose:
Methotrexate ew
Mode of Administration:
Orally or sc
Duration of Treatment:  Up to 32 weeks
Criteria for Evaluation:
Effectiveness:
Primary Endpoint
The proportion of subjects in MDA at Week 16 on adalimumab 40 mg eow plus MTX 15 mg ew as 
compared with subjects on MTX alone escalated to 20-25 mg or highest tolerable dose ew.
Secondary Endpoints
•
The following outcomes after 16 Weeks of treatment with adalimumab 40 mg eow plus MTX 
15 mg ew compared with MTX alone escalated to 20-25 mg or highest tolerable dose ew:
o
Change in PASDAS from baseline
o
Change in DAPSA score from baseline
o
Change in PsAID score from baseline
o
Proportion of subjects achieving ACR 20/50/70 response
o
Change in DAS28-CRP score from baseline
o
Proportion of subjects achieving PASI 75/90/100 response among subjects with BSA ≥ 3%
o
Change in HAQ-DI score from baseline
o
Changes in total SF-36 score, PCS and MCS from baseline
o
Change in DLQI score from baseline
o
Change in Leeds Enthesitis Index (LEI) from baseline
o
Change in tender dactylitic digit count from baseline
•
The proportion of subjects in MDA at Week 32 on each of the four different treatment regimens 
(Arms 1-4) in Part 2 of the study.
Exploratory Variables:
Clinical Effectiveness Variables
Clinical effectiveness outcomes listed under the secondary endpoints at Week 32 on the 4 different 
treatment regimens (Arms 1-4) in Part 2 of the study.


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Criteria for Evaluation (Continued):
Ultrasound Variables
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from baseline to 
Week 16 in subjects who had adalimumab introduced compared with those who had MTX 
escalated to 20-25 mg or highest tolerable dose ew.
•
The change in OMERACT enthesitis score from baseline to Week 16 in subjects who had 
adalimumab introduced compared with those who had MTX escalated to 20-25 mg or highest 
tolerable dose ew.
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from Week 16-32 in the 
4 arms of Part 2 of the study.
•
The change in OMERACT enthesitis score from Week 16-32 in the 4 arms of Part 2 of the 
study.
Pharmacokinetic and Immunogenicity:  For subjects receiving adalimumab, blood samples will be 
collected for determination of adalimumab serum concentrations and the presence of anti-adalimumab 
antibodies (AAA).
Exploratory Research Variables and Validation Studies (Optional):  Optional samples may be 
collected to conduct exploratory investigations into known and novel biomarkers.  The types of 
biomarkers to be analyzed may include, but are not limited to:  nucleic acids, proteins, lipids or 
metabolites.
Safety:  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.
Statistical Methods:
Effectiveness:  The primary and secondary effectiveness variables will be analyzed for the intent-to-
treat (ITT) population, defined as all subjects who were randomized and received at least one dose of 
study medication.  Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level 
(2-sided).  Descriptive statistics will be provided including but not limited to the number of observations, 
mean, standard deviation, median, minimum and maximum for continuous variables; and counts and 
percentages for discrete variables.  Statistical comparisons for the primary and secondary effectiveness 
endpoints will be performed at Week 16 between the Part 1 treatment groups.  No multiplicity 
adjustment will be performed for the statistical tests.  An interim database lock is planned when all 
randomized subjects have completed Week 16 (Part 1) of the study.  To account for missing data for the 
discrete effectiveness endpoints, a non-responder imputation approach (NRI) will be used, i.e., subjects 
who discontinue during Part 1 with missing data will be imputed as a non-responder.  The last 
observation carried forward (LOCF) rule will be used to impute missing continuous effectiveness 
endpoints.  In addition, an analysis using all observed data adjusting for baseline values will be 
performed as a sensitivity analysis for the effectiveness endpoints, using mixed-effects model repeated 
measures (MMRM) for continuous variables and logistic random-effect model for binary endpoints.  The 
rescued patients' last observation on or before the rescued visit will be included in the analysis of Part 2 
treatments.  The efficacy and safety after the rescue will be summarized separately for the rescued 
patients.


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Statistical Methods (Continued):
Effectiveness (Continued):
The response rates for the primary endpoint will be tested using a Cochran-Mantel-Haenszel (CMH) test 
adjusting for strata (duration of baseline use of MTX).  Stratum is defined as the duration of baseline 
MTX use at 15 mg ew ≤ 3 months or > 3 months.  Secondary analyses of the primary endpoint will be 
conducted using all observed cases up to Week 16.  Logistic regression model with stratum, treatment, 
visit, and treatment-by-visit interaction as fixed effects, subject as random intercept and baseline as 
covariate will be employed.
Discrete secondary variables will be summarized using count and percentages and will be compared 
between treatment groups using CMH test.  Continuous secondary variables will be summarized by 
summary statistics (number of subjects, mean, 95% confidence interval, standard deviation, first quartile, 
median, third quartile, minimum, maximum).  Change from Baseline in the continuous variables will be 
analyzed using analysis of covariance (ANCOVA) with treatment as fixed effect and baseline value as a 
covariate for LOCF imputation.  MMRM will be used for observed cases with stratum, treatment, visit, 
and treatment-by-visit interaction as fixed effects, subject as random effect and baseline value as 
covariate.
Pharmacokinetic and Immunogenicity:  Adalimumab serum trough concentrations will be 
summarized by treatment arm 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.  In addition, pharmacokinetic model-
based analyses may be performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F).
AAA will be evaluated for each subject receiving adalimumab and each treatment regimen, and rates of 
AAA positivity will be calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, 
efficacy variable(s), and treatment emergent adverse events may be evaluated.
Ultrasound:  Analysis will be performed using similar methods to those described for the primary and 
secondary effectiveness variables.  Baseline weight will also be included as additional covariate in 
ANCOVA and MMRM.
Safety:  Safety analyses will be carried out using safety population, which includes all subjects that 
received at least one dose of study medication.  Treatment-emergent, and pre- and post-treatment 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, and up to within 70 days after the last dose of the study medication.  All treatment emergent 
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA®).  The 
number and percent of subjects experiencing AEs will be tabulated by system organ class and preferred 
term.  In addition, a summary of AEs by severity and relationship to study drug will be presented.  AEs, 
which are serious, severe, or life-threatening, which lead to premature study discontinuation will be 
listed and described in detail.  Adverse events of special interest (AESI) will also be tabulated. 


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Statistical Methods (Continued):
Safety:
Mean change in vital signs and laboratory variables at each visit as compared to baseline will be 
summarized for all treated subjects, and compared between treatment groups using a one way ANOVA.  
The last evaluation prior to the first dose of study drug will be used as Baseline 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 Baseline 
according to the normal range will also be provided for laboratory variable.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-496
Name of Study Drug:  Adalimumab
Phase of Development:  4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  03 June 2019
Protocol Title:  A Phase 4 open-label randomized controlled study COmparing the effectiveness of 
adalimumab iNTROduction and methotrexate dose escaLation in subjects with Psoriatic Arthritis 
(CONTROL)
Objectives:
Primary Objective
The primary objective is to compare the effectiveness based on the achievement of minimal disease 
activity (MDA) at Week 16 between subjects who had adalimumab introduced and those that had 
methotrexate (MTX) escalated to the highest recommended dose of 20 – 25 mg every week (ew) or 
highest tolerable dose up to 25 mg ew after inadequate disease control on the initial MTX therapy.
Secondary Objectives
•
To compare the effectiveness at Week 16 between subjects who had adalimumab introduced 
and those that had MTX escalated to the highest recommended dose of 20 – 25 mg ew or 
highest tolerable up to 25 mg ew based on the following clinical, functional and quality of life 
measures:
o
Psoriatic Arthritis Disease Activity Score (PASDAS)
o
Disease Activity in Psoriatic Arthritis (DAPSA) score
o
Psoriatic Arthritis Impact of Disease (PsAID) score
o
American College of Rheumatology criteria (ACR) 
o
Disease Activity Score 28 (DAS28)
o
Psoriasis Area and Severity Index (PASI)
o
Health Assessment Questionnaire Disability Index (HAQ-DI)
o
Short Form Health Survey 36 (SF-36) scores:  total, physical component summary (PCS) 
and mental component summary (MCS)
o
Dermatology Life Quality Index (DLQI)
o
Leeds Enthesitis Index (LEI)
o
Tender dactylitic digit count
•
To evaluate the achievement of MDA at Week 32 on each of the four different treatment 
regimens involving adalimumab and/or MTX in Part 2 of the study.
The study also has the following Exploratory Objectives:
•
To evaluate the effectiveness at Week 32 based on the clinical, physical function and quality of 
life measures described under the secondary objectives on each of the four different treatment 
regimens involving adalimumab and/or MTX in the second part of the study.
•
To evaluate ultrasound detected synovitis and enthesitis at joint and enthesis level, and 
treatment effect on each of the study treatment regimens.


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Objectives (Continued):  
Exploratory Objectives (Continued)
•
To assess the pharmacokinetic and immunogenicity of adalimumab with and without 
concomitant MTX.
•
To investigate various biomarkers and their associations with treatment responses and 
outcomes.
Investigators:  Multi-center
Study Sites:  Approximately 60 sites
Study Population:  Approximately 240 adult subjects with active PsA (defined as not in MDA and 
having at least 3 tender and 3 swollen joints) despite having been treated with the first course of MTX at 
the dose of 15 mg ew for ≥ 4 weeks and biologic naive who meet all the inclusion and none of the
exclusion criteria are planned to be enrolled in the study.
Number of Subjects to be Enrolled:  240 subjects in total, 120 subjects per randomized arm.
Methodology:  This interventional Phase 4 open-label, randomized, controlled, parallel-group, 
multicenter study will be conducted in two (2) parts, each of 16-week duration.
Part 1 (Day 1-Week 16) is designed to compare the achievement of MDA on adalimumab introduced in 
combination with MTX versus MTX alone escalated to the highest recommended dose of 20 – 25 mg ew 
or highest tolerable dose up to 25 mg ew, whatever feasible, in PsA subjects inadequately controlled 
after the initial course of MTX at 15 mg ew.  Part 1 will be open-label, randomized, controlled, parallel 
group.
Part 2 (Week 16-32) is to evaluate the effectiveness of four (4) different treatment regimens consisting 
of adalimumab and/or MTX in maintaining or attaining MDA, as applicable.  Part 2 will be open-label, 
parallel group.  Subjects will be assigned into the four treatment arms based on their MDA status at 
Week 16 and initial randomized treatment.  Starting at Week 24, there will be rescue treatment option 
based on not achieving MDA and investigator's judgment.
Following a maximum 30-day screening period, subjects meeting the selection criteria will be 
randomized in a 1:1 ratio to either of the two (2) arms and treated for 16 weeks in Part 1:
•
Arm 1/Part 1:  Adalimumab 40 mg eow in combination with MTX 15 mg ew (adalimumab 
40 mg eow + MTX 15 mg ew),
•
Arm 2/Part 1:  MTX escalated to 20 – 25 mg or highest tolerable dose ew (MTX 20 – 25 mg or 
highest tolerable dose ew)*
*
MTX will be escalated by increments of 5.0 mg every 2 weeks, starting at 20 mg ew as the 
first MTX dose on or after Day 1, depending on the subject's MTX administration schedule 
prior to the study.  In the case of suspected MTX intolerance or toxicity, the MTX dose 
may be de-escalated by 5 mg and the subject may stay on the highest tolerable MTX dose 
below 20 – 25 mg ew as described per the protocol.  MTX dose should not exceed 25 mg 
ew in this study.


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Methodology (Continued):  
After the assessment of MDA at Week 16 (primary endpoint), subjects will be assigned to one of the 
4 treatment arms based on the achievement of MDA and initial randomized treatment, and treated for 
additional 16 weeks in Part 2 as follows:
•
Arm 1/Part 2:  Subjects achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have MTX completely withdrawn at Week 16 and continue receiving 
adalimumab as monotherapy (adalimumab 40 mg eow),
•
Arm 2/Part 2:  Subjects not achieving MDA at Week 16 on adalimumab 40 mg eow plus MTX 
15 mg ew, will have adalimumab escalated to 40 mg ew in combination with MTX 15 mg ew 
(adalimumab 40 mg ew plus MTX 15 mg ew),
•
Arm 3/Part 2:  Subjects achieving MDA at Week 16 on MTX escalated to 20 – 25 mg or 
highest tolerable dose ew, will continue with the same MTX dose (MTX 20 – 25 mg or highest 
tolerable dose ew),
•
Arm 4/Part 2:  Subjects not achieving MDA at Week 16 on MTX escalated to 20 – 25 mg or 
highest tolerable dose ew, will receive adalimumab 40 mg eow in combination with MTX 20 –
25 mg or highest tolerable dose ew (adalimumab 40 mg eow plus MTX 20 – 25 mg or highest 
tolerable dose ew).
Subjects in Arms 1-4 of Part 2 of the study will have the option of being rescued, starting at Week 24 
and based on the subject not achieving MDA and the Investigator's judgment.  The selection of the 
rescue treatment regimen will be at the discretion of the Investigator, but should involve adalimumab 
and/or MTX and should not involve prohibited medications per the protocol.  The recommended rescue 
treatment regimens are as follows:
•
Subjects not achieving MDA on adalimumab 40 mg eow (Arm 1) have MTX 15 mg ew added,
•
Subjects not achieving MDA on adalimumab 40 mg ew + MTX 15 mg ew (Arm 2) have MTX 
escalated to 20 – 25 mg ew,
•
Subjects not achieving MDA on MTX 20 – 25 mg or highest tolerable dose ew (Arm 3) have 
adalimumab 40 mg eow added,
•
Subjects not achieving MDA on adalimumab 40 mg eow + MTX 20 – 25 mg or highest 
tolerable dose ew (Arm 4) have adalimumab escalated to 40 mg ew.


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Methodology (Continued):
A schematic of the study design is shown in the following figure:
Both adalimumab and MTX will be provided as study drugs.
MTX will be provided as a study drug for either oral or subcutaneous (sc) administration.  The route of 
MTX administration can be selected at the discretion of the Investigator and may be exchanged between 
oral and sc at any time during the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years of age at Screening
2.
PsA diagnosis established at least 4 weeks prior to the date of the Screening visit and confirmed by 
C1ASsification of Psoriatic Arthritis (CASPAR) criteria at the Screening visit
3.
Not in MDA at the time of screening, defined as not meeting at least 5 of the following 7 criteria:
•
Tender joint count (TJC) ≤ 1 out of 68 assessed
•
Swollen joint count (SJC) ≤ 1 out of 66 assessed
•
PASI ≤ 1 or Body Surface Area (BSA) ≤ 3
•
Patient's assessment of pain visual analogue scale (VAS) ≤ 15


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
•
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
•
HAQ-DI score ≤ 0.5
•
Tender entheseal points ≤ 1 out of 8 assessed
4.
Has active arthritis defined as fulfilling both the below criteria at screening and baseline visits:
•
≥ 3 tender joints (out of 68 assessed)
•
≥ 3 swollen joints (out of 66 assessed)
5.
Treated with MTX 15 mg ew for PsA defined as:
•
Oral or subcutaneous (sc) administration of MTX for at least 4 weeks prior to screening,
•
Change of the MTX administration route (oral or sc) is permitted in this time period if the 
administered dose of MTX 15 mg ew is not changed,
•
This is the first course of MTX the subject has been receiving for the treatment of PsA,
•
Subject has not received a dosage of MTX higher than 15 mg ew prior to the screening visit
•
Subject could have been receiving MTX doses lower than 15 mg ew before reaching the stable 
dose of MTX 15 mg ew defined above,
•
If the subject had been on MTX 15 mg ew for ≥ 12 weeks, temporary MTX discontinuation or 
dose decrease below 15 mg ew for up to 4 weeks is allowed.
6.
If subject is receiving concomitant oral corticosteroids, prednisone or equivalent must be 
≤10 mg/day and the dose must be stable for at least 1 week prior to the baseline visit.
7.
If subject is receiving nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 
(COX) 2 selective inhibitors, paracetamol (up to the maximum recommended dose in the local 
country label), the dose must be stable for at least 1 week prior to the Baseline Visit
8.
If subject is receiving other csDMARDs in addition to MTX (i.e., sulfasalazine), the dose must be 
stable for at least 4 weeks prior to the baseline visit.  If csDMARDs are discontinued before study 
enrollment, the discontinuation must occur at least 4 weeks prior to the baseline Visit.
•
Leflunomide should be discontinued at least 4 weeks prior to the baseline visit.
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Has contraindication(s) to adalimumab therapy and/or known hypersensitivity to adalimumab or its 
excipients (refer to SmPC or prescribing information)
2.
Has history of MTX intolerance/toxicity
3.
Has medical condition(s) precluding MTX dose increase above 15 mg ew
4.
Has had prior exposure to any tumor necrosis factor (TNF) inhibitor, other mechanism of action 
biologic DMARD (bDMARD) or any systemic biologic agent in general


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Investigational Product:
Adalimumab, solution for injection 50 mg/mL (40 mg/0.8 mL) pre-
filled syringe (PFS)
Doses:
40 mg administered eow or ew
Mode of Administration:
Subcutaneous (sc) injection
Reference Therapy:
Methotrexate Tablets:  5 mg 
Methotrexate Pre-filled PEN:
15 mg/0.30 ml
20 mg/0.40 ml
25 mg/0.50 ml
Dose:
Methotrexate ew
Mode of Administration:
Orally or sc
Duration of Treatment:  Up to 32 weeks
Criteria for Evaluation:
Effectiveness:
Primary Endpoint
The proportion of subjects in MDA at Week 16 on adalimumab 40 mg eow plus MTX 15 mg ew as 
compared with subjects on MTX alone escalated to 20-25 mg or highest tolerable dose ew.
Secondary Endpoints
•
The following outcomes after 16 Weeks of treatment with adalimumab 40 mg eow plus MTX 
15 mg ew compared with MTX alone escalated to 20-25 mg or highest tolerable dose ew:
o
Change in PASDAS from baseline
o
Change in DAPSA score from baseline
o
Change in PsAID score from baseline
o
Proportion of subjects achieving ACR 20/50/70 response
o
Change in DAS28-CRP score from baseline
o
Proportion of subjects achieving PASI 75/90/100 response among subjects with BSA ≥ 3%
o
Change in HAQ-DI score from baseline
o
Changes in total SF-36 score, PCS and MCS from baseline
o
Change in DLQI score from baseline
o
Change in Leeds Enthesitis Index (LEI) from baseline
o
Change in tender dactylitic digit count from baseline
•
The proportion of subjects in MDA at Week 32 on each of the four different treatment regimens 
(Arms 1 – 4) in Part 2 of the study.
Exploratory Endpoints:
Clinical Effectiveness 
Clinical effectiveness outcomes listed under the secondary endpoints will be analyzed at Week 32 as 
exploratory endpoints on the 4 different treatment regimens (Arms 1-4) in Part 2 of the study.


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Criteria for Evaluation (Continued):
Ultrasound
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from baseline to 
Week 16 in subjects who had adalimumab introduced compared with those who had MTX 
escalated to 20 – 25 mg or highest tolerable dose ew.
•
The change in OMERACT enthesitis score from baseline to Week 16 in subjects who had 
adalimumab introduced compared with those who had MTX escalated to 20 – 25 mg or highest 
tolerable dose ew.
•
The change in Global OMERACT-EULAR synovitis score (GLOESS) from Week 16 – 32 in 
the 4 arms of Part 2 of the study.
•
The change in OMERACT enthesitis score from Week 16 – 32 in the 4 arms of Part 2 of the 
study.
Pharmacokinetic and Immunogenicity:  For subjects receiving adalimumab, blood samples will be 
collected for determination of adalimumab serum concentrations and the presence of anti-adalimumab 
antibodies (AAA).
Exploratory Research Variables and Validation Studies (Optional):  Optional samples may be 
collected to conduct exploratory investigations into known and novel biomarkers.  The types of 
biomarkers to be analyzed may include, but are not limited to:  nucleic acids, proteins, lipids or 
metabolites.
Safety:  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.
Statistical Methods:
Effectiveness:  The primary and secondary efficacy endpoints will be analyzed for the intent-to-treat 
(ITT) population, defined as all subjects who were randomized and received at least one dose of study 
medication.  Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level (2-sided).  A 
Week 16 database lock is planned when all randomized subjects have completed Week 16 (Part 1) of the 
study and statistical comparisons for the primary and secondary efficacy endpoints will be performed at 
Week 16 between the Part 1 treatment groups.  No multiplicity adjustment will be performed for the 
statistical testing.  
To account for missing data for the binary effectiveness endpoints, a non-responder imputation approach 
(NRI) will be used, e.g., subjects who discontinue during Part 1 with missing data will be imputed as a 
non-responder.  For continuous endpoints, the Mixed-effects Model Repeated Measures (MMRM) 
analysis based on all observed data will be used.


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Statistical Methods (Continued):
Effectiveness (Continued):
The response rates for the primary endpoint will be compared between the treatment groups using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factor, the duration of prior MTX 
use of ≤ 3 months or > 3 months. The primary analysis will be based on NRI and the sensitivity analysis 
will be based on OC.  
Binary secondary endpoints in Part 1 will be analyzed using a similar method as the primary endpoint.  
Change from baseline in continuous secondary endpoints will be analyzed using MMRM with treatment, 
stratification factor of duration of prior MTX use, visit, and treatment-by-visit interaction as fixed 
effects, subject as random effect and baseline value as a covariate.
Pharmacokinetic and Immunogenicity:  Adalimumab serum trough concentrations will be 
summarized by treatment arm 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.  In addition, pharmacokinetic model-
based analyses may be performed with the focus on apparent clearance (CL/F) and apparent volume of 
distribution (V/F).
AAA will be evaluated for each subject receiving adalimumab and each treatment regimen, and rates of 
AAA positivity will be calculated.  As appropriate, the effect of AAA on adalimumab pharmacokinetics, 
efficacy variable(s), and treatment emergent adverse events may be evaluated.
Ultrasound:  For the analysis of ultrasound endpoints in Part 1, similar MMRM model as described for 
the continuous secondary endpoints will be used and baseline weight will be included as an additional 
covariate in the MMRM model.
Safety:  Safety analyses will be carried out using safety population, which includes all subjects that 
received at least one dose of study medication.  Treatment-emergent 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, and up to within 70 days after the last dose of the study medication.  All treatment emergent 
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA®).  The 
number and percent of subjects experiencing AEs will be tabulated by system organ class and preferred 
term.  In addition, a summary of AEs by severity and relationship to study drug will be presented.  AEs, 
which are serious, severe, or life-threatening, which lead to premature study discontinuation will be 
listed and described in detail.  Adverse events of special interest (AESI) will also be tabulated. 


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Statistical Methods (Continued):
Safety:
Observed values of vital signs and laboratory variables at each visit will be summarized for all treated 
subjects, and change from baseline in selected lab variables will be compared between treatment groups 
using a one way ANOVA.  The last evaluation prior to the first dose of study drug will be used as 
Baseline for the analyses in Part 1.  For selected parameters, a listing of all subjects with any laboratory 
determination meeting Common Toxicity Criteria (CTC) (Version 3) of Grade 3 or higher will be 
provided.  Shift tables for changes from Baseline according to the normal range will also be provided for 
laboratory variables.
Section 5.5.2.2  Storage and Disposition of Study Drugs
First paragraph, fifth sentence previously read:
Malfunctions or any temperature excursion must be reported to the Sponsor immediately.
Has been changed to read: 
Malfunctions and temperature excursions must be reported to the Sponsor immediately.
Section 5.5.7  Drug Accountability
Third paragraph
Fourth, fifth, sixth, seventh, and eighth sentence previously read:
Empty boxes, bottles and returned Sharps containers will be retained (unless prohibited by 
local law) until the site monitor is on site to confirm the returned medication.  Site 
monitors and site staff will complete study medication accountability via IRT, source 
documents, subject dosing diaries, empty IP boxes, bottles and by visually inspecting the 
syringes and/or pens in the Sharps container whenever possible.  Used Sharps containers 
should never be opened.  Once the site monitor has verified drug accountability at the site, 
the site staff and site monitor will document that the used pre-filled syringes and/or pens 
have been destroyed, using appropriate biohazard precautions, when appropriate.  
Has been changed to read:
Site staff will complete study medication accountability in IRT, using source documents, 
subject dosing diaries, empty IP boxes, bottles and by visually inspecting the syringes 
and/or pens in the Sharps container whenever possible.  Used Sharps containers should 




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Section 8.1.1  Analysis Population
First paragraph, first sentence previously read:
The primary and secondary effectiveness variables will be analyzed for the intent-to-treat 
(ITT) population, defined as all subjects who were randomized and received at least 
one dose of study medication.
Has been changed to read:
The primary and secondary efficacy endpoints will be analyzed for the intent-to-treat 
(ITT) population, defined as all subjects who were randomized and received at least 
one dose of study medication.
Section 8.1.1.  Analysis population
Frist paragraph, last sentence previously read:
In order to evaluate the impact of major protocol violations on the results of the trial, 
additional analysis of the primary effectiveness variable may be conducted on the per 
protocol population, which consists of all ITT subjects who entered the randomized period 
of the study and did not meet any major protocol violation during the Part 1 of the study.
Has been changed to read:
In order to evaluate the impact of major protocol violations on the results of the trial, 
additional analysis of the primary efficacy endpoint may be conducted on the per protocol 
population if deemed necessary.  The Per Protocol population consists of all ITT subjects 
who entered the randomized period of the study and did not meet any major protocol 
violation during the Part 1 of the study.
Section 8.1.2  Statistical and Analytical Plan
Second, third, fourth, fifth, sixth and seventh paragraph previously read:
Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level (2-sided).  
Descriptive statistics will be provided including but not limited to the number of 


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observations, mean, standard deviation, median, minimum and maximum for continuous 
variables; and counts and percentages for discrete variables.  
Statistical comparisons for the primary and secondary effectiveness endpoints will be 
performed at Week 16 between the Part 1 treatment groups.  No multiplicity adjustment 
will be performed for the statistical tests. 
An interim database lock is planned when all randomized subjects have completed 
Week 16 (Part 1) of the study.  The 16 week study results (through Week 16) will be 
based on this database lock.  
Data from the subsequent period (Part 2) will be reported at the completion of the study 
by Part 2 treatment groups.  
The last available pre-treatment values recorded on or before Day 1 (the first dose of 
Part 1) will be considered as the Baseline value. All subsequent study visits will be 
determined in reference to the baseline. 
To account for missing data for the discrete effectiveness endpoints, a non-responder 
imputation approach (NRI) will be used, i.e., subjects who discontinue during Part 1 with 
missing data will be imputed as a non-responder.  The last observation carried forward 
(LOCF) rule will be used to impute missing continuous effectiveness endpoints.  That is, 
the subject's last non missing value assessed in the study while on study drug will be used 
in the analysis.  In addition, an analysis using all observed data adjusting for baseline 
values will be performed as a sensitivity analysis for the effectiveness endpoints, using 
mixed-effects model repeated measures (MMRM) for continuous variables and logistic 
random-effect model for binary endpoints.
Has been changed to read:
Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level (2-sided).  
Descriptive statistics will be provided including but not limited to the number of 


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observations, mean, standard deviation, median, minimum and maximum for continuous 
endpoints; and counts and percentages for binary endpoints.  
A Week 16 database lock is planned when all randomized subjects have completed 
Week 16 (Part 1) of the study.  The Week 16 study results (through Week 16) will be 
based on this database lock.  Statistical comparisons for the primary and secondary 
efficacy endpoints will be performed at Week 16 between the Part 1 treatment groups.  No 
multiplicity adjustment will be performed for the statistical tests since there is only 
one primary endpoint. 
Data from the subsequent period (Part 2) will be reported at the completion of the study 
by Part 2 treatment groups.  
The last available pre-treatment values recorded on or before Day 1 (the first dose of 
Part 1) will be considered as the Baseline value for efficacy analysis.  All subsequent 
study visits will be determined in reference to the baseline. 
To account for missing data for the binary efficacy endpoints, a non-responder imputation 
approach (NRI) will be used, i.e., subjects who discontinue during Part 1 with missing 
data will be imputed as a non-responder.  For continuous endpoints, the Mixed-effects 
Model Repeated Measures (MMRM) analysis based on all observed data will be used.  
Section 8.1.3  Analysis of Demographic Data and Baseline Disease Characteristics
First paragraph previously read:
Demographic and Baseline characteristics will be summarized and compared among 
treatment groups.  The number of observations, mean, standard deviation, median, 
minimum and maximum will be summarized for continuous variables; and treatment 
group homogeneity will be assessed using a one-way analysis of variance (ANOVA) 
model using treatment, as the independent factor.  Discrete variables will be summarized 
via counts and percentages; and treatment group homogeneity will be evaluated using the 
appropriate chi-square test.


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Has been changed to read:
Demographic and Baseline characteristics will be summarized by treatment groups.  The 
number of observations, mean, standard deviation, median, minimum and maximum will 
be summarized for continuous variables; Binary endpoints will be summarized via counts 
and percentages.
Section 8.1.4.1.1  Primary Analysis of Primary Efficacy Endpoint
Delete:  Section title
8.1.4.1.1
Primary Analysis of Primary Efficacy Endpoint
Section 8.1.4.1.1  Primary Analysis of Primary Efficacy Endpoint
Second paragraph previously read:
The null hypothesis is that there is no difference in response rates between the 
adalimumab + MTX and MTX groups; the alternative hypothesis is that the response rates 
between the treatment groups are different.  The response rates will be tested using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for strata (duration of baseline use of 
MTX at 15 mg ew).  Stratum is defined as the duration of baseline MTX 15 mg ew use of 
≤ 3 months or > 3 months.
Has been changed to read:
The null hypothesis is that there is no difference in response rates between the 
adalimumab + MTX and MTX groups; the alternative hypothesis is that the response rates 
between the treatment groups are different.  The response rates will be tested using a 
Cochran-Mantel-Haenszel (CMH) test adjusting for the stratification factor of the duration 
of prior (to screening) use of MTX at 15 mg ew.  The stratification factor is defined as the 
duration of prior MTX 15 mg ew use of ≤ 3 months or > 3 months.
Sensitivity analyses will be conducted using the same method described above using 
observed cases (OC).


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Section 8.1.4.1.2  Secondary Analysis of Primary Efficacy Endpoint
Delete:  section title and text
8.1.4.1.2
Secondary Analysis of Primary Efficacy Endpoint
Secondary analyses of the primary endpoint will be conducted using all observed cases up 
to Week 16.  Logistic regression model with stratum, treatment, visit, and treatment-by-
visit interaction as fixed effects, subject as random intercept and baseline as covariate will 
be employed.
Section 8.1.4.2  Analyses of Secondary Efficacy Variables
Previously read:
A complete list of secondary effectiveness variables is provided in Section 5.3.3.2.  
Discrete secondary variables will be summarized using count and percentages and will be 
compared between treatment groups using CMH test.
Continuous secondary variables will be summarized by summary statistics (number of 
subjects, mean, 95% confidence interval, standard deviation, first quartile, median, 
third quartile, minimum, maximum).  Change from Baseline in the continuous variables 
will be analyzed using analysis of covariance (ANCOVA) with treatment as fixed effect 
and baseline value as a covariate for LOCF imputation.  MMRM will be used for 
observed cases with stratum, treatment, visit, and treatment-by-visit interaction as fixed 
effects, subject as random effect and baseline value as covariate.
Has been changed to read:
A complete list of secondary efficacy endpoints is provided in Section 5.3.3.2.  Binary 
secondary endpoints in Part 1 will be summarized using count and percentages and will be 
compared between treatment groups using CMH test adjusting for the stratification factor 
of the duration of prior use of MTX.
MDA at Week 32 is a Part 2 endpoint and it will be summarized by four treatment 
regimens.  No statistical testing will be performed. 


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For the continuous secondary endpoints, the change from baseline at Week 16 will be 
analyzed using MMRM with treatment, stratification factor of prior MTX use, visit, and 
treatment-by-visit interaction as fixed effects, subject as random effect and baseline value 
as a covariate.  The MMRM analysis is based on all observed data.  The LS mean, 95% CI 
and standard error for each randomized treatment group, the LS mean of the treatment 
difference and its associated 95% CI and p-value from the MMRM model will be 
presented.
Section 8.1.4.3  Other Exploratory Analyses
Previously read:
Analysis for other effectiveness variables referenced in (Section 5.3.3.3) will be 
performed using similar methods to those described in Section 8.1.4.2.
For ultrasound assessment, baseline weight will also be included as additional covariate in 
ANCOVA and MMRM.
Has been changed to read:
Analysis for other efficacy endpoints referenced in (Section 5.3.3.3) will be performed 
using similar methods to those described in Section 8.1.4.2.
For ultrasound assessment in Part 1, baseline weight will also be included as additional 
covariate in MMRM.
Section 8.1.5  Statistical Analyses of Safety
First paragraph, last sentence previously read:
Treatment-emergent, and pre- and post-treatment AEs will be summarized and reported.
Has been changed to read:
Treatment-emergent AEs will be summarized and reported.


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Section 8.1.5  Statistical Analyses of Safety
Last paragraph previously read:
Mean change in vital signs and laboratory variables at each visit as compared to baseline 
will be summarized for all treated subjects, and compared between treatment groups using 
a one way ANOVA.  The last evaluation prior to the first dose of study drug will be used 
as Baseline 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 Baseline according to the normal range 
will also be provided for laboratory variable.
Has been changed to read:
Observed values of vital signs and laboratory variables at each visit will be summarized 
for all treated subjects, and change from baseline in selected lab variables will be 
compared between treatment groups using a one way ANOVA.  The last evaluation prior 
to the first dose of study drug will be used as Baseline for the analyses in Part 1.  For 
selected parameters, a listing of all subjects with any laboratory determination meeting 
Common Toxicity Criteria (CTC) (Version 3) of Grade 3 or higher will be provided.  
Shift tables for changes from Baseline according to the normal range will also be provided 
for laboratory variable.
Section 8.1.6  Subject Disposition and Study Drug Exposure
First paragraph, first sentence previously read:
The number of subjects will be tabulated by investigator site and overall for the following 
categories:  randomized, ITT population, completed (e.g., Part 1), and discontinued for 
each treatment group and for the total sample as appropriate.  
Has been changed to read:
The number of subjects will be tabulated overall for the following categories:  
randomized, ITT population, completed (e.g., Part 1), and discontinued for each treatment 
group and for the total sample as appropriate.  


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Section 8.2  Determination of Sample Size
Last sentence previously read:
Assuming an MDA response rate of 40% in the adalimumab + MTX group and 20% in 
the escalated MTX group, a total sample size of 240 subjects, 120 subjects per arm, will 
provide at least 90% statistical power to detect the difference between the two treatment 
groups by a 2-sided Cochran-Mantel-Haenszel (CMH) test with a significance level of 
0.05, allowing approximately 10% dropout.
Has been changed to read:
Assuming an MDA response rate of 40% in the adalimumab + MTX group and 20% in 
the escalated MTX group, a total sample size of 240 subjects, 120 subjects per arm, will 
provide at least 90% statistical power to detect the difference between the two treatment 
groups with a significance level of 0.05, allowing approximately 10% dropout.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Global Medical Affairs
Global Medical Affairs
Clinical Pharmacology & 
Pharmacometrics
Statistics
Bioanalysis
Clinical Program Development


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Has been changed to read:
Name
Title
Functional Area
Global Medical Affairs
Global Medical Affairs
Clinical Pharmacology & 
Pharmacometrics
Statistics
Bioanalysis
Clinical Program Development
Statistics

SAP_001.pdf: 
Adalimumab
M14-496 – Statistical Analysis Plan
Version 1.0 – 10 June 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M14-496
A Phase 4 open-label randomized controlled study
COmparing the effectiveness of adalimumab
iNTROduction and methotrexate dose escaLation in
subjects with Psoriatic Arthritis (CONTROL)
Date:  10 June 2019
Version 1.0 
NCT02814175


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Background...................................................................5
4.1
Objective....................................................................................................5
4.2
Study Design..............................................................................................6
4.2.1
Study Design and Design Diagram............................................................6
4.2.2
Variables used for Stratification at Randomization...................................9
4.3
Endpoint.....................................................................................................9
4.3.1
Primary Efficacy Endpoint ........................................................................9
4.3.2
Secondary Efficacy Endpoints...................................................................9
4.3.3
Exploratory Efficacy Endpoints...............................................................10
4.3.4
Safety Endpoint........................................................................................11
4.3.5
Pharmacological Endpoint.......................................................................11
4.4
Sample Size Justification .........................................................................11
4.5
Part 1 Analysis .........................................................................................11
4.6
Multiplicity Testing Procedures for Type-I Error Control ......................11
4.7
Missing Data Imputation..........................................................................11
5.0
Analysis Populations and Important Subgroups ...............12
5.1
Analysis Populations................................................................................12
5.2
Subgroup..................................................................................................14
6.0
Efficacy Analyses...................................................................14
6.1
General Considerations............................................................................14
6.2
Primary Efficacy Analysis .......................................................................15
6.3
Secondary Efficacy Analyses...................................................................16
6.4
Other Efficacy Analyses ..........................................................................17
6.5
Efficacy Subgroup Analyses....................................................................18
6.6
Efficacy Analysis for Rescued Patients ...................................................19
7.0
Safety Analyses ......................................................................19
7.1
General Considerations............................................................................19
7.2
Analysis of Adverse Events.....................................................................20


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7.2.1
Treatment-Emergent Adverse Events ......................................................20
7.2.1.1
Adverse Event Overview .........................................................................21
7.2.1.2
Adverse Events by System Organ Class and Preferred Term..................22
7.2.1.3
TEAEs by Maximum Severity.................................................................22
7.2.1.4
TEAEs by Relationship............................................................................22
7.2.1.5
Frequent (≥ 5%) Adverse Events by System Organ Class and 
Preferred Term.........................................................................................23
7.2.1.6
Adverse Events of Special Interest ..........................................................23
7.2.2
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................23
7.3
Analysis of Laboratory Data....................................................................23
7.3.1
Analysis for Continuous Laboratory Data ...............................................23
7.3.2
Shift Table Analyses ................................................................................24
7.3.3
Analysis for Potentially Clinically Significant Laboratory Values .........25
7.4
Analysis of Vital Signs and Weight.........................................................26
7.5
Analysis of ECG Parameters....................................................................26
8.0
Summary of Changes ............................................................27
8.1
Summary of Changes Between the Previous Version and the 
Current Version........................................................................................27
8.2
Summary of Changes in Previous Version ..............................................27
9.0
Appendix.................................................................................27
10.0
References...............................................................................36
List of Tables
Table 1.
Subgroups for Efficacy Analysis .............................................................19
Table 2.
Criteria for Potentially Clinically Significant Vital Sign Findings..........26
List of Figures
Figure 1.
A schematic of the study design ................................................................8


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List of Appendices
Appendix A.
AESI List and Search Strategies..............................................................28


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3.0
Introduction
This Statistical Analysis Plan (SAP) was created based on Study Protocol M14-496 
Amendment 3 dated 03 June 2019.
This statistical analysis plan describes the statistical analyses to be completed by the Data 
and Statistical Science Department for Study M14-496.  It provides the details to further 
elaborate statistical methods as outlined in the protocol before the Part 1 database lock.  
However, features of the study and the data collected may suggest that deviations from the 
approach presented in this analysis plan are appropriate, and exploratory analyses can be 
added.  A detailed description of any substantive modifications to this SAP will be 
included in the final clinical study report (CSR).  Serum adalimumab (ADA) 
concentration and anti-ADA antibodies (AAA) will be studied by a pharmacokinetics 
group, the corresponding analysis plan is documented separately and is not in the scope of 
this SAP.  A final CSR is planned after the study is completed. 
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
4.0
Study Background
4.1
Objective
The primary objective is to compare the effectiveness based on the achievement of 
minimal disease activity (MDA) at Week 16 between subjects who had ADA introduced 
and those that had methotrexate (MTX) escalated to the highest recommended dose of 
20 - 25 mg every week (ew) or highest tolerable dose up to 25 mg ew after inadequate 
disease control on the initial MTX therapy. 
The secondary objectives are:
●
To compare the effectiveness at Week 16 between subjects who had ADA 
introduced and those that had MTX escalated to the highest recommended 


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dose of 20 - 25 mg ew or highest tolerable up to 25 mg ew based on the 
following clinical, functional and quality of life measures: 
○
Psoriatic Arthritis Disease Activity Score (PASDAS)
○
Disease Activity in Psoriatic Arthritis (DAPSA) score
○
Psoriatic Arthritis Impact of Disease (PsAID) score
○
American College of Rheumatology (ACR) 20/50/70 response
○
Disease Activity Score 28 (DAS28)-CRP
○
Psoriasis Area and Severity Index (PASI)
○
Health Assessment Questionnaire Disability Index (HAQ-DI)
○
Short Form Health Survey 36 (SF-36) scores:  physical component 
summary (PCS) and mental component summary (MCS)
○
Dermatology Life Quality Index (DLQI)
○
Leeds Enthesitis Index (LEI)
○
Tender dactylitic digit count
●
To evaluate the achievement of MDA at Week 32 on each of the four different 
treatment groups involving ADA and/or MTX in Part 2 of the study.
4.2
Study Design
4.2.1
Study Design and Design Diagram
This interventional Phase 4 open-label, randomized, controlled, parallel-group, 
multicenter study will be conducted in two (2) parts, each of 16-week duration.
Part 1 (Day 1 - Week 16) is to compare the achievement of MDA on ADA introduced in 
combination with MTX versus MTX alone escalated to the highest recommended dose of 
20 - 25 mg ew1,2 or highest tolerable dose up to 25 mg ew, whatever feasible, in PsA 
subjects inadequately controlled after the initial course of MTX at 15 mg ew.  Part 1 will 
be open-label, randomized, controlled, parallel group.
Part 2 (Week 16 - 32) is to evaluate the effectiveness of four (4) different treatment 
regimens consisting of ADA and/or MTX in maintaining or attaining MDA, as applicable.  


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Part 2 will be open-label, parallel group.  Subjects will be assigned into the four treatment 
arms based on their MDA status at Week 16 and initial randomized treatment.  Starting at 
Week 24, there will be rescue treatment option based on not achieving MDA and 
investigator's judgment.
The study is designed to enroll approximately 240 subjects at approximately 60 sites to 
meet scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  
Following a screening period of up to 30 days, subjects meeting the selection criteria will 
be randomized in a 1:1 ratio to either of the two (2) arms and treated for 16 weeks in 
Part 1:
●
Arm 1/Part 1:  ADA 40 mg eow in combination with MTX 15 mg ew (ADA 
40 mg eow + MTX 15 mg ew),
●
Arm 2/Part 1:  MTX escalated to 20 - 25 mg or highest tolerable dose ew 
(MTX 20 - 25 mg or highest tolerable dose ew).
After the assessment of MDA at Week 16 (primary endpoint), subjects will be assigned to 
one of the four (4) treatment arms based on the achievement of MDA and initial 
randomized treatment, and treated for additional 16 weeks in Part 2 as follows:
●
Arm 1/Part 2:  Subjects achieving MDA at Week 16 on ADA 40 mg eow plus 
MTX 15 mg ew, will have MTX completely withdrawn at Week 16 and 
continue receiving ADA as monotherapy (ADA 40 mg eow),
●
Arm 2/Part 2:  Subjects not achieving MDA at Week 16 on ADA 40 mg eow 
plus MTX 15 mg ew, will have ADA escalated to 40 mg ew in combination 
with MTX 15 mg ew (ADA 40 mg ew plus MTX 15 mg ew),
●
Arm 3/Part 2:  Subjects achieving MDA at Week 16 on MTX escalated to 20 -
25 mg or highest tolerable dose ew, will continue with the same MTX dose 
(MTX 20 - 25 mg or highest tolerable dose ew),
●
Arm 4/Part 2:  Subjects not achieving MDA at Week 16 on MTX escalated to 
20 - 25 mg or highest tolerable dose ew, will receive ADA 40 mg eow in 


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combination with MTX 20 - 25 mg or highest tolerable dose ew (ADA 40 mg 
eow plus MTX 20 - 25 mg or highest tolerable dose ew).
Subjects in Arms 1 - 4 of Part 2 of the study will have the option of being rescued, starting 
at Week 24 and based on the subject not achieving MDA and the Investigator's judgment.  
The selection of the rescue treatment regimen will be at the discretion of the Investigator, 
but should involve ADA and/or MTX and should not involve prohibited medications per
the protocol.  
A schematic of the study design is shown below in Figure 1:
Figure 1.
A schematic of the study design


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4.2.2
Variables used for Stratification at Randomization 
Randomization was stratified by the duration of prior MTX treatment at 15 mg ew:
≤3 months and > 3 months.  
4.3
Endpoint
4.3.1
Primary Efficacy Endpoint
The primary endpoint is the proportion of subjects achieving MDA at Week 16 on ADA 
40 mg eow plus MTX 15 mg ew as compared with subjects on MTX alone escalated to 
20 - 25 mg or highest tolerable dose ew.
MDA in PsA is defined as fulfilling at least 5 of the 7 following criteria:3,4
●
TJC ≤ 1 (out of TJC68 assessed in this study)
●
SJC ≤ 1 (out of SJC66 assessed in this study)
●
PASI ≤ 1 or BSA ≤ 3
●
Patient's assessment of pain VAS ≤ 15
●
Patient's global assessment of disease activity (PtGA) VAS ≤ 20
●
HAQ-DI score ≤ 0.5
●
Tender entheseal points ≤ 1 (out of 8 assessed in this study)
4.3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include: 
●
At Week 16:
○
Change from baseline in PASDAS
○
Change from baseline in DAPSA score
○
Change from baseline in PsAID score
○
Proportion of subjects achieving ACR 20/50/70 response
○
Change from baseline in DAS28-CRP score


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○
Proportion of subjects achieving PASI 75/90/100 response (for subjects 
with BSA ≥ 3% at baseline)
○
Change from baseline in HAQ-DI score
○
Changes from baseline in SF-36PCS and SF-36MCS
○
Change from baseline in DLQI score
○
Change from baseline in Leeds Enthesitis Index (LEI) (for subjects with 
presence of enthesitis at baseline)
○
Change from baseline in tender dactylitic digit count (for subjects with 
presence of dactylitis at baseline)
●
The proportion of subjects in MDA at Week 32.
4.3.3
Exploratory Efficacy Endpoints
Clinical Efficacy 
Clinical efficacy outcomes listed under the secondary endpoints (refer to Section 4.3.2) 
will be analyzed as exploratory endpoints at Week 32 on the 4 different treatment 
regimens.
Ultrasound 
●
The change in Global OMERACT-EULAR synovitis score (GLOESS) from 
baseline to Week 16 in randomized treatment groups of Part 1 of the study. 
●
The change in OMERACT enthesitis score from baseline to Week 16 in 
randomized treatment groups of Part 1 of the study.
●
The change in Global OMERACT-EULAR synovitis score (GLOESS) from 
Week 16 - 32 in the 4 arms of Part 2 of the study. 
●
The change in OMERACT enthesitis score from Week 16 - 32 in the 4 arms of 
Part 2 of the study. 


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4.3.4
Safety Endpoint
The following safety evaluations will be performed during the study: concomitant 
medication review, adverse event (AE) monitoring, vital signs, and laboratory tests.
4.3.5
Pharmacological Endpoint
For subjects receiving ADA, blood samples will be collected for determination of ADA 
serum concentrations and the presence of anti-ADA antibodies (AAA). Analysis will be 
conducted separately and not in the scope of this SAP. 
4.4
Sample Size Justification
The study is powered to detect the difference in MDA response rates at Week 16 between 
ADA + MTX 15 mg and MTX escalated dose groups.  Assuming an MDA response rate 
of 40% in the ADA + MTX group and 20% in the escalated MTX group, a total sample 
size of 240 subjects, 120 subjects per arm, will provide at least 90% power to detect the 
difference between the two treatment groups at a significance level of 2-sided 0.05, 
accounting for 10% dropout.
4.5
Part 1 Analysis
Part 1 database lock is planned when all randomized subjects have completed Week 16 of 
the study. The 16-week study results (through Week 16) will be based on this database 
lock. 
4.6
Multiplicity Testing Procedures for Type-I Error Control
There is only one primary endpoint in this study and therefore multiplicity adjustment is 
not applicable. 
4.7
Missing Data Imputation
The following missing data imputation will be performed for efficacy analysis. 


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Non-Responder Imputation (NRI) Approach
To account for missing data for the binary efficacy endpoints, a non-responder imputation 
approach (NRI) will be used, e.g., subjects who have missing data at a specific visit will 
be treated as non-responder for that visit, or who prematurely discontinue or have been 
rescued will be considered as a non-responder for all subsequent visits.  
Mixed-Effects Model Repeated Measures (MMRM)
The repeated measure analysis will be conducted using mixed models based on observed 
data at all visits.  For the MMRM analysis (of continuous variables), data collected after 
premature discontinuation of study drug will be excluded.  The mixed model includes 
treatment, visit, treatment-by-visit interaction, and the stratification factor of duration of 
prior MTX use (≤ 3 months or > 3 months) as fixed effects, subject as random effect and 
baseline measurement as a covariate.  An unstructured variance covariance matrix will be 
used.  The parameter estimations assume data being missing at random (MAR) and using 
the method of restrictive maximum likelihood (REML). 
Observed Cases (OC)
The OC analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the OC analysis 
for that visit.  In addition, OC will not include values after subject have rescue visit or 
after premature discontinuation of study drug. 
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Populations
Intent-to-Treat Population Part 1 
The Intent-To-Treat Part 1 (ITT Part 1) population comprises all subjects who were 
randomized and received at least one dose of the study medication during the Part 1 
period.  The data collected up to Week 16 will be included and analyzed by the treatment 


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group assignment given at the time of randomization, even if the subject does not receive 
the correct treatment, is not compliant to the protocol procedures, or does not follow the 
protocol until completion.
Intent-to-Treat Population Long Term 
The Intent-To-Treat Long Term (ITT LT) population comprises all subjects who entered 
Part 2 period and received at least one dose of Part 2 study medication.  The data collected 
from randomization and up to Week 32 will be included and analyzed by the 
four treatment regimens as follows:
●
ADA 40 mg eow + MTX 15 mg ew/ADA 40 mg eow
●
ADA 40 mg eow + MTX 15 mg ew/ADA 40 mg ew + MTX 15 mg ew
●
MTX 20 - 25 mg or highest tolerable dose ew
●
MTX 20 - 25 mg or highest tolerable dose ew/ADA 40 mg eow + MTX 20 -
25 mg or highest tolerable dose ew
Per Protocol Population
In order to evaluate the impact of major protocol violations on the results of the trial, 
additional analysis of the primary effectiveness variable may be conducted on the per 
protocol population, which consists of all ITT Part 1 subjects who entered the randomized 
period of the study and did not meet any major protocol violation during the Part 1 of the 
study.  The determination of major protocol violation will be finalized prior to the final 
database lock.
Safety Population Part 1
The Safety population Part 1 consists of all subjects who received at least one dose of the 
study medication during the Part 1 period.  The data collected up to Week 16 will be 
included and analyzed by the two "As treated" treatment groups in Part 1. "As treated" is 
determined by the treatment a subject received during majority of the subject's drug 
exposure time in the analysis period, regardless of the treatment randomized.  


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Safety Population Part 2
The Safety population Part 2 consists of all subjects who received at least one dose of the 
Part 2 study medication. The data collected from Week 16 to Week 32 will be included 
and analyzed by "as treated" treatment groups that subjects received when entering in 
Part 2. The data collected after the initiation of the rescue medication will be summarized 
separately, and not be included in the analysis. 
"As treated" treatment groups are defined as follows:
1.
ADA 40 mg eow
2.
ADA 40 mg ew + MTX 15 mg ew
3.
MTX 20 - 25 mg or highest tolerable dose ew
4.
ADA 40 mg eow + MTX 20 - 25 mg or highest tolerable dose ew
Rescue Population
The Rescue population consists of all subjects who received at least one dose of the rescue 
medication after Week 24 visit. The data collected after the initiation of the rescue 
medication will be summarized separately by the Part 2 treatment groups as well as 
overall.  
5.2
Subgroup
Age, gender, BMI, race, region, prior MTX use (> 3 months or ≤3 months) will be the 
subgroups for the subgroup analysis.
6.0
Efficacy Analyses
6.1
General Considerations
There are two sets of planned efficacy analysis: Part 1 analysis and long-term analysis. 


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Part 1 Efficacy Analysis 
Standard efficacy analysis by the randomized treatment groups (ADA 40 mg eow + MTX 
15 mg ew, MTX 20 - 25 mg or highest tolerable dose ew) will be performed on the 
efficacy data up to Week 16 based on ITT Part 1 population. Formal statistical inference 
will be generated with missing data handling, and statistical testing will be conducted at 
α = 0.05 level (2-sided). Results from this set of analysis will be used as the key efficacy 
findings of this study.  
No protocol-defined rescue will occur prior to the time point. 
Long Term Efficacy Analysis 
Long term efficacy analysis from baseline to Week 32 will be performed based on the ITT 
LT Population by the 4 treatment regimens as described in Section 5.1. Descriptive 
statistics will be summarized by the four treatment regimens. The between-treatment 
comparison is not applicable for the long term analysis. No missing data imputation will 
be performed for long term efficacy analysis. 
Rescue handling will be applied for long term efficacy analysis. The data collected after 
the initiation of the rescue medication will be summarized separately. 
6.2
Primary Efficacy Analysis
The primary endpoint is the proportion of subjects achieving MDA at Week 16. The null 
hypothesis is that there is no difference in the rate of MDA between the two randomized 
treatment groups of ADA 40 mg eow + MTX 15 mg ew and MTX 20 - 25 mg or highest 
tolerable dose ew; the alternative hypothesis is that the rates of MDA between the 
two groups are different. 
Point estimate and 95% CI using normal approximation will be provided for the rate of 
MDA for each randomized treatment group. Treatment comparisons will be made 
between the randomized treatment groups using a Cochran-Mantel-Haenszel (CMH) 


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test5,6 (refer to Appendix A), adjusting for the stratification factor which is the duration of 
prior MTX 15 mg ew use of ≤ 3 months or > 3 months.  Point estimate of the treatment 
difference and the associated 95% CI using normal approximation will also be presented.  
To account for missing data for the primary endpoint, a non-responder imputation 
approach (NRI) will be used, e.g., subjects who discontinue during Part 1 with missing 
data will be imputed as a non-responder (NRI) in the subsequent visits.  
Sensitivity analyses will be conducted using the same method described above based on 
observed cases (OC) data.  
6.3
Secondary Efficacy Analyses
Part 1 Analysis
A complete list of secondary efficacy endpoints is provided in Section 4.3.2.  Binary 
endpoints will be analyzed in a similar way as the primary endpoint.  
For the continuous endpoints, the change from baseline at Week 16 will be analyzed using 
MMRM with treatment, the stratification factor of duration of prior MTX use (≤ 3 months 
or > 3 months), visit, and treatment-by-visit interaction as fixed effects, subject as random 
effect and baseline measurement as a covariate. The MMRM analysis is based on 
observed data. The LS mean, 95% CI and standard error for each randomized treatment 
group, the LS mean of the treatment difference and its associated 95% CI and p-value 
from the MMRM model will be presented.  
Long Term Analysis
The achievement of MDA at Week 32 on each of the four different treatment regimens 
will be evaluated. The proportion of subjects who achieved MDA at Week 32 will be 
summarized by counts and percentages for the four treatment regimens. Point estimate 
and 95% CI using normal approximation will be provided for each treatment regimen as 
well.  The subjects who were rescued prior to Week 32 will be considered as non-


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responders (MDA = 0) at Week 32. No comparison between treatment regimens will be 
performed.
6.4
Other Efficacy Analyses
Clinical Efficacy Variables
Binary secondary endpoints described in Section 4.3.2 will be analyzed as exploratory 
endpoints at Week 32 using count and percentages on each of the four different treatment 
regimens. Point estimate and 95% CI using normal approximation will be provided as 
well. The data occurred after initiation of the rescue medication will be imputed using 
NRI for the subsequent visits in this summary. 
Continuous secondary endpoints described in Section 4.3.2 will be analyzed as 
exploratory endpoints at Week 32 by summary statistics (number of subjects, mean, 95% 
confidence interval, standard deviation, median, minimum, maximum) for each treatment 
regimen. All observed data will be used to summarize the continuous exploratory 
endpoints. The data occurring after initiation of the rescue medication will be overwitten
by the last observation prior to treatment rescue (Last observation carried forward: 
LOCF) for the subsequent visits in this summary.   
Ultrasound Variables
For ultrasound assessment at Week 16, analysis will be performed using similar methods 
to those described for the secondary continuous efficacy endpoints. In addition, baseline 
weight will also be included as an additional covariate in MMRM. The LS mean, 95% CI 
and standard error for each randomized treatment group and the LS mean of the treatment 
difference, its associated 95% CI and p-values will be presented.  
For the ultrasound assessment at Week 32, summary statistics (number of subjects, mean, 
95% confidence interval, standard deviation, median, minimum, maximum) will be 
presented for each treatment regimen. All observed data will be used to summarize the 


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continuous exploratory endpoints. The data occurring after initiation of the rescue 
medication will be overwritten by LOCF for the subsequent visits in this summary.
Summary of Efficacy Endpoints by Visit
Summary of the primary and secondary efficacy endpoints at the scheduled time points 
will be presented by two treatment groups in the Part 1 analysis and by four treatment 
regimens in the long-term analysis. Achievement of each MDA component as binary 
endpoints will be summarized similarly as well.
For Part 1 analysis, binary efficacy endpoints will be analyzed in a similar way as the 
primary endpoint and continuous efficacy endpoints will be analyzed from the same 
MMRM model for the Wk16 endpoints. 
For the long term by-visit summary of binary and continuous efficacy endpoints, 
summary statistics will be provided by the four treatment regimens and by visit. For 
binary endpoints, subjects who were rescued after Week 24 will be considered as non-
responders for all subsequent visits after initiation of the rescue medication in this 
summary. For continuous efficacy endpoints, the Data occurred after initiation of the 
rescue medication will be overwitten by LOCF for the subsequent visits in this summary.
6.5
Efficacy Subgroup Analyses
The primary efficacy endpoint will be examined in the subgroups listed in Table 1 below.  
Point estimate of the treatment differences and 95% CI between the randomized treatment 
groups will be presented for each subgroup.  No p-value will be provided for subgroup 
analysis.  If any of the resulting subgroups for a variable has fewer than 20% of the 
planned study size (i.e., < 48 subjects), the subgroup analyses for that variable will not be 
presented.


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Table 1.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 40, [40, 65), ≥ 65
Sex
Male or Female
BMI
< 25 kg/m2 or ≥ 25 kg/m2
Race
White, Non-white
Geographic region
US, Western Europe/Canada, Eastern Europe/Middle East/Africa, Latin America, 
Japan/Asia/Pacific
Prior MTX usage
≤ 3 months or > 3 months
6.6
Efficacy Analysis for Rescued Patients
For the subjects who take at least of one dose of rescue medication, MDA status will be 
evaluated after rescue at the Week 28 and Week 32. Point estimate and 95% CI using 
normal approximation will be provided for the response rate of the MDA by 4 treatment 
regimens as well as overall.  The subjects who are rescued at Week 24 and Week 28 will 
be summarized separately. 
7.0
Safety Analyses
7.1
General Considerations
There will be 2 sets of safety analyses to be performed. 
1.
Safety analyses during Part 1 (up to Week 16). 
2.
Safety analyses during Part 2 (Week 16 to Week 32).
Safety analyses will include reporting of adverse events (AEs), laboratory, and vital signs 
measurements. Treatment-emergent AEs will be summarized and reported.  Missing 
safety data will not be imputed. Part 1 and Part 2 safety analyses will be carried out using 
the Safety Population Part 1 and Safety Population Part 2, respectively.


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Safety Analysis during Part 1 (up to Week 16)
Standard safety analysis by the "as treated" treatment groups of ADA 40 mg eow + MTX 
15 mg ew and MTX 20 - 25 mg or highest tolerable dose ew will be performed on safety 
data up to Week 16.  No protocol-defined treatment switching will occur prior to this time 
point.
Frequency tables of subjects with treatment-emergent adverse events (TEAEs) by system 
organ class (SOC) and by preferred term (PT) as in the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary will be provided by as-treated treatment groups.  
Observed values in all continuous laboratory parameters and vital signs variables at each 
visit will be summarized by "as treated" treatment groups.  Frequency tables of subjects 
meeting criteria for potentially clinically significant vital sign values and for potentially 
clinically significant laboratory values will be provided by as-treated treatment groups.  
Missing safety data will not be imputed.
Safety Analysis during Part 2 (Week 16 to Week 32)
Similar standard safety analysis by the "as treated" treatment groups will be performed on 
safety data from Week 16 to Week 32 based on Safety Population Part 2.
7.2
Analysis of Adverse Events
7.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) will be defined based on the following:
●
Part 1: TEAEs will be defined as any event with an onset date that is on or 
after the first dose of Part 1 study drug, and 
○
no more than 70 days after the last dose of ADA and 30 days after the last 
dose of MTX, if the subject discontinued prematurely from Treatment 
Part 1 or did not enter the Part 2, or 
○
prior to date of first dose of Part 2 study drug if the subject entered Part 2.


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●
Part 2: TEAEs will be defined as any event with an onset date that is on or
after the first dose of Part 2 study drug and with an onset date no more than 
70 days after the last dose of ADA or 30 days after the last dose of MTX.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the adverse event start time are 
collected and the adverse event start time is prior to the study drug start time. If an 
incomplete onset date was collected for an adverse event, the event will be assumed to be 
treatment emergent unless there is other evidence that confirms the event was not 
treatment-emergent (e.g., the event end date was prior to the study drug start date).
Adverse event data will be presented by SOCs and PTs using MedDRA Version 21.1 or 
most up to date version.  
7.2.1.1
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized for the 
following AE categories by the two treatment groups in Part 1 and by the four treatment 
groups in Part 2:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.  


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7.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated by 
SOC and MedDRA PT by the two treatment groups in Part 1 and by the four treatment 
groups in Part 2.  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables).  Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
7.2.1.3
TEAEs by Maximum Severity
TEAEs will also be summarized by maximum severity by the two treatment groups in 
Part 1 and by the four treatment groups in Part 2.  If a subject has an AE with an unknown 
severity, then the subject will be counted in the severity category of unknown, even if the 
subject has another occurrence of the same event with a severity present.  The only 
exception is that if the subject has another occurrence of the same AE with the most 
extreme severity – severe.  In this case, the subject will be counted under the severe 
category.
7.2.1.4
TEAEs by Relationship
TEAEs will also be summarized by relationship to study drug, as assessed by the 
investigator, by the two treatment groups in Part 1 and by the four treatment groups in 
Part 2.  If a subject has a TEAE with an unknown relationship, then the subject will be 
counted in the relationship category of "unknown," even if the subject has another 
occurrence of the same event with a relationship present.  The only exception is if the 
subject has another occurrence of the same TEAE with a relationship assessment of 
"reasonable possibility."  In this case, the subject will be counted under the "reasonable 
possibility" category.


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7.2.1.5
Frequent (≥ 5%) Adverse Events by System Organ Class 
and Preferred Term
TEAEs occurring for more than 5% of the subjects in any of the two treatment groups in 
Part 1 or any of the four treatment groups in Part 2 will be summarized by SOC and PT in 
decreasing frequency separately.
7.2.1.6
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories by SOC and PT will be 
summarized and presented by the two treatment groups in Part 1 and by the four treatment 
groups in Part 2.  The details of AESI list and search criteria are stated in Appendix A, 
which are extracted from Adalimumab Product Safety Statistical Analysis Plan 
Version 8.0.  
7.2.2
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be listed.  The number and percentage of subjects experiencing SAEs 
(including deaths) and adverse events leading to discontinuation of study drug will be 
tabulated according to the primary MedDRA SOC and MedDRA PT for each treatment 
group in Part 1 and for each treatment groups in Part 2.
7.3
Analysis of Laboratory Data
7.3.1
Analysis for Continuous Laboratory Data
Observed values of hematology, chemistry, and urinalysis variables which are measured 
longitudinally will be summarized by visits and by the two treatment groups in Part 1 and 
by the four treatment groups in Part 2.  The following summary statistics of each visit will 
be presented for each treatment group:  sample size, observed mean, standard deviation, 
minimum, median, and maximum. 


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Mean change and percent change from baseline in selected laboratory variables will be 
summarized by the two treatment groups in Part 1 and by the four treatment groups in 
Part 2 at each visit.  Mean difference between the two treatment groups in Part 1 will be 
compared using one-way ANOVA with treatment as a factor.  Mean difference and the 
associated 95% CIs will be presented at each visit.  The selected laboratory variables of 
clinical interest include:  Hematocrit, hemoglobin, Red Blood Cell (RBC) count, White 
Blood Cell (WBC) count, platelet count, lymphocytes, neutrophils, creatinine, Aspartate 
aminotransferase (AST), aminotransferase (ALT), Cholesterol, Glucose, Triglycerides.
The last evaluation prior to the first dose of study drug in Part 1 or Part 2 will be used as 
Baseline for Part 1 or Part 2, respectively.  
7.3.2
Shift Table Analyses
Shift tables for changes from Baseline according to the normal range will also be provided 
for laboratory variable. The baseline and post-baseline laboratory observations will be 
categorized by grades according to NCI CTC criteria.
For each laboratory variable, shift tables will be generated that cross tabulate the subjects 
as deemed appropriate by the two treatment groups in Part 1 and by the four treatment 
groups in Part 2, respectively:
●
Category of the baseline value versus category of the final value.  
●
Category of the baseline value versus maximum category.  
●
Category of the baseline value versus minimum category.
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.
No statistical tests will be performed for this analysis.


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7.3.3
Analysis for Potentially Clinically Significant Laboratory 
Values 
For selected laboratory parameters, the criteria for potentially clinically significant 
laboratory values will be determined by CTC criteria of Grade 3 or above.  The number 
and percentage of subjects meeting the criteria for potentially clinically significant 
laboratory values will be summarized by the two treatment groups in Part 1 and by the 
four treatment groups in Part 2. 
A listing of all subjects with any laboratory determination during each Part meeting 
Common Toxicity Criteria (CTC) (Version 3) of Grade 3 or higher will be provided. For 
each of these subjects, the whole course of the respective parameter will be listed.
A listing of potentially clinically significant liver function laboratory values will be 
provided. The listing will include all subjects who met any of the following criteria:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
ALP ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN


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7.4
Analysis of Vital Signs and Weight
The vital sign variables are defined in Section 4.3.4.3 Observed values of vital sign 
variables which are measured longitudinally will be summarized at each visit by the 
two treatment groups in Part 1 and by the four treatment groups in Part 2, respectively. 
Summary statistics such as number of subjects, baseline mean, visit mean, standard 
deviation, minimum and maximum will be provided. 
The criteria for potentially clinically significant vital sign findings are presented in 
Table 2. The number and percentage of subjects meeting the criteria for potentially 
clinically significant vital sign values will be summarized by the two treatment groups in 
Part 1 and by the four treatment groups in Part 2. Vital sign results satisfying the criteria 
for potentially clinically significant findings will be identified in a listing.
Table 2.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
The last evaluation prior to the first dose of study drug in Part 1 or Part 2 will be used as 
Baseline for Part 1 or Part 2, respectively.  
7.5
Analysis of ECG Parameters
No post-baseline ECGs were obtained for this study.


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8.0
Summary of Changes
8.1
Summary of Changes Between the Previous Version and the 
Current Version
Not applicable. 
8.2
Summary of Changes in Previous Version
Not applicable. 
9.0
Appendix 


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Appendix A.
AESI List and Search Strategies
There are two types of search strategies may be used for categorizing AESI categories are 
as follow:
●
Lowest Level MedDRA Queries (LMQs).
●
Standard MedDRA Queries (SMQs)/Company MedDRA Queries 
(CMQs)/Product-specific MedDRA Queries (PMQs)
LMQs will be the default search strategy unless otherwise stated in the safety analysis 
request.  SMQs/CMQs/PMQs will have limited use as a search strategy, e.g., aggregated 
safety review or any other special requests as deemed appropriate.  LMQs will be used in 
our study.
The following table includes all AESI for Humira with the LMQ searches.
AESI
LMQ Name
LMQ Search Term Definition
Infection
All Infection
Infection LMQ
Terms clearly identifying an infection.
Serious Infection
Infection LMQ
All Infections – Subset for SAEs.
Legionella Infection
Legionella Infection 
LMQ
Terms Legionella infections.
Culture and isolation of Legionella from respiratory 
secretions and/or pleural fluid.
Direct fluorescent antibody (DFA) staining that identifies 
Legionella in respiratory secretions and/or pleural fluid.
Four-fold increase in Legionella antibody titer or a single 
titer of 1:128.
Diverticulitis
Diverticulitis LMQ
Leukocytosis, CT Findings (Phlegmon, free air bubbles, 
abscess, colonic wall thickening, free fluid, obstruction), 
Fistulas (colovesica, rectovaginal).


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AESI
LMQ Name
LMQ Search Term Definition
Infection (continued)
Opportunistic Infection 
Excluding Oral 
Candidiasis and TB
Opportunistic 
Infection LMQ
Terms describing unusually severe forms of infections by a 
microbe typically seen only in immunocompromised 
individuals e.g., the term 'Herpes sepsis' is included.
Investigations for infections that generally occur 
exclusively in immunocompromised patients e.g., JC virus 
test positive.
Broader terms for infections typically only seen in 
immunocompromised persons when a more specific term 
for that infection type is not available e.g., the term 
'stomatoccal infection' is included.
Terms describing specific forms of fungal infections or 
tuberculosis infections which typically occur only in 
immunocompromised patients e.g., the term 'disseminated 
TB' is included.
Oral Candidiasis
Oral Candidiasis 
LMQ
Terms describing Oral Candidiasis only.
Tuberculosis
Active tuberculosis and latent tuberculosis combined.
Active Tuberculosis
Active Tuberculosis 
LMQ
Terms that describe active disease of tuberculosis.
Latent Tuberculosis
Latent Tuberculosis 
LMQ
Terms that describe positive results for TB screening tests 
(either skin or blood tests).
Terms that describe TB infection or latent infection.
Parasitic Infection
Parasitic Infection 
LMQ
Protozoal infectious disorders, Helminthic Disorders, and 
Ectoparasitic infestations.
Skin and subcutaneous arthropod and parasitic infestations, 
Parasitic lower respiratory tract infections.
Investigations terms for parasite identification and 
serology tests.
Reactivation of 
Hepatitis B
Reactivation of 
Hepatitis B Viral 
Infection LMQ
HBVsAg positive, HBeAb positive, PCR test for viral titer, 
HBVsAb positive, HBVc Ab positive.
Progressive Multifocal 
Leukoencephalopathy 
(PML)
Progressive 
Multifocal 
Leukoencephalopathy 
LMQ
PML definitive diagnosis.


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AESI
LMQ Name
LMQ Search Term Definition
Malignancies
Malignancies
Malignancies LMQ
All MedDRA terms for malignant or unspecified tumors:
•
Malignancy related conditions.
•
Terms for malignancy related conditions.
•
Terms for therapeutic and diagnostic procedures used 
to treat malignancies; treated malignancy to be 
specified.
•
Some of these procedures are also used for the 
treatment of non-malignant conditions.
•
Laboratory tests (incl. the results) that are specific for 
the malignancies.
•
To make agreement on "in situ" stage whether they 
fall under malignancies or not; currently assessed as 
malignancies.
•
To make agreement on general terms of "neoplasm;" 
whether considered as malignancies when no further 
details provided.
•
Tumour markers.
•
Terms related to tumor markers including the result.
For European Group on Tumour Markers, please 
reference the web site at 
http://ar.iiarjournals.org/content/27/4A/1901.abstract:
•
Terms related to benign tumors.
•
Terms related to premalignant conditions.
•
Treatment and diagnostic procedures that do not
specify a malignancy indicated.
•
Malignancy related therapeutic and diagnostic 
procedures includes a variety of terms which 
describe chemotherapy or radiotherapy treatment.
Please be aware, however, that there are some terms which 
relate to chemotherapeutic.  Such terms are not linked to 
chemotherapy or radiotherapy terms.
Lymphoma
Lymphoma LMQ
All terms for malignant or unspecified tumors.
Terms for malignancy related conditions.
Terms for therapeutic and diagnostic procedures used to 
treat malignancies.
Some of these procedures are also used for the treatment of 
non-malignant conditions terms related to tumor markers.
Hepatosplenic T-Cell 
Lymphoma (HSTCL)
Hepatosplenic T-Cell 
Lymphoma (HSTLC) 
LMQ
The most specific inclusion criteria is the diagnosis based 
on T-cell histology for the lymphoma of T-cell receptor 
type.
Non-Melanoma Skin 
Cancer (NMSC)
Non-Melanoma Skin 
Cancer LMQ
"Skin Neoplasms, Malignant and Unspecified" And Add 
the Preferred Terms.
"Squamous Cell Carcinoma" and "Bowen's Disease" to this 
Search.


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AESI
LMQ Name
LMQ Search Term Definition
Malignancies (continued)
Melanoma
Melanoma LMQ
The most common skin cancers are basal cell carcinoma 
and squamous cell carcinoma, but this category includes 
malignancies arising from other types of skin cells 
(e.g., Merkel cell carcinoma) and appendegeal cells 
(e.g., eccrine carcinoma).
Leukaemia
Leukemia LMQ
Terms for Lymphoid leukemia (e.g., Acute lymphoblastic 
leukemia, ALL, Chronic lymphocytic leukemia, CLL).
Terms for Myeloid leukemia (e.g., Acute myeloblastic 
leukemia, AML, Chronic myeloid leukemia, CML, 
Myeloid sarcoma).
Terms for Monocytic leukemia (e.g., Acute monoblastic 
leukemia, Acute monocytic leukemia, AML, Chronic 
myelomonocytic leukemia).
Terms for Other leukemia s of specified cell type 
(e.g., Acute erythroid leukemia).
Terms for Leukemia of unspecified cell type.
Terms for Leukemia in remission.
Other Malignancies 
Except Lymphoma, 
HSTCL, Leukemia, 
NMSC, and Melanoma
If an AE is identified as a "malignancy" in the 
"Malignancies LMQ" search above but not a "Lymphoma," 
"HSTCL," "Leukemia," "NMSC," or a "Melanoma," then 
it belongs to "Other Malignancies" category.
Immune Reactions
Allergic Reactions 
Including Angioedema/ 
Anaphylaxis
Allergic Reactions 
LMQ
Any terms representing events which include anaphylaxis, 
allergic events, hypersensitivity, angioedema, 
angioneurotic edema, urticarial (hives).
Lupus-Like Reactions 
and Systemic Lupus 
Erythematosus (SLE)
Lupus-Like Reactions 
and Systemic Lupus 
Erythematosus (SLE) 
LMQ
Lupus erythematosus and associated conditions in both 
primary and secondary locations in this are included except 
Lupoid hepatic cirrhosis, which is excluded.
Additional terms representing the diagnostic criteria of the 
American College of Rheumatology (ACR), e.g., Malar 
rash, Arthritis, Renal disorder, etc.


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AESI
LMQ Name
LMQ Search Term Definition
Immune Reactions (continued)
Vasculitis
Vasculitis LMQ
Terms for primary vasculitides (e.g., Henoch-Schonlein 
purpura, Behçet's syndrome, or Granulomatosis with 
polyangiitis (which includes Wegener's granulomatosis).
Terms containing vasculitis (e.g., Cutaneous vasculitis, 
Lupus vasculitis, or Rheumatoid vasculitis).
Terms containing arteritis (e.g., Arteritis coronary or 
Polyarteritis nodosa).
Terms containing angiitis (e.g., Microscopic polyangiitis 
or Thromboangiitis obliterans).
Terms for forms of purpura indicative of a vascular 
condition such as Henoch Schonlein purpura and Chronic 
pigmented purpura (narrow, which includes Majocchi's 
purpura) and Palpable purpura (broad).
Terms for laboratory test results that may indicate 
vasculitis (e.g., Antineutrophil cytoplasmic antibody 
increased).
Cutaneous Vasculitis
Cutaneous Vasculitis 
LMQ
Terms for vasculitides clearly identifiable as cutaneous 
(e.g., Cutaneous vasculitis, Skin vasculitis, Majocchi's 
purpura, Leukocytoclasitc, vasculitis, vasculitis legs, 
Necrotizing vasculitis, polyangiitis or Vasculitic rash).
Non-Cutaneous 
Vasculitis
Terms for vasculitides that are NOT in Cutaneous 
Vasculitis LMQ.
Sarcoidosis
Sarcoidosis LMQ
Sarcoidosis of any organ.
Autoimmune Hepatitis
Autoimmune 
Hepatitis LMQ
Cardiovascular/Vascular
Myocardial Infarction
Myocardial Infarction 
LMQ
Myocardial Infarction.
Terms which included the words 'myocardial infarction, 
heart attack, cardiac enzymes increased, cardiac troponin 
increased, CK-MB increased, ECG ST elevation, Q wave 
abnormal.'
Cerebrovascular 
Accident
Cerebrovascular 
Accident LMQ
Terms for conditions specific for cerebrovascular accident 
disorders irrespective of cause and irrespective of 
acuteness or chronicity.
Congestive Heart 
Failure
Congestive Heart 
Failure LMQ
Terms describing existing cardiac failure in its various 
forms with or without right/left ventricular specified.
A small number of terms for symptoms, signs and 
investigational findings that are pathognomonic of the 
condition.
Pulmonary Embolism
Pulmonary Embolism 
LMQ
Terms that are specifically assigned to describe the 
condition where an embolic event occurred in the lung of a 
patient, chronic or acute, arterial or venous.


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LMQ Name
LMQ Search Term Definition
Respiratory
Interstitial Lung 
Disease
Interstitial Lung 
Disease LMQ
ILDs include inflammatory and fibrotic diseases that 
ultimately disrupt the alveolar capillary interface, leading 
to hypoxemia.  ILDs usually manifest with a restrictive 
physiology, but airway involvement can cause obstruction 
or mixed physiology.
ILDs are associated with many clinical settings, including 
connective tissue disease; occupational, environmental and 
drug exposures; and primary pulmonary disorders.
Gastrointestinal Events
Intestinal Perforation
Intestinal Perforation 
LMQ
Terms for/related to any part of GI Tract, GI ulcers, 
obstruction, hemorrhage.
Intestinal Stricture in 
CDa
Intestinal Stricture 
LMQ
Abdominal Pain.
Radiographic Findings:  Bowl loop distension, gas-fluid 
level, bowel wall thickening.
Pancreatitis
Pancreatitis LMQ
Terms with the word "pancreatitis" (other than those 
indicative of chronic conditions).
Terms indicative of pancreatic dysfunction (such as 
pancreatorenal syndrome).
Terms for typical complications, e.g., Pancreatic 
pseudocyst.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson 
Syndrome
Severe Skin Reaction 
Stevens-Johnson 
Syndrome LMQ
This falls within the erythema multiforme-toxic epidermal 
necrolysis spectrum, representing an intermediate severity.  
All terms and their synonyms specifically linked to 
erythema multiforme, Stevens Johnson syndrome, and 
toxic epidermal necrolysis are included.  No procedure 
terms or appropriate investigation terms are specific.
Erythema Multiforme
Erythema Multiforme 
LMQ
Diagnosis terms that represent the condition Erythema 
Multiforme are included.  Terms that represent the 
signs/symptoms that are specific for Erythema Multiforme 
and included in the criteria for the diagnosis of Erythema 
Multiforme are included.
Worsening and New 
Onset of Psoriasis
Worsening New 
Onset of Psoriasis 
LMQ
Psoriasis can present in guttate form, where the lesions are 
smaller, or involve flexural parts of the body (e.g., axilla, 
inframammary areas), or involve fingernails or toenails 
(i.e., nail psoriasis), or involve palms or soles.  
In pustular psoriasis, the presentation is characterized by 
sterile pustules on a brightly erythematous base.  When 
pustular psoriasis involves the palms and soles, it is termed 
palmoplantar pustulosis.  Other variants of psoriasis 
include psoriasiform dermatitis and acrodermatitis 
continua.


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LMQ Name
LMQ Search Term Definition
Nervous System Disorder
Demyelinating 
Disorders Including 
Multiple Sclerosis, 
Guillain-Barré 
Syndrome, and Optic 
Neuritis and Others
Demyelinating 
Disorders LMQ
Terms for encephalomyelitis and leukoencephalopathies 
related to demyelination (e.g., Acute haemorrhagic 
leukoencephalitis and Progressive multifocal 
leukoencephalopathy).
Trigeminal neuralgia is included in broad terms due to 
possible association with multiple sclerosis or other 
demyelinating conditions.
Terms representing a disability scale which is highly 
specific for MS (e.g., Expanded disability status scale 
score increased).
Amyotrophic Lateral 
Sclerosis
Amyotrophic Lateral 
Sclerosis LMQ
There are no specific tests to provide a definite diagnosis 
of ALS although the presence of upper and lower motor 
neuron signs in a single limb is strongly suggestive.  The 
diagnosis is based on symptoms and signs as well as a 
series of tests to assess muscle weakness and atrophy, 
hyperreflexia, and spasticity which gets progressively 
worse.  For these reasons the search terms recommended 
for adjudication purposes would need to be consistent with 
the diagnosis of ALS and not with non-specific findings 
describing all the different types of motor neuron diseases.
Patients may exhibit symptoms and signs of the disease 
such as hyperreflexia, and spasticity.  Tests such as muscle 
biopsy, nerve conduction velocity, electromyography as 
well as MRI scans of the brain or spinal cord may also 
point to a possible diagnosis of ALS although none of 
these tests are definitive and will therefore not be included 
in the search.
Amyotrophic Lateral 
Sclerosis (continued)
ALS-related syndromes include progressive muscular 
atrophy, primary lateral sclerosis and progressive bulbar 
palsy will be included in the search.
Reversible Posterior 
Leukoencephalopathy 
Syndrome (RPLS)
Reversible Posterior 
Leukoencephalopathy 
Sydrome (RPLS) 
LMQ
Reversible Posterior Leukoencephalopathy Syndrome 
definitive diagnosis.
Posterior Reversible Encephalopathy Syndrome definitive 
diagnosis.
Hematologic Events
Hematologic Disorders 
Including Pancytopenia
Hematologic 
Disorders Including 
Pancytopenia LMQ
Terms referring to direct alterations of the hematopoiesis.
Hematological signs and diagnoses of bone marrow 
depression.
Hematological investigation results of bone marrow 
depression.
Neonatal terms are included in the broad search (the term 
neonatal does not allow a conclusion whether the condition 
is of acquired or inherited origin).
Certain abnormal terms are included in the broad searches.


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LMQ Name
LMQ Search Term Definition
Hepatic Events
Liver Failure and Other 
Liver Events (Except 
Gall Bladder Related 
Events)
Liver Events LMQ
Terms representing liver related diagnoses or diagnoses 
that can be related histological descriptions.  Also included 
are conditions associated with jaundice or cholestasis of 
possible hepatic origin and therefore excludes terms 
indicating jaundice caused by haemolytic conditions, such 
as Jaundice extrahepatic obstructive.  Diagnoses associated 
with pregnancy are included.
Other
Humira Administration 
Related Medication 
Error
Medication Errors 
LMQ
Medication errors.  Product Quality Issues.
Terms which included the words Medication errors that 
relates to 'adalimumab use.'
Injection Site 
Reactions
Injection Site 
Reaction LMQ
Terms in the Injection Site Reactions, Infusion Site 
Reactions, Vaccination Site Reactions.
Terms which included the words injection site, infusion 
site, application site, administration site, and 'vaccination 
site.'
The search is focused on local reactions to injections.
a.
In CD program only.  Any calculation of AE incident rate will only include patients in the CD program.


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