Clinical trial NCT02196701
Conditions: Psoriasis
Keywords: methotrexate adalimumab biologic psoriasis Tumor necrosis factor (TNF)-α inhibitor
Sponsor: AbbVie
Start date: 2014-08-05; Completion date: 2017-03-17
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the safety and efficacy of the use of the combination therapy adalimumab (ADA) every other week (EOW) with methotrexate (MTX) in suboptimal responders to ADA monotherapy.

Detailed description:

Arms: arm 1: Participants received 40 mg adalimumab every other week and methotrexate, between 7.5 and 25 mg/week at the discretion of the Investigator, for 24 weeks.
Interventions: intervention 1: Adalimumab intervention 2: Methotrexate
Intervention descriptions: intervention 1: Administered by subcutaneous injection every other week. intervention 2: Methotrexate was provided as 2.5 mg tablets for oral administration.

Protocol documents:
Prot_000.pdf: 
Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
1 
1.0 
Title Page 
Clinical Study Protocol W14-406
Concomitant longitudinal evaluation of adalimumab with 
methotrexate in the real world:  the CLEAR study 
Amendment 2 
AbbVie Investigational
Products: 
Adalimumab and Methotrexate 
Date:
22 April 2016 
Development Phase:
3b
Study Design: 
Multicenter, Single Arm, Open-Label, Longitudinal Study 
EudraCT Number: 
n/a 
Investigator(s):
Investigator information on file at 
AbbVie  
Sponsor: 
AbbVie Corporation
8401, Trans-Canada Highway
Saint-Laurent, Quebec 
H4S 1Z1, CANADA
Sponsor/Emergency  
  Contact: 
NCT02196701


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
2
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory requirements, 
including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
3
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
12 March 2014
Amendment 1
02 July2015
The purpose of this amendment is to incorporate the changes summarized below.
x
Applied administrative changes throughout protocol.
Rationale for change:  Text was revised to improve consistency and 
readability, and/or provide clarification.
x
Number of Subjects to be Enrolled and number of Study Sites were changed 
throughout the protocol.
Rationale for change: Due to low recruitment rate, the study population 
sample size was reviewed from approximately 200 to approximately 50, and 
number of study sites clarified to approximately 25.Changed to reflect to the 
current standard protocol template and to be consistent throughout protocol. 
x
Section 1.2, Synopsis. Updated
Rationale for change:  Synopsis was revised to be consistent with 
Amendment 2 revisions.
x
Section 5.2.1, Inclusion Criteria: Criteria 5 updated.
Rationale for change: Criteria updated as per AbbVie latest protocol standard 
text and add precision to the inclusion of female of childbearing potential and 
male subject with childbearing potential female partner.
x
Section 5.2.2, Exclusion Criteria: Criteria 17 added.
Rationale for change: Criteria added as per AbbVie latest protocol standard 
text and to clarify exclusion in regards to male subject considering fathering a 
child or donating sperm
x
Section 5.2.4, Contraception Recommendations and Pregnancy Testing: new
Rationale for change: Section added as per AbbVie latest protocol standard 
text and to add precision to acceptable contraception.


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
4
x
Section 5.3.1.1, Study Procedures: Hepatitis B and Hepatitis C Testing.
Rationale for change: Text updated to clarify exclusion of subjects with a 
positive HBc Ab Total test, indicating a previous Hep B exposure, link to a 
risk of reactivation or worsening of hepatitis B with MTX.
x
Section 5.3.1.1, Study Procedures: Pregnancy Tests.
Rationale for change: Addition of pregnancy tests at week 8 and 16 due to
methotrexate embryotoxicity, and teratogenic effects and AbbVie latest 
protocol standard text.
x
Section 8.2, Determination of Sample Size. Updated.
Rationale for change: Section revised to reflect modification of study sample 
size .


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
5
1.2
Synopsis
AbbVie Corporation
Protocol Number: W14-406
Name of Study Drugs:
Adalimumab and 
Methotrexate
Phase of Development: 3b
Name of Active Ingredients:
Adalimumab and Methotrexate
Date of Protocol Synopsis: 22/Apr/2016
Protocol Title: Concomitant longitudinal evaluation of adalimumab with methotrexate in the real world: 
the CLEAR study
Objective(s):
Primary objective:
To determine the proportion of primary and secondary sub-optimal responders to adalimumab (ADA) 
monotherapy1 (sub-optimal responders defined as subjects with an unsatisfactory response to psoriasis 
(Ps) treatment based on Investigator assessment)2 with a PGA > 3, and a PASI > 5.0 who have a 
satisfactory response after 16 weeks of treatment with ADA/methotrexate (MTX) combination therapy, 
based on Investigator and subject satisfaction assessments (using satisfaction questionnaires).
Secondary objectives:
x
To determine the proportion of primary and secondary sub-optimal responders to ADA 
monotherapy1 (sub-optimal responders defined as subjects with an unsatisfactory response to 
treatment based on Investigator assessment) with a PGA > 3 and a PASI > 5.0 who reach PASI 50, 
PASI 75 and PASI 90 16 weeks after initiation of ADA/MTX combination therapy;
x
To define the demographic and clinical profile of subjects benefiting from ADA/MTX 
combination therapy;
x
To determine the magnitude, timing and maintenance of the benefit of adding MTX to ADA by 
assessing Investigator/subject satisfaction with treatment, PGA, PASI and Dermatology Life 
Quality Index (DLQI) at 8, 16 and 24 weeks after addition of MTX to therapy;
x
To determine change in DLQI from baseline in subjects initiated on ADA/MTX treatment;
x
To determine change in serum levels of ADA following addition of MTX and to characterize a 
possible correlation with changes in Investigator/subject satisfaction with treatment, PGA, PASI 
and DLQI over the study period.  Serum levels will be evaluated at baseline (initiation of 
ADA+MTX) and at weeks 8, 16 and 24.
Investigator(s): Multicenter
1 Note that subjects may also be receiving topical treatments if they were prescribed prior to enrolment in the study
2 Investigator assessment based on a questionnaire response; see Satisfaction questionnaire section


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
6
Study Site(s): Approximately 25 Canadian sites
Study Population:
Adult subjects 18 years of age or older, with a clinical diagnosis of moderate to 
severe Ps for at least 6 months who have been receiving ADA monotherapy at a dose of 40 mg every-
other-week (eow) or greater for at least 16 weeks and who, in the opinion of the treating Investigator, 
have a sub-optimal response to treatment, or have not maintained an initial positive response (secondary 
sub-optimal responders) (sub-optimal response and secondary sub-optimal responders defined as subjects 
with an unsatisfactory response to treatment based on Investigator assessment) AND have a PGA score of 
> 3 (or at least moderate disease) and a PASI of > 5.0.
Number of Subjects to be Enrolled: Approximately 50
Methodology: The study entails a 24-week treatment period and a 70-day safety follow-up period. 
Subjects, who in the opinion of the Investigator are not responding optimally to ADA monotherapy (40 
mg eow or greater) at least 16 weeks after initiating treatment (primary sub-optimal responders) or who, 
after an initial positive response to ADA monotherapy (40 mg eow or greater) have failed to maintain an 
optimal level of response (secondary sub-optimal responders) (sub-optimal responders defined as subjects 
with an unsatisfactory response to treatment based on Investigator assessment) and have a PGA ≥3 and a 
PASI ≥5 will be potentially eligible for participation in the study. Potential subjects receiving ADA 40 
mg once weekly will only be eligible for the study after a wash-out period of 8 weeks on ADA 40 mg 
eow. Following identification of potential subjects, the Investigator will arrange a pre-screening visit to 
discuss treatment status with the subject and outline the proposed study with the understanding that the 
subject must meet all inclusion criteria before participation. If subjects provide written consent, they will 
then complete a satisfaction questionnaire, and PGA and PASI status will be determined at a screening 
visit and inclusion/exclusion criteria assessed. Subjects eligible for participation in the study must have a 
PGA score of > 3 and a PASI of > 5. 
Data collected at a baseline visit will include: subject demographics, disease history, comorbidities, vital 
signs, laboratory investigations, PGA, PASI and DLQI scores and serum levels of ADA.  Subjects will 
continue to self-administer ADA (40 mg eow) but will have oral MTX added to their treatment at a dose 
to be defined by the Investigator. At site visits 8, 16 and 24 weeks after initiation of ADA/MTX, the 
following parameters will be assessed: physician assessment of disease status (using a satisfaction
questionnaire); subject self-assessment of disease status (using a satisfaction questionnaire); PGA; PASI; 
DLQI; adverse events (AEs); serum levels of ADA.
Satisfaction questionnaire:  Both Investigators and subjects will be asked how satisfied they are with the 
Ps control provided by the subject’s current treatment. The provided responses will be: completely 
dissatisfied; moderately dissatisfied; slightly satisfied; highly satisfied; completely satisfied. Subjects 
with an Investigator assessment of completely or moderately dissatisfied with treatment will be 
categorized as a sub-optimal responder.
The 70-day safety follow-up period begins from the last dose of ADA. Subjects will be discontinued from 
the study if they withdraw consent or if they are deemed unsuitable to continue for any reason by the 
Investigator in consultation with the AbbVie Medical Monitor.


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
7
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subjects who have been on ADA monotherapy (40 mg eow or greater) for at least 16 weeks but 
who in the opinion of the Investigator have shown a sub-optimal response to treatment and have a 
PGA of > 3 and a PASI of > 5; or
Subjects who after an initial positive response to ADA monotherapy (40 mg eow or greater) have 
failed to maintain an optimal level of response, based on the opinion of the Investigator, and have a 
PGA of > 3 and a PASI of > 5;
2.
Subjects who are receiving 40 mg ADA once weekly must be on ADA 40 mg eow for 8 weeks 
prior to screening;
3.
Subjects with at least a 6 month history of chronic plaque Ps;
4.
Subjects greater than or equal to 18 years of age;
5.
If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 
year or surgically sterile or is of childbearing potential and is practicing birth control;
6.
The results of the serum pregnancy test performed during the Screening Period and urine 
pregnancy test performed at the Baseline Visit must be negative;
7.
Subject is judged to be in good general health as determined by the Principal Investigator;
8.
Subjects must be evaluated for latent TB infection; 
9.
Subjects must be able and willing to provide written informed consent and comply with the 
requirements of the study protocol;
10.
Subjects must be willing and able to self-administer subcutaneous (SC) injections or have a 
qualified person available to administer SC injections.
Main Exclusion:
1.
Subject has any contraindications to MTX or ADA;
2.
Subject has a previous failed response or poor tolerance to ADA;
3.
Subject has a poorly controlled medical condition which, in the opinion of the Investigator, would 
put the subject at risk by participation in the study;
4.
Subject has a history of clinically significant hematologic, renal or liver disease;
5.
Subject has a history of neurologic symptoms suggestive of central nervous system (CNS) 
demyelinating disease and/or diagnosis of central demyelinating disease;
6.
Subject has evidence of dysplasia or history of malignancy (including lymphoma and leukemia) 
other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or 
localized carcinoma in situ of the cervix;
7.
Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or 
recent active infections requiring hospitalization or treatment with intravenous (iv) anti-infectives 
within 30 days or oral anti-infectives within 14 days prior to the Baseline visit;
8.
Subject is known to have immune deficiency, history of HIV or is immunocompromised;
9.
Subject currently uses or plans to use anti-retroviral therapy at any time during the study;
10.
Female subject who is pregnant or breast-feeding or considering becoming pregnant during the 
study or for 150 days after the last dose of study medication; 


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
8
Main Exclusion (contd.):
11.
Subject has a history of clinically significant drug or alcohol usage in the last year or cannot 
maintain an alcohol intake of 30 g a day or less throughout the study (one standard drink is defined 
as 180 mL/6 oz (approx. 10 g) of wine, 360 mL/12 oz (approx. 15 g) of regular beer, or 45 mL/1.5 
oz (approx. 10 g) of spirits;
12.
Screening clinical laboratory analyses show any of the following abnormal laboratory results:  
x
Aspartate transaminase (AST) or alanine transaminase (ALT) > 2x the upper limit of normal 
(ULN);
x
Serum total bilirubin > 1.5 mg/dL (> 26 micromol/L), except for subjects with Gilbert’s 
Syndrome; 
x
Creatinine > 1.5 mg/dL (133 micromol/L) in subjects ≤65 years old and > upper limit of 
normal range in subjects > 65;
x
Positive Hepatitis B or C serology indicative of previous or current infection.
13.
Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the 
study;
14.
The following treatments are prohibited for all subjects during the study:
1.
Phototherapy (PUVA (within 4 weeks of the Baseline Visit) and/or UVB (within 2 weeks of 
the Baseline Visit);
2.
Other biologic therapies (including any other anti-TNF) within 4 weeks of the Baseline Visit;
3.
Any investigational agents of chemical or biologic nature within a minimum of 30 days or 5 
half-lives (whichever is longer) of the drug prior to the Baseline visit ;
4.
Any other systemic drug therapies for Ps within 4 weeks of the Baseline Visit;
5.
Oral or injectable corticosteroids, new prescription topical therapies, or changes in the 
concentration of current prescription topical therapies (including corticosteroids) that are being 
used, within 2 weeks of the Baseline Visit. Subjects may continue using previously prescribed 
topical therapies (including corticosteroids) during the study.  
15.
Prior exposure to biologics that have a potential or known association with Progressive 
multifocal leukoencephalopathy PML (i.e., natalizumab (Tysabri®) or rituximab (Rituxan®)); 
16.
Subjects with any active viral infection that based on the investigator’s clinical assessment 
makes the subject an unsuitable candidate for the study;
Investigational Product(s):   ADA and MTX
Dose(s):
ADA:  40 mg eow beginning at study Week 0 through Week 22.
MTX:  Dose is up to the discretion of the investigator but recommended 
dose should be between 10 and 25 mg/week, beginning at Week 0 
through Week 23.  The minimum initial dose of MTX should be 10 
mg/week. MTX dose can be increased at any time over the study period, 
based on the clinical judgment of the Investigator.  
Mode of Administration:
ADA:  SC injections self-administered by subjects via pens.
MTX:  Oral administration.
Reference Therapy:
There is no reference therapy in this study
Dose(s):
Mode of Administration:


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
9
Duration of Treatment: ADA will be administered for 24 weeks (last dose of ADA will be at Week 
22); following this period decision to continue ADA will be at the discretion of the Investigator; 
Study-related MTX will be administered for 24 weeks (last dose of MTX will be at Week 23); following 
this period decision to continue MTX will be at the discretion of the Investigator.
Criteria for Evaluation:
Efficacy: The primary efficacy endpoints will be:
x
Based on investigator assessment, the proportion of subjects (primary and secondary sub-optimal 
responders) achieving a satisfactory response to ADA + MTX treatment after 16 weeks 
(satisfactory response defined as highly or completely satisfied with subject’s therapy using the 
satisfaction questionnaire);
x
Based on subject self-assessment, the proportion of subjects (primary and secondary sub-optimal 
responders) achieving a satisfactory response to ADA + MTX treatment after 16 weeks 
(satisfactory response defined as highly or completely satisfied with therapy using the satisfaction 
questionnaire).
Secondary efficacy endpoints will include:
x
The proportion of subjects (primary and secondary sub-optimal responders) achieving 50%, 75%, 
90% and 100% reductions in PASI at 8, 16 and 24 weeks after initiation of ADA + MTX (change 
in PASI based on score at initiation of ADA + MTX therapy);
x
The proportion of primary sub-optimal responders achieving 50%, 75%, 90% and 100% reductions 
in PASI at 8, 16 and 24 weeks after initiation of ADA + MTX (change in PASI based on score at 
initiation of ADA + MTX therapy);
x
The proportion of secondary sub-optimal responders achieving 50%, 75%, 90% and 100% 
reductions in PASI at 8, 16 and 24 weeks after initiation of ADA + MTX (change in PASI based 
on score at initiation of ADA + MTX therapy);
x
The proportion of subjects on ADA 40 mg eow prior to baseline or 40 mg once weekly prior to 
wash-out achieving 50%, 75%, 90% and 100% reductions in PASI 16 weeks after initiation of 
ADA + MTX (change in PASI based on score at initiation of ADA + MTX therapy);
x
Proportion of primary and secondary sub-optimal responders achieving a clinical response defined 
as a PGA of “Clear” or “Minimal” at 8, 16 and 24 weeks after initiation of ADA + MTX;
x
DLQI scores at baseline (at initiation of ADA + MTX) and at weeks 8, 16 and 24;
x
Change and percent change in DLQI from baseline to weeks 8, 16 and 24; 
x
Proportion of subjects with each of the five categories of satisfaction with treatment at baseline (at 
initiation of ADA + MTX) and at weeks 8, 16 and 24 (subject self-assessment and investigator 
assessment using the satisfaction questionnaires);
x
Proportion of primary and secondary sub-optimal responders achieving a DLQI score of 0 or 1, at
8, 16 and 24 weeks after initiation of ADA + MTX;
x
Serum levels of ADA in subjects at baseline (at initiation of ADA + MTX) and at weeks 8, 16 and 
24.


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
10
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of ADA + MTX. 
Incidence of AEs, changes in vital signs, physical examination results, and clinical laboratory tests will
be assessed.
Statistical Methods:
Efficacy:
The primary analyses will be the proportion of subjects with Ps who have a satisfactory response to ADA 
+ MTX treatment, based on a self-assessment by subjects and an assessment by the treating Investigator. 
Secondary analyses will include an evaluation of the efficacy of ADA + MTX in subjects with Ps and 
characterization of the possible relationship between serum levels of ADA and efficacy outcomes.
This study will have a 12 month recruitment period where it is anticipated that approximately 50 subjects 
will be recruited. With this sample size the proportion of responders, after 16 weeks of ADA + MTX 
therapy, based on an Investigator assessment and subject self-assessment, can be estimated within ± 4.9% 
with 95% confidence when the point estimate is 15%, within ± 6.4% with 95% confidence when the point 
estimate is 30%, or within ± 6.9% with 95% confidence when the point estimate is 50%.
Due to the recent enrollment plan change, this study will only enroll 50 patients or as the number of 
enrollment by 31-Dec-2016,  With 50 subjects the same proportion of responders can be estimated within 
± 9.9% with 95% confidence when the point estimate is 15%, within ± 12.7% with 95% confidence when 
the point estimate is 30%, or within ± 13.9% with 95% confidence when the point estimate is 50%.
The primary and secondary efficacy analyses will be conducted on the ITT population (subjects who 
receive at least one dose of ADA and MTX).  The primary efficacy analyses will also be conducted for 
the following subgroups:
x
Subjects defined as primary sub-optimal responders at baseline, based on Investigator assessment;
x
Subjects defined as secondary sub-optimal responders at baseline, based on Investigator 
assessment.
For the primary and secondary efficacy analyses, sub-optimal responder imputation (imputing missing 
satisfaction data as “dissatisfied”) will be used.  In the event that greater than 5% of the satisfaction data 
are missing, last observation carried forward will also be carried out to impute the missing data in 
sensitivity analyses. Secondary outcomes will be analyzed using available data at each assessment point 
and changes over time will be estimated using a Mixed Model. Exploratory analysis to determine 
associations between ADA serum levels and PASI, PGA and DLQI scores will be carried out.
Safety:
All AEs, SAEs, and AEs leading to discontinuation will be collected during the study and up to 70 days 
after the last dose of ADA. Safety analyses will be carried out using the Safety Population. A treatment-
emergent AE is defined as an event with onset or worsening after the first dose of study drugs (ADA + 
MTX) and within 70 days after the last dose of ADA. The number and percent of subjects experiencing 
treatment-emergent AEs will be tabulated using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA®) system organ class and preferred term. Summaries (including percentages and event per 100 
patient-years) of SAEs, deaths and AEs leading to discontinuation from the study will be provided.


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
11
1.3
List of Abbreviations and Definition of Terms
Abbreviations
oC
Degrees Celsius
ADA
Adalimumab
AE
Adverse Event
ALT
Alanine Transaminase
ANA
Antinuclear Antibody
Anti-ds DNA
Anti-Double-Stranded Deoxyribonucleic acid
AS
Ankylosing Spondylitis 
AST
ATEMS
Aspartate Transaminase
AbbVie Temperature Excursion Management System
BCG
Bacille Calmette-Guerin
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CD
Crohn’s Disease
CNS
Central Nervous System
CRA
Clinical Research Associate (Monitor)
CRF
Case Report Form
CRP
C-Reactive Protein
CXR
Chest X-Ray
DLQI
Dermatology Life Quality Index
dsDNA
Double Stranded Deoxyribonucleic  Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMEA
European Agency for the Evaluation of Medicinal Products
Eow
Every other week
ESR
Erythrocyte Sedimentation Rate
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
HAV-IgM
Hepatitis A virus immunoglobulin M
HBc Ab
Hepatitis B Core Antibody
HBs Ab
Hepatitis B Surface Antigen


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
12
HBs Ag
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV Ab
Hepatitis C virus antibody
HIV
Human Immunodeficiency Virus
hsCRP
Highly Sensitive C-Reactive Protein
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRAs
Interferon-Gamma Release Assays
INH
Isoniazid
IRB
Institutional Review Board
ITT
IVRS/IWRS
Intent-to-Treat
Interactive Voice Response System/Interactive Web Response 
System
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
mL
Milliliter
MMR
Measles-Mumps-Rubella 
MTX
Methotrexate
OPV
Oral Polio Vaccine 
PASI
Psoriasis Area Severity Index
PCR
Polymerase Chain Reaction
PGA
Physician’s Global Assessment
PK
PML
POR
Pharmacokinetic
Progressive Multifocal Leukoencephalopathy
Proof of Receipt
PPD
Purified Protein Derivative 
Ps
Psoriasis
PsA
Psoriatic Arthritis
PUVA
Ultraviolet A with Psoralen
RA
Rheumatoid Arthritis
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous (injection)


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
13
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
TB
Tuberculosis
TNF-α
Tumor Necrosis Factor-Alpha
UC
Ulcerative Colitis 
UV
Ultraviolet
RNA
Ribonucleic acid
Definition of Terms
PASI 50
50% reduction in Baseline PASI score
PASI 75
75% reduction in Baseline PASI score
PASI 90
90% reduction in Baseline PASI score
PASI 100
100% reduction in Baseline PASI score
Sub-optimal response to therapy: Based on completely dissatisfied or moderately 
dissatisfied responses on the Satisfaction Questionnaire
Satisfactory response to therapy: Based on highly satisfied or completely satisfied 
responses on the Satisfaction Questionnaire


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
14
2.0
Table of Contents
1.0 
Title Page..................................................................................1 
1.1 
Summary of Changes.................................................................................3 
1.2 
Synopsis .....................................................................................................5 
1.3 
List of Abbreviations and Definition of Terms........................................11 
2.0 
Table of Contents...................................................................14 
3.0 
Introduction ...........................................................................18 
3.1 
Differences Statement..............................................................................22 
3.2 
Benefits and Risks....................................................................................22 
3.3 
Adalimumab Overview............................................................................23 
3.4 
Safety Information ...................................................................................23 
4.0 
Study Objective......................................................................24 
4.1 
Primary objective.....................................................................................24 
4.2 
Secondary objectives................................................................................24 
5.0 
Investigational Plan...............................................................25 
5.1 
Overall Study Design and Plan:  Description ..........................................25 
5.2 
Selection of Study Population..................................................................28 
5.2.1 
Inclusion Criteria......................................................................................28 
5.2.2 
Exclusion Criteria ....................................................................................30 
5.2.3 
Prior and Concomitant Therapy...............................................................32 
5.2.3.1 
Prior Therapy ...........................................................................................32 
5.2.3.2 
Concomitant Therapy...............................................................................33 
5.2.3.3 
Prohibited Therapy...................................................................................33 
5.2.3.4 
Rescue Therapy........................................................................................34 
5.3 
Efficacy, Pharmacokinetic and Safety Assessments/Variables ...............36 
5.3.1 
Efficacy and Safety Measurements Assessed and Flow Chart ................36 
5.3.1.1 
Study Procedures......................................................................................40 
5.3.2 
Drug Concentration Measurements .........................................................52 
5.3.2.1 
Collection of Samples for Analysis .........................................................52 
5.3.2.2 
Handling/Processing of Samples .............................................................52 
5.3.2.3 
Disposition of Samples ............................................................................52 
5.3.2.4 
Measurement Methods.............................................................................53 


Adalimumab/Methotrexate
W14-406 Protocol
Amendment 2, 22April 2016
15
5.3.3 
Efficacy Variables....................................................................................53 
5.3.3.1 
Primary Variable(s)..................................................................................53 
5.3.3.2 
Secondary Variable(s)..............................................................................53 
5.3.4 
Safety Variables .......................................................................................54 
5.3.5 
Pharmacokinetic Variables ......................................................................54 
5.4 
Removal of Subjects from Therapy or Assessment.................................55 
5.4.1 
Discontinuation of Individual Subjects....................................................55 
5.4.2 
Discontinuation of Entire Study...............................................................56 
5.5 
Treatments................................................................................................57 
5.5.1 
Treatments Administered.........................................................................57 
5.5.2 
Identity of Investigational Product(s) ......................................................58 
5.5.2.1 
Packaging and Labeling...........................................................................58 
5.5.2.2 
Storage and Disposition of Study Drug(s)...............................................59 
5.5.3 
Method of Assigning Subjects to Treatment Groups...............................59 
5.5.4 
Selection and Timing of Dose for Each Subject......................................60 
5.5.5 
Blinding....................................................................................................61 
5.5.6 
Treatment Compliance.............................................................................61 
5.5.7 
Drug Accountability.................................................................................62 
5.6 
Discussion and Justification of Study Design..........................................63 
5.6.1 
Discussion of Study Design and Choice of Control Groups....................63 
5.6.2 
Appropriateness of Measurements...........................................................64 
5.6.3 
Suitability of Subject Population .............................................................64 
5.6.4 
Selection of Doses in the Study ...............................................................64 
6.0 
Complaints .............................................................................65 
6.1 
Medical Complaints.................................................................................65 
6.1.1 
Definitions................................................................................................66 
6.1.1.1 
Adverse Event..........................................................................................66 
6.1.1.2 
Serious Adverse Events ...........................................................................66 
6.1.1.3
Adverse Events of Special Interest ..........................................................68
6.1.2 
Adverse Event Severity............................................................................68 
6.1.3 
Relationship to Study Drug......................................................................68 
6.1.4 
Adverse Event Collection Period.............................................................68 
6.1.5 
Adverse Event Reporting.........................................................................69 


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6.1.6 
Pregnancy.................................................................................................71 
6.1.7 
Toxicity Management ..............................................................................71 
6.2 
Product Complaint ...................................................................................72 
6.2.1 
Definition .................................................................................................72 
6.2.2 
Reporting..................................................................................................73 
7.0 
Protocol Deviations................................................................73 
8.0 
Statistical Methods and Determination of Sample 
Size ..........................................................................................74 
8.1 
Statistical and Analytical Plans................................................................74 
8.1.1 
Analysis Population .................................................................................75 
8.1.2 
Planned Methods for Statistical Analysis ................................................75 
8.1.3 
Demographics and Baseline Characteristics............................................75 
8.1.4 
Statistical Analysis of Efficacy................................................................76 
8.1.5 
Statistical Analysis of Safety ...................................................................77 
8.1.6 
Interim Analysis.......................................................................................77 
8.2 
Determination of Sample Size .................................................................77 
8.3 
Statistical Analysis of ADA Serum Levels..............................................79 
9.0 
Ethics.......................................................................................80 
9.1 
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)..............................................................................................80 
9.2 
Ethical Conduct of the Study ...................................................................81 
9.3 
Subject Information and Consent.............................................................81 
10.0 
Source Documents and Case Report Form 
Completion .............................................................................81 
10.1 
Source Documents ...................................................................................81 
10.2 
Case Report Forms...................................................................................82 
11.0 
Data Quality Assurance ...........................................................................84 
12.0 
Use of Information...................................................................................84 
13.0 
Completion of the Study..........................................................................85 
14.0 
Investigator's Agreement .........................................................................86 
15.0 
Reference List ..........................................................................................87 


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List of Tables
Table 1. 
Study Activities........................................................................................37 
Table 2. 
Clinical Laboratory Tests.........................................................................48 
Table 3: 
Identity of Investigational Products.........................................................58 
Table 4: 
Accuracy Estimates with a Sample Size of 200 Subjects ........................78
Table 5: 
Accuracy Estimates with a Sample Size of 50 Subjects ..........................80 
List of Figures
Figure 1: 
Study Design Schematic ..........................................................................27 
Figure 2. 
Adverse Event Collection ........................................................................69 
List of Appendices
Appendix A. 
Responsibilities of the Clinical Investigator............................................90 
Appendix B. 
List of Protocol Signatories......................................................................92 
Appendix C. 
Satisfaction Questionnaire .......................................................................93 
Appendix D. 
Psoriasis Area Severity Index (PASI) Scoring Instructions.....................95 
Appendix E. 
Physician Global Assessment of Skin (PGA-S) ......................................97 
Appendix F. 
Dermatology Life Quality Index (DLQI).................................................98 
Appendix G. 
70-Day Follow-Up (Phone Call)............................................................100 
Appendix H. 
Adalimumab injection instructions........................................................101 


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3.0
Introduction
Psoriasis (Ps) is an immune-mediated, chronic, inflammatory skin disorder that impacts 
both physical and emotional aspects of an individual’s quality of life and requires lifelong 
care (1,2). In addition, subjects with Ps are at an increased risk for clinical comorbidities 
including cardiovascular disease, metabolic syndrome, diabetes and lymphoproliferative 
malignancies that complicate overall disease management and can lead to significant 
reductions in life expectancy (2,3). There is also an increased risk of diseases with a 
related inflammatory origin, the most common being psoriatic arthritis (PsA), which can 
develop many years after the initial diagnosis of skin Ps (3). The age specific prevalence 
of Ps in Canada has been estimated at approximately 1.7% meaning that more than 
500,000 Canadians suffer from the disease (2).  Ps can occur at any age but most often 
develops between the ages of 15 and 25 and men and women are affected in equal 
proportions (4). Approximately 17% of patients previously diagnosed with Ps will have 
moderate to severe disease (5) and the estimated prevalence of PsA in a population with 
Ps is approximately 30% (6).  
Although traditional systemic therapies such as methotrexate (MTX), cyclosporine and 
acitretin can be effective in treatment of Ps, they are associated with adverse events (AEs) 
which can limit their long-term use and also require extensive laboratory monitoring 
(1,2,4). However, biologic therapies, which specifically target the overactive immune 
system characteristic of Ps, have provided a significant advance in the treatment of this 
disease (4). These agents work by targeting specific steps in the inflammatory cascade (4). 
One of the key targets in this cascade is tumor necrosis factor (TNF), a cytokine that plays 
a role in the development of Ps (1,2,4). Several biologics (adalimumab (ADA), etanercept 
and infliximab) specifically target TNF by different mechanisms and all have 
demonstrated effectiveness in the treatment of Ps and other inflammatory diseases, 
including PsA, rheumatoid arthritis (RA), Crohn’s disease (CD) and ankylosing 
spondylitis (AS) (2,7,8). ADA is a fully human monoclonal antibody that binds with high 
affinity and specificity to human TNF, neutralizing the biologic activities of the cytokine 
by blocking its interaction with cell surface TNF receptors, and suppressing the 


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downstream biologic responses (1). Currently in Canada, ADA is indicated for the 
treatment of RA, polyarticular juvenile idiopathic arthritis (JIA), PsA, AS, adult and 
pediatric CD, ulcerative colitis (UC), Ps, and hidradenitis suppurativa (HS) (9).  
The efficacy and safety of ADA in Ps has been demonstrated in a number of Phase III
trials (1,10,11,12). In the pivotal REVEAL clinical trial, subjects with moderate to severe 
plaque Ps receiving ADA (40 mg every other week (eow) after an initial 80 mg dose at 
baseline) had a week 16 Psoriasis Area and Severity Index (PASI) 75 response rate of 
71% compared to 7% for subjects receiving placebo (p<.001); PASI 90 and 100 rates at 
week 16 were 45% and 20% with ADA compared to responses of 2% and 1% in placebo 
subjects, respectively (p<.001 for both comparisons) (1). Additional data from the 
REVEAL study showed that continuous treatment with ADA may be required to maintain 
the therapeutic response; when subjects with PASI 75 response at 33 weeks were 
randomized to placebo or continued ADA therapy, only 5% of the latter group lost 
adequate response (defined as <50% improvement in the PASI response relative to 
baseline and at least a 6-point increase in PASI score from week 33) by week 52 
compared to 28% of subjects randomized to placebo (p<.001) (1). In an open label 
extension of the REVEAL study, ADA efficacy was generally well maintained for over 3 
years in subjects who had a sustained PASI 75 response during the clinical trial (13).  
Although TNF-α antagonists are effective in the treatment of inflammatory diseases, not 
all subjects respond to initial treatment and some may fail to maintain an initial positive 
response with prolonged therapy (8,14). This is particularly evident with infliximab and 
ADA and has been observed in RA, PsA, CD and AS (14,15). The mechanisms behind 
this loss of optimal response are not fully understood but there is evidence that one of the 
contributing factors is the development of antibodies against TNF-α antagonists which 
lower the serum drug concentration to sub-therapeutic levels (8,14,15).  A recent meta-
analysis of studies involving subjects with different immune-mediated inflammatory 
diseases found that antibodies against infliximab and ADA reduced overall drug response 
rates by 68% (8). 


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Antibodies against ADA have been shown to contribute to lower treatment response in 
RA, PsA, CD and AS (8, 14-20). However, information on the relationship between TNF 
inhibitor serum levels, antibodies and clinical response with respect to Ps is limited 
(8,14,15). It is clear that subjects with Ps can develop antibodies against ADA, although 
the actual reported proportions with an immune response is variable, ranging from 6% 
following treatment discontinuation and relapse (21), 8.8% in the pivotal Phase III 
REVEAL clinical trial (1) and 16% and 45% in two prospective observational studies 
(14,22,23). The latter studies showed that trough levels of ADA were positively 
associated with clinical response and were significantly lower in subjects with anti-ADA
antibodies (14,22,23). For example, Lecluse et al. (22) found that in 29 Ps subjects (mean 
PASI at baseline, 15.5; disease duration 22 years; mean number of prior systemic 
therapies, 4.2) who were initiated on ADA, 45% had developed anti-ADA antibodies at 
24 weeks. In these subjects, titers of anti-ADA antibodies were associated with low ADA 
serum levels which in turn correlated with low treatment response (22). A recent study by 
Mahil et al. (14) confirms that antibodies against ADA contribute to a poor treatment 
response in Ps; after 4 weeks, ADA serum levels were significantly higher in clinical 
responders compared to non-responders (p=0.003) and anti-ADA antibodies were 
detected in 25% of non-responders compared to none of the responders (14).
In addition to treatment failure, the presence of anti-TNF antagonist antibodies can lead to 
an increased risk of AEs such as acute or delayed infusion reactions which can decrease 
adherence to treatment regimens and lower treatment response (15).  
Clinical responses to treatment failure in inflammatory diseases include dose escalation, 
concomitant administration of an immunosuppressant, or a switch to a different TNF 
antagonist (24-27). With ADA, dose escalation is accomplished by decreasing the dosing 
interval from two weeks to one week, and with respect to Ps, Leonardi et al. (24) found 
that 26.6% of subjects who initially failed ADA therapy (defined as subjects with a < 
PASI 50 response after 24 weeks) were PASI 75 responders 12 weeks after dose 
escalation. However, dose escalation is associated with increased treatment costs (24) and 


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means weekly injections for patients which may negatively impact patient compliance 
with treatment.
An alternative to dose escalation is the concomitant administration of an 
immunosuppressant such as MTX (8). There is evidence in RA that addition of MTX to 
ADA significantly increases clinical response (25,26). Krieckaert et al. (26) found that RA 
subjects using concomitant MTX developed anti-ADA antibodies less often than subjects 
not using MTX (Odds Ratio (OR) 0.20 (95% CI 0.12, 0.34, p<0.001) (26). Preliminary 
data from van den Reek et al. (27), based on a small number of subjects (n = 11), shows 
that subjects with Ps may also benefit from the addition of MTX to ADA therapy; in 
subjects with an insufficient response to ADA monotherapy (40 mg eow), addition of 
MTX (9.5 mg per week) increased the effectiveness of therapy. 
The present study is designed to provide further information on the impact of adding 
MTX to ADA monotherapy in subjects with Ps who have failed to achieve an optimal 
response to initial ADA therapy or have not maintained an initial positive response to 
treatment. In addition to traditional clinical measures of disease activity, the study also 
incorporates a measure of the Investigator’s satisfaction with treatment response in 
individual subjects, and each subject’s personal level of satisfaction with treatment. This 
outcome measure reflects the most recent Canadian Ps treatment guidelines which 
emphasize “patient-centered Ps care” in real clinical practice and encourage treatment 
choice based not only on a potential effective clinical outcome but also on the subject’s 
preference for a specific treatment (2). As a result, in the current study Investigator and 
subject satisfaction plays an important role both in defining subjects who have “failed” 
ADA monotherapy and in quantifying the response after addition of MTX to ADA 
therapy. In addition, although the clinical impact of addition of MTX to ADA therapy 
may result from a reduction in anti-ADA antibodies, this study focuses on ADA trough 
concentrations as a parameter rather than anti-ADA antibody levels. Measurement of anti-
drug antibodies can be technically challenging and, depending on the assay, serum ADA 
can interfere with antibody measurements in a concentration dependent manner (29), 
complicating interpretation of the data. Because of the potential limitations associated 


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with antibody assays, the present study focuses on ADA serum concentrations and 
changes in levels after addition of MTX to therapy.
3.1
Differences Statement
This study is being conducted to assess the efficacy and safety of combination therapy 
with ADA and MTX in the treatment of Ps. While previous Phase II to Phase IV studies 
have been conducted on the use of ADA monotherapy (usually in combination with 
additional topical therapies) in treatment of Ps, this is one of the first to assess the impact 
of adding MTX to ADA therapy in subjects who have had a sub-optimal response to ADA 
alone. Furthermore, reflecting the most recent Canadian Ps treatment guidelines (2), 
which emphasize patient centered Ps care, this study includes subject and Investigator 
satisfaction with therapy as a primary endpoint, in addition to traditional measures of 
treatment response in Ps. 
3.2
Benefits and Risks
ADA has generated extensive clinical and post-marketing data in a wide range of disease 
states including the dermatological indication of Ps (an approved indication in Canada). 
The safety profile of ADA in this and other approved indications is well established (9).
The Investigator is referred to the current Investigator's Brochure where additional and 
more detailed information regarding potential risks and benefits of ADA can be found. 
The potential benefit of this proposed study in Ps is the demonstration that the addition of 
MTX to ADA therapy is associated with a reduction in symptoms of Ps, an improvement 
in subject quality of life and an increase in satisfaction with therapy in subjects who have 
moderate to severe Ps but who are not responding optimally to ADA therapy alone. As Ps 
is associated with debilitating symptoms and has a substantial quality of life impact, any 
improvement in Ps symptoms with the addition of MTX could directly benefit patients. 
Subjects in the study will have MTX added to their ADA therapy and therefore will have 
the added risk of AEs associated with MTX or the combination of MTX and ADA. The 
Investigator is referred to the current ADA Product Monograph (9) where detailed 


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information is provided on the risks associated with ADA and MTX in the treatment of 
approved indications in Canada are described. Investigators can assume that the risks 
associated with ADA and MTX in currently approved indications for inflammatory 
diseases can also be expected in the treatment of Ps. In addition, Investigators are referred 
to the Product Monograph for MTX for additional information on the risks associated 
with use of this immunosuppressant.
3.3
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-D but not to lymphotoxin-D (TNF-E). 
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.
3.4
Safety Information
ADA 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 rheumatoid arthritis. A detailed discussion of the pre-
clinical toxicology, metabolism, pharmacology and safety experience with ADA can be 


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found in the current Investigator's Brochure. AbbVie is committed to continue to collect 
safety information including those events that may occur in this trial in order to confirm 
this established safety profile and to identify any unknown potential adverse reactions, 
rare events and those events with a long latency. AbbVie is participating in an FDA-
requested, TNF inhibitor class wide exploration of the rare appearance of malignancy in 
patients who are 30 years of age or younger at the time of diagnosis. The risk of 
malignancy in this age group has not been established and is difficult to study due to its 
rarity. AbbVie appreciates your attention to the additional reporting requirements needed 
in this unlikely event, outlined in Section 6.1.5 under Adverse Event Reporting.
4.0
Study Objective
4.1
Primary objective
To determine the proportion of primary and secondary sub-optimal responders to ADA 
monotherapy3 (sub-optimal responders defined as subjects with an unsatisfactory response 
to treatment based on Investigator assessment4) with a PGA > 3 and a PASI > 5 who have 
a satisfactory response after 16 weeks of treatment with ADA/MTX combination therapy, 
based on Investigator and subject satisfaction assessments.
4.2
Secondary objectives
x
To determine the proportion of primary and secondary sub-optimal responders to 
ADA monotherapy (sub-optimal responders defined as subjects with an 
unsatisfactory response to treatment based on Investigator assessment) with a PGA 
> 3 and a PASI > 5 who reach PASI 50, PASI 75 and PASI 90 16 weeks after 
initiation of ADA/MTX combination therapy;
x
To define the demographic and clinical profile of subjects benefiting from 
ADA/MTX combination therapy;
x
To determine the magnitude, timing and maintenance of the benefit of adding MTX 
to ADA by assessing Investigator/subject satisfaction with treatment, PGA, PASI 
3 Note that subjects may also be receiving topical treatments if they were prescribed prior to enrolment in this study
4 Investigator assessment based on a questionnaire response; see Satisfaction questionnaire section


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and Dermatology Life Quality Index (DLQI) at 8, 16 and 24 weeks after addition of 
MTX to therapy;
x
To determine change in DLQI from baseline in subjects initiated on ADA/MTX 
treatment;
x
To determine change in serum levels of ADA following addition of MTX and to 
characterize a possible correlation with changes in Investigator/subject satisfaction 
with treatment, PGA, PASI and DLQI over the study period. Serum levels will be 
evaluated at baseline (initiation of ADA+MTX) and at weeks 8, 16 and 24.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a multicenter, single arm, open label longitudinal study. The study entails a -
screening period up to 35 days, a 24-week treatment period and a 70-day safety follow-up 
period. Subjects, who in the opinion of the Investigator are not responding optimally to 
ADA monotherapy (40 mg eow or greater) at least 16 weeks after initiating treatment
(primary sub-optimal responder) or who, after an initial positive response to ADA 
monotherapy (40 mg eow or greater) have failed to maintain an optimal level of response
(secondary sub-optimal responders) (sub-optimal responders defined as subjects with an 
unsatisfactory response to treatment based on Investigator assessment) and who have a
PGA score of > 3 and a PASI of > 5 will be potentially eligible for participation in the 
study. 
For potential subjects on ADA 40 mg once weekly, the Investigator will arrange a pre-
screening visit to discuss treatment status with the subject and outline the proposed study 
with the understanding that the subject must meet all inclusion criteria before 
participation. If the potential subjects signed the consent form, they will start the washout 
period and the subjects will be eligible for the screening visit after 8 weeks on ADA 40 
mg eow.
If subjects provide written consent, they will then complete a satisfaction questionnaire 
(Appendix C), and PGA and PASI status will be determined at a screening visit and 
inclusion/exclusion criteria will be assessed. In addition to the Investigator assessment of 


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sub-optimal response to current ADA monotherapy, subjects eligible for participation in 
the study must have a PGA score of > 3 and a PASI of > 5. Data collected at a screening 
visit will include: subject demographics, disease history, comorbidities, vital signs, 
laboratory investigations and PGA, PASI and DLQI scores. Starting at the baseline visit
(Day 0), subjects will continue to self-administer ADA (40 mg eow) and will have oral 
MTX added to their treatment at a dose to be defined by the Investigator (between 10 mg 
and 25 mg per week). All subjects will also receive the non-investigational medicinal 
product oral folic acid as a dietary supplement since MTX acts as a folic acid antagonist. 
The folic acid tablets will be provided by the Investigator at a dose of 1.0 mg per day. 
The required folic acid dose must be taken every day of the week except on the day when 
MTX is taken. The Investigator will provide specific instructions on the number of folic 
acid tablets each subject should take. 
In the event a subject forgets to take the tablets or takes more or less than is required, they
will be instructed to contact the Investigator for guidance. Unused folic acid tablets should 
be returned to the investigative site and accounted for to assess subject’s compliance.
At site visits 8, 16 and 24 weeks after initiation of ADA/MTX, the following parameters 
will be assessed: Investigator assessment of disease status (using a satisfaction 
questionnaire); subject self-assessment of disease status (using a satisfaction 
questionnaire); PGA; PASI; DLQI; AEs; serum levels of ADA. A schematic of the study 
design is shown in Figure 1.
The 70-day safety follow-up period begins from the last dose of ADA. Subjects will be 
discontinued from the study if they withdraw consent or if they are deemed unsuitable to 
continue for any reason by the Investigator in consultation with the AbbVie Medical 
Monitor.


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Figure 1:
Study Design Schematic
The study was designed to enroll 50 subjects to meet scientific objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target number of subjects has been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.


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5.2
Selection of Study Population
5.2.1
Inclusion Criteria
1. Subjects who have been on ADA monotherapy (40 mg eow or greater) for at least 
16 weeks but, who in the opinion of the Investigator, have shown a sub-optimal 
response to treatment (sub-optimal response defined as subjects with an 
unsatisfactory response to treatment, based on Investigator assessment) and have a 
PGA of > 3 and a PASI of > 5; or
Subjects who after an initial positive response to ADA monotherapy (40 mg eow or 
greater) have failed to maintain an optimal level of response, based on the opinion of 
the Investigator (sub-optimal response defined as subjects with an unsatisfactory 
response to treatment based on Investigator assessment) and have a PGA of > 3 and 
a PASI of > 5;
2. Subjects who are receiving 40 mg ADA once weekly must be on ADA 40 mg eow 
for 8 weeks prior to screening;
3. Subjects with at least a 6 month history of chronic plaque Ps;
4. Subjects greater than or equal to 18 years of age;
5. If female, subject is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral 
oophorectomy or hysterectomy) or is of childbearing potential and is practicing one 
of the following methods of birth control throughout the study and for 150 days after 
the last dose of study drug:
x
Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD);
x
Contraceptives (oral, parenteral, transdermal) for three months prior to study 
drug administration;
x
A vasectomized partner.
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 150 days after the last dose of 
study drug to practice the protocol specified contraception (Section 5.2.4).
6. The results of the serum pregnancy test performed during the Screening Period and 
urine pregnancy test performed at the Baseline Visit must be negative for females of
childbearing potential;


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7. Subject is judged to be in good general health as determined by the Investigator
based upon the results of medical history, laboratory profile, physical examination, 
chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed during
Screening;
8. Subjects must be evaluated for latent TB infection with a purified protein derivative 
(PPD) test or QuantiFERON-TB test and chest X-ray. For this protocol, evidence of 
latent TB infection is defined as an induration (not erythema) of 5 mm or greater, 
48-72 hrs after placement or a positive QuantiFERON-TB test result.  Subjects who 
demonstrate evidence of latent TB infection, irrespective of Bacille Calmette -
Guérin (BCG) vaccination status, and negative CXR findings for active TB and/or 
suspicious CXR findings, will be allowed to participate in the study provided that 
one of the following conditions are satisfied;
x
Prophylactic treatment is initiated at least two weeks prior to administration of 
study drug; however the course of prophylaxis does not need to be completed 
prior to the onset of study drug. Prophylactic treatment will be according to the 
United States Centers for Disease Control [CDC] recommended preventive 
therapy for TB or per local guidelines. Prophylactic treatment should be captured 
on the concomitant medications page in the CRF and in the source documents
x
Subject has documented completion of a full course of TB prophylaxis
9. Subjects must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol;
10. Subjects must be willing and able to self-administer subcutaneous (SC) injections or 
have a qualified person available to administer SC injections.
These inclusion criteria reflect the subject population necessary to fulfill the study design. 
In particular, the criteria mean that subjects showing a sub-optimal response to ADA
monotherapy, based primarily on Investigator assessment, will be recruited for the study. 
To expand the potential subject pool, the inclusion criteria include primary and secondary 
sub-optimal responders to ADA therapy and includes subjects who are receiving more 
than 40 mg ADA eow (i.e., 40 mg once weekly). However, in the latter case, subjects 
must be on ADA 40 mg eow for at least 8 weeks prior to screening. This wash-out phase 
should begin after subject consent.


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5.2.2
Exclusion Criteria
1. Subject has any contraindications to MTX or ADA;
2. Subject has a previous failed response or poor tolerance to ADA;
3. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, 
unstable heart disease, congestive heart failure, recent cerebrovascular accidents and 
any other condition which, in the opinion of the Investigator, would put the subject 
at risk by participation in the study;
4. Subject has a history of clinically significant hematologic (e.g., severe anemia, 
leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis, 
hepatitis);
5. Subject has history of neurologic symptoms suggestive of central nervous system 
(CNS) demyelinating disease and/or diagnosis of central demyelinating disease;
6. Subject has evidence of dysplasia or history of malignancy (including lymphoma 
and leukemia) other than a successfully treated non-metastatic cutaneous squamous 
cell or basal cell carcinoma or localized carcinoma in situ of the cervix;
7. Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic 
infections, or recent active infections requiring hospitalization or treatment with 
intravenous (iv) anti-infectives within 30 days or oral anti-infectives within 14 days 
prior to the Baseline visit;
8. Subject is known to have immune deficiency, history of HIV or is 
immunocompromised;
9. Subject currently uses or plans to use anti-retroviral therapy at any time during the 
study;
10. Female subject who is pregnant or breast-feeding or considering becoming pregnant 
during the study or for 150 days after the last dose of study medications;
11. Subject has a history of clinically significant drug or alcohol usage in the last year
(12 months) or cannot maintain an alcohol intake of 30 g a day or less throughout 
the study.  One standard drink is defined as 180 mL/6 oz (approx. 10 g) of wine, 360 
mL/12 oz (approx. 15 g) of regular beer, or 45 mL/1.5 oz (approx. 10 g) of spirits;
12. Screening clinical laboratory analyses show any of the following abnormal 
laboratory results:  
x
Aspartate transaminase (AST) or alanine transaminase (ALT) >2x the upper 
limit of normal (ULN);


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x
Serum total bilirubin > 1.5 mg/dL (> 26 micromol/L), except for subjects with 
Gilbert’s Syndrome;
x
Creatinine > 1.5 mg/dL (133 micromol/L) in subjects ≤65 years old and > ULN
range in subjects > 65;
x
Positive Hepatitis B or C serology indicative of previous or current infection.
13. Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study;
14. The following treatments are prohibited for all subjects during the study:
x
Phototherapy (PUVA (within 4 weeks of the baseline visit) and/or UVB (within 
2 weeks of the baseline visit));
x
Other biologic therapies (including any other anti-TNF) within 4 weeks of the 
baseline visit (except for ADA);
x
Any investigational agents of chemical or biologic nature within a minimum of 
30 days or 5 half-lives (whichever is longer) of the drug prior to the Baseline 
visit;
x
Any other systemic drug therapies for Ps, including cyclosporine, retinoids, and 
fumaric acid esters, within 4 weeks of the baseline visit;
x
Oral or injectable corticosteroids, new prescription topical therapies (including 
shampoos with corticosteroids), or changes in the concentration of current 
prescription of topical therapies (including corticosteroids) that are being used,
within 2 weeks of the baseline visit. However, subjects may continue using 
previously prescribed topical therapies (including corticosteroids) during the 
study. Inhaled corticosteroids are allowed. .
15. Prior exposure to biologics that have a potential or known association with PML 
(i.e., natalizumab (Tysabri®) or rituximab (Rituxan®);
16. Subjects with any active viral infection that based on the investigator’s clinical 
assessment makes the subject an unsuitable candidate for the study.
17. Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 150 days after the last dose of study drug.
These criteria reflect the usual exclusion criteria in Phase III studies assessing ADA and 
MTX in the treatment of Ps.


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5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of screening,
or receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.
The AbbVie Medical Monitor identified in Section 6.1.5 should be contacted if there are 
any questions regarding concomitant or prior therapy(ies).
In addition, for subjects age ≤ 30 with a reported malignancy event during the study, prior
exposure to, or current use of, antineoplastics, or other drugs which have a risk of
malignancy as stated in their label, and other relevant dosing information to estimate total
exposure, will be collected in the source documents and appropriate eCRF pages. At the
time of the reported malignancy AE, sites will be asked if any of the prior and
concomitant medications contributed to the event. Any medications used prior to the study 
will be captured on the appropriate eCRF. Information on the reason for use, date(s) of 
administration including start and end dates, highest maintained dose, dosage information 
including dose, route and frequency, and reason for stopping the medication will be 
collected in the source documents and appropriate eCRF pages.
5.2.3.1
Prior Therapy
Anti-Ps systemic therapy and phototherapy treatment since initial diagnosis and topical 
therapies since the last six months prior to Screening (as determined through medical 
history records or through subject interview), and any administered treatments within the 
past 28 days prior to Screening should also be recorded on the appropriate CRF.
Each vaccine administered to the subject within 28 days prior to screening should be 
listed as a concomitant medication. Live vaccines are prohibited (Section 5.2.3.3).


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For subjects previously treated with biologics e.g., etanercept, and/or infliximab, the 
duration of therapy, maximum dose, reason for use and reason(s) for termination of 
treatment with these products should be documented.
5.2.3.2
Concomitant Therapy
Any medication, including vaccines, the subject receives during the study (and within 28 
days of the Screening visit) should be recorded. Subjects may continue using previously 
prescribed topical therapies (including corticosteroids) during the study. However, 
application of these topical therapies for Ps should not occur within 24 hours of a study 
visit so as not to interfere with clinical assessments for Ps.
All subjects in the study will be taking oral MTX (between 10 mg and 25 mg per week) 
and should also take a dietary supplement of oral folic acid every day, except on the day 
the subject is taking MTX over the study period.
For subjects who require isoniazid (INH) for TB prophylaxis, consideration should be 
given to administer pyridoxine (Vitamin B6) to prevent peripheral neuropathy.
5.2.3.3
Prohibited Therapy
The following treatments are prohibited for all subjects during the study:
x
Phototherapy (PUVA and/or UVB): UVB within 2 weeks of the baseline visit and 
PUVA phototherapy within 4 weeks of the baseline visit;
x
Other systemic therapies for Ps, PsA and nail Ps (excluding MTX), including 
cyclosporine, retinoids and fumaric acid esters, within 4 weeks of the baseline visit;
x
Oral or injectable corticosteroids and new prescription topical therapies, including 
shampoos with corticosteroids
or changes in the concentration of current
prescription topical therapies (including corticosteroids) that are being used, within 
2 weeks of the baseline visit. However, subjects may continue using previously 
prescribed topical therapies (including corticosteroids) during the study.
All 


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biologic therapies that would have a potential impact on Ps including but not limited 
to the following:
o
Remicade (infliximab)
o
Enbrel (etanercept)
o
Tysabri (natalizumab)
o
Kineret (anakinra)
o
Rituxan (rituximab)
o
Actemra (tocilizumab)
o
Cimzia (certolizumab)
o
Benlysta (belimumab)
o
Simponi (golimumab)
o
Orencia (abatacept)
o
Stelara (ustekinumab)
x
Live vaccines (during the study and for 70 days after the last dose of study drugs) 
(including but not limited to the following: monovalent live attenuated influenza A 
(H1N1) [intranasal], seasonal trivalent live attenuated influenza (intranasal), herpes 
zoster, rotavirus, varicella (chicken pox), measles-mumps-rubella (MMR) or 
measles-mumps-rubella-varicella (MMRV), oral polio vaccine (OPV), smallpox, 
yellow fever, Bacillus Calmette-Guerin (BCG) or typhoid);
x
Any investigational agents.
Contact the AbbVie Medical Monitor identified in Section 6.1.5 if there are any questions 
regarding prohibited therapy (ies).
5.2.3.4
Rescue Therapy
There are no rescue therapy protocols for this study.


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5.2.4
Contraception Recommendations and Pregnancy Testing
For female subjects:
●
If female, subject must be either 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.
OR
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
●
Practicing at least one of the following methods of birth control, on Study 
Day 1 (or earlier) through at least 150 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 3 month prior to Study Day 1.
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 3 month prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation.
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the WOCBP trial participant.
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
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).
For male subjects:
If the male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.


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If the male subject is sexually active with female partner(s) of childbearing potential, he 
must agree from Study Day 1 through 150 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 150 days after the last dose of study drug.
5.3
Efficacy, Pharmacokinetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Safety data will be collected in the form of AEs, vital signs, physical examination results, 
and clinical laboratory tests throughout the treatment period. AEs will be collected for all 
subjects up to 70 days after the last study drug injection of ADA, or until the subject 
begins use of commercial ADA, whichever comes first.
The visit window for all scheduled study visits is ± 3 days for all visits following the
Baseline study visit. If a subject has an out of window visit, the next visit should occur as
originally scheduled based on the first date of study drug administration (Baseline visit).
All study data will be recorded in the source documents and on the appropriate eCRF. 
Study procedures will be performed as summarized in the visit schedule presented in
Table 1.


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Table 1.
Study Activities
Activity
Pre-
screening
( >Day -35)
Screening
(Day -35 to 
– 3)
Day –0/
Baselinet
Week
8
+/- 3
days
Week
16
+/- 3
days
Week
24/ET
+/- 3
days
70-Day 
F/Ua
Unsch.
Visitb
Satisfaction questionnaire-
Investigator
X
X
X
X
Informed Consent
Xc
X
Inclusion/Exclusion criteria
X
X
Medical and Surgical History
X
X
Alcohol and Nicotine Use
X
Physical Examd
X
X
X
X
X
X
12-Lead ECG
Xe
Chest X-Ray
Xf
TB testing
Xg, h
Vital Signs/Weight/Heighti, j
X
X
X
X
X
Xk
Concomitant medication
X
X
X
X
X
Hematology
X
Xl
X
X
X
Chemistry
X
Xl
X
X
X
Urinalysis
X
Xl
X
X
X
HBV and HCV screening
X
HIV
Xm
Pregnancy Test
Xn
Xo
Xo
Xo
Xo


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ANA/dsDNA
X
Serum samples for PK (ADA)
X
X
X
X
Hs-CRP
X
X
ADA wash-out (for subjects on 
ADA 40 mg once weekly)p
X
Satisfaction questionnaire-
Subject
X
X
X
X
PASI evaluation
X
X
X
X
X
Physicians Global Assessment 
of Ps (PGA)
X
X
X
X
X
DLQI
X
X
X
X
X
Body Surface Area (BSA)
X
X
X
X
X
Monitor Adverse Events q, r
X
X
X
X
X
Dispense Study Drugss
X
X
X
Perform drug accountability
X
X
X
Subject dosing diary dispensing
X
Subject dosing diary review
X
X
X
a.
Subjects will be contacted approximately 70 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects that continue on
ADA therapy after the end of study participation.
b.
If an unscheduled visit falls within 7 days of the next planned visit, and if all the required procedures of the planned visit are performed, the unscheduled visit accounts for the 
planned visit.  The CRF for the planned visit should be completed.
c.
Only for subjects requiring an ADA washout period.
d.
A full physical examination should be performed at Screening, Baseline and the Week 24 visits. A symptom directed physical examination should be performed at all other 
visits if, in the opinion of the Investigator, it is warranted
e.
ECG will not be required if normal ECG has been taken within 90 days of the Screening visit and documentation is available


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f.
A chest X-ray will not be required if the subject had a previous normal X-ray within 90 days prior to Screening (and films with required report results are available)
g.
PPD or an IGRA test (QuantiFERON-TB Gold In-Tube test or T-SPOT TB test) will be performed and assessed locally, when available, at Screening
h.
If a subject had a negative PPD or IGRA test within 90 days prior to Screening, and all protocol required documentation is available, this test does not need to be repeated.
Subjects who have had an ulcerating reaction to tuberculin skin or IGRA test in the past should not be re-exposed and should not be tested. Those subjects with a positive PPD 
history do not need to be tested, but must have had a documented full course of prophylactic treatment or must begin and have taken at least two weeks of prophylactic
treatment prior to first study drug administration. Prophylaxis may also be initiated if a subject has significant exposure to a patient with active TB
i.
Vital sign determinations include sitting blood pressure, heart rate, respiratory rate, and body temperature
j.
Height will only be measured at the Baseline visit
k.
Only the vital signs are required at an unscheduled visit
l.
Laboratory assessments will only need to be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if the subject's health status has
changed to warrant a repeat test
m.
Documentation from the physician that the subjects are not known to be HIV positive, or at risk for HIV risk factors, will be sufficient. HIV testing is not required unless, in 
the opinion of the Investigator, it is warranted. A subject will not be eligible for study participation if documentation indicates a positive HIV infection. AbbVie will not 
receive results from any HIV testing and will not be made aware of any positive result
n.
All females of childbearing potential will have a serum pregnancy test at Screening
o.
All females of childbearing potential will have a urine sample performed locally at Baseline prior to study enrollment, at week 8, 16 and study discontinuation/completion.
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
p.
Wash out procedure for subjects on 40 mg once weekly; these subjects should be started on ADA 40 mg eow for at least 8 weeks prior to study enrollment
q.
All AEs reported from the time of study drug administration until 70 days following last study drug injection will be collected
r.
SAEs will be collected from the time the subject signed the study-specific informed consent form until 70 days following last study drug injection
s.
Last dose of MTX will be taken on Week 23 and last dose of ADA will be taken at Week 22. Drugs will not be dispensed at Week 24
t.
Subjects should continue to receive adalimumab every other week during the screening period (if applicable) and the Baseline visit should coincide with the next planned dose 
of ADA.


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5.3.1.1
Study Procedures
The study procedures as specified in Table 1 are discussed in detail in this section. All 
study data are to be recorded in the source documents and transcribed onto the appropriate 
eCRF. 
Subjects that initially screen fail for the study may be permitted to re-screen only one time 
following re-consent. All screening procedures with the possible exceptions noted below 
will be repeated. The subject must meet all inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study. There is no minimum period of 
time a subject must wait to re-screen for the study. If the subject had a complete initial 
screening evaluation including the assessment of a PPD test or a QuantiFERON-TB Gold 
test ,Chest x-ray and ECG, these tests will not be required to be repeated for re-screening 
provided the conditions noted in Section 5.2 are met and no more than 3 months (90 days) 
have passed. As appropriate, sites are encouraged to contact the AbbVie Medical Monitor 
to confirm if subjects should or should not be re-screened.
Informed Consent
A signed informed consent will be obtained from the subject or their legally authorized 
representative before any study-related procedures are undertaken (including completion 
of the satisfaction questionnaire), or before any medications are withheld from the subject 
in order to participate in this study. Details about how informed consent will be obtained 
and documented are provided in Section 9.3.
Inclusion/Exclusion Criteria
Subjects will be eligible for study enrollment if he/she meets all inclusion criteria and 
none of the exclusion criteria at the Screening and Baseline visits.
Medical and Surgical History


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A complete non-Ps related medical and surgical history, as well as a history of alcohol 
use, will be obtained from each subject during the Screening Visit. Whenever possible, 
the subject’s medical chart will be obtained from the family physician or the referring 
physician. In addition, a list of each subject’s specific Ps related medical and surgical 
history should be recorded at Screening. An updated medical history will be obtained 
prior to study drug administration at Baseline and updated as necessary throughout the 
study.
A detailed medical history with respect to TB exposure needs to be documented. This
information should include BCG vaccination, cohabitation with individuals who have had 
TB, and/or who reside or work in TB endemic locations.
Concomitant Medication
All concomitant medications and treatments are to be recorded in the appropriate eCRF as 
outlined in Section 5.2.3.
Physical Examination
A full physical exam will be performed at the designated study visits as described in Table 
1. A symptom-directed physical examination should be performed at all visits if, in the 
opinion of the Investigator, it is warranted by the subject's AE status or upon review of 
symptoms. Physical exam abnormalities noted by the Investigator at Baseline prior to the 
first dose of study medication should be recorded in the subject's medical history. 
Abnormalities noted after the Baseline visit and first dose of the study medications should 
be evaluated and documented by the Investigator as to whether or not these are AEs. All 
physical examination findings, whether related to an AE or part of each subject's medical 
history, should be captured on the appropriate eCRF page.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the screening visit. A qualified physician will 
interpret, sign, and date each ECG. Any clinically significant findings will be documented 


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in the source documents and later transcribed on to the appropriate eCRF. Each signed 
original ECG will be monitored by the responsible Clinical Research Associate (CRA) 
and kept with the subject's source documentation 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 Medical Monitor
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).
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 Principal 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 Principal Investigator or their delegate must indicate the 
presence or absence of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) 
signs of active TB. 
A PPD skin test (alternatively, also known as tuberculin skin test) must be placed or a
QuantiFERON-TB Gold 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 test or QuantiFERON-TB Gold test within 
90 days prior to Screening, and all protocol required documentation is available, the test 


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does not need to be repeated, provided nothing has changed in the subject's medical 
history to warrant a repeat test. These cases must be discussed with the Medical Monitor
For the PPD test:
The subject will be required to have the PPD test read by a licensed healthcare
professional 48 to 72 hours (or according to manufacturer's guide) after placement, when 
the induration is maximal. An induration (not erythema) of 5 mm or greater will be 
considered as PPD positive, irrespective of BCG status or local guidelines.
The induration must be recorded in mm not as positive or negative. The absence of 
induration should be recorded, as "0 mm," not "negative." A two-step test may be 
performed if required 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 tuberculin 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.
A radiologist must perform an assessment of the CXR. The Principal 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 Principal 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 the CXR demonstrates changes suggestive of previous TB (e.g., 
calcified nodule, fibrotic scar, apical or basilar pleural thickening) or other findings that 
are clinically significant, the Principal Investigator must contact the AbbVie Medical 
Monitor before enrolling the subject.
If PPD or QuantiFERON-TB Gold testis 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 Centers for Disease Control 


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(CDC) recommended prophylaxis or prophylaxis per local guidelines prior to starting 
study therapy.
Subjects with a prior history of latent TB that have a documented completion of the CDC
recommended or local guideline recommended prophylaxis may be permitted to enroll. If
the subject has a prior history of latent TB but has not completed or received prophylaxis,
prophylaxis must be initiated for at least 2 weeks (or per local guidelines, whichever is
longer) before enrolling into the study.
If the subject has a prior history of active TB they must have documentation of
completion of CDC recommended or local guideline recommended treatment and
documentation of resolution of the infection.
In the event both a PPD test and QuantiFERON-TB Gold test are performed, the result of 
the QuantiFERON-TB Gold test test will supersede the result of the PPD test. If the 
QuantiFERON-TB Gold test test is indeterminate, the site should repeat the test with 
another 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.
Under no circumstances can a subject with a positive PPD result and no prior history of 
treatment for active or latent TB be allowed into this trial.
Vital Signs/Weight/Height
Vital sign determinations of sitting blood pressure, heart rate, respiratory rate, and body
temperature will be obtained at each visit. Weight will be obtained at each visit.  Subject's 
height will be measured at the Baseline visit only. All measurements will be recorded in 
metric units where applicable.


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Satisfaction with Treatment Evaluation
Satisfaction with treatment will be assessed using a questionnaire similar to one 
developed by Christophers et al (28) for quantifying physician and Ps subject satisfaction 
with biologic therapy. In this study, dermatologists and subjects were surveyed regarding 
their satisfaction with therapy using the following questions:
Dermatologist survey question:  Overall, at this point in time, how satisfied are you with 
the Ps control provided by the subject’s current treatment regimen?
Subject survey question:  Overall, how satisfied are you with your current treatment for 
Ps?
The same questions will be used in the present study. The response choices provided will 
be:
x
Completely dissatisfied
x
Moderately dissatisfied
x
Slightly satisfied
x
Highly satisfied
x
Completely satisfied
Within the context of the study, Investigators indicating complete or moderate 
dissatisfaction with treatment will be combined to indicate subjects eligible for the study 
during screening (i.e., subjects with a sub-optimal response to ADA). Satisfaction with 
therapy will be defined by the combination of highly or completely satisfied responses. 
The questionnaires will be administered during screening and after 8, 16 and 24 weeks of 
ADA/MTX. Additional details of the questionnaire structure are provided in Appendix C.
Psoriasis Area and Severity Index (PASI) Evaluation
A qualified physician or qualified designee will perform the PASI assessment at the 
designated study visits identified in Table 1. The site will make every attempt to have the 
same investigator or qualified designee perform this assessment throughout the study for 


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each subject.
All raw data used to determine the PASI will be documented on a 
worksheet and transcribed onto the appropriate eCRF. The PASI worksheets will be kept 
by the site in the subject's source documentation. Information and instructions on the 
calculation of the PASI score are provided in Appendix D. AbbVie will provide training 
for any Investigator or qualified designee who has not previously performed the PASI 
assessment.
Physician’s Global Assessment (PGA) of Ps
The PGA is a 6-point scale used to measure the severity of a subject's Ps. The Investigator
or qualified designee will perform a PGA of Ps (Appendix E) at the designated study 
visits identified in Table 1.
The site will make every attempt to have the same 
investigator or qualified designee perform this assessment throughout the study for each 
subject.  


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Dermatology Life Quality Index (DLQI)30
Subjects will complete the DLQI at Baseline and Weeks 8, 16 and 24. Details of the 
DLQI are provided in Appendix F.
Body Surface Area Affected by Ps
Body surface area affected by Ps will be measured at the designated study visits indicated 
in Table 1. The subject's hand should be used 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%. Measurement of the total area of involvement by the 
Investigator or qualified designee is aided by imagining if scattered plaques were moved 
so that they were next to each other and then estimating the total area involved. The site 
will make every attempt to have the same investigator or qualified designee perform this 
assessment throughout the study for each subject.  
Clinical Laboratory Tests
For this study, Investigators will use a central laboratory for all laboratory tests and should 
follow the instructions regarding processing and shipment of samples provided by the 
laboratory and AbbVie.
Blood and urine samples will be obtained for clinical laboratory tests. When blood draws 
are performed as part of a clinic visit, the draws should be performed after completion of 
questionnaires and vital sign measurement, and before study drug administration. Blood 
specimens for hematology and chemistry will be obtained at Screening, Baseline and 
Weeks 8, 16 and 24 study visits. Blood specimens will also be drawn at the same visits for 
analysis of ADA serum concentrations; in this case it is particularly important that blood 
samples be drawn before administration of ADA.
Urine samples will be obtained for urinalysis testing at Screening, Baseline, and Weeks 8, 
16, and 24. The central laboratory should perform a macroscopic urinalysis (urine 
dipstick) on the collected urine specimens. Specified abnormal macroscopic urinalyses 


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defined as leukocytes, nitrite, protein, ketones or blood greater than negative, or glucose 
greater than normal should be followed up with a microscopic analysis at the central 
laboratory.
All required clinical laboratory tests are outlined in Table 2.
Table 2.
Clinical Laboratory Tests
Chemistry
Hematology
Urinalysis
Quantiferon 
TB Gold
Other
Albumin
Alkaline
Phosphatase
ALT
AST
Calcium
Cholesterol
Creatinine, 
Enzymatic
Glucose, Random, 
Serum
Phosphate
Potassium
Sodium
Total Bilirubin
Total Protein
Triglycerides
Urea (BUN)
Uric Acid
Basophils
Eosinophils
HCT
HGB
Lymphocytes
Monocytes
Neutrophils
Platelets
RBC
WBC
Blood
Glucose, Urine
Ketones
Leukocytes
Nitrite
pH
Protein, Urine
Specific Gravity
Urine Microscopic
Quantiferon Mit. 
minus NIL
Quantiferon NIL
Quantiferon TB 
Gold
Quantiferon TB 
minus NIL
ANA Pattern
Anti-ds DNA
Antinuclear 
Antibody
C-Reactive Protein, 
HS
HBV DNA PCR 
Taqman
HCG, Quantitative
Hep B Core Ab
Hep B Surface Ab
Hep B Surface Ag
HIV 1 & 2 EIA Ab 
Screen
Hep C Ab Screen
Hepatitis B and Hepatitis C Testing
All subjects will be tested for the presence of the Hepatitis C Virus (HCV) and Hepatitis 
B Virus (HBV) at Screening. A positive result for Hepatitis C and/or 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 


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exclusionary. Also, subjects showing a positive HBc Ab Total test, indicating a previous 
Hep B exposure, will be excluded due to risk of reactivation or worsening of hepatitis B 
with MTX.
Subjects with a negative HBs Ag test and tests showing the results below, do not require 
HBV DNA PCR qualitative testing. 
x
HBc Ab Total (-) and HBs Ab (-)
x
HBc Ab Total (-) and HBs Ab (+) 
x
HBc Ab Total (+) and HBs Ab (+)  
Human Immunodeficiency Virus (HIV) Testing
Documentation from the physician that subjects are not known to be HIV positive or do 
not have a high risk for HIV infection will be sufficient for this study. Details of this 
documentation should be recorded in the eCRF. However, in the absence of such 
documentation subjects should be tested for antibodies to HIV at Screening, and test 
results documented. A subject will not be eligible for study participation if test results 
indicate a positive HIV infection. AbbVie will not receive results from any testing and 
will not be made aware of any positive result.
Immunologic Laboratory Testing
High sensitivity C-reactive protein (hs-CRP), antinuclear antibody (ANA) and anti-
double-stranded DNA (anti-dsDNA) assessments will be performed in a central laboratory 
as indicated in Table 1.
Pregnancy Tests
A serum pregnancy test will be performed at the Screening visit on all female subjects of
childbearing potential. At the Baseline visit, as well as at week 8, 16 and 24, subjects of 
childbearing potential will have a urine pregnancy test performed locally by designated 
study personnel. If any urine pregnancy test is positive, a serum pregnancy test will be 


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performed. A lactating or pregnant female will not be eligible for participation or 
continuation in this study.
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined above) at Screening do not require pregnancy testing.
Pharmacokinetic (PK)/serum ADA Sampling
Blood collection will be performed prior to medication dosing according to the visit 
schedule outlined in Table 1. Refer to Section 5.3.2 for sample collection and handling 
instructions.
Subject Enrollment 
All Screening laboratory results must be reviewed, signed and dated by the Principal 
Investigator or Sub-Investigator at each site prior to the Baseline visit. Subjects will not be 
enrolled into the study if laboratory or other Screening result abnormalities are deemed 
clinically significant by the Principal Investigator or sub-Investigator.
Subjects should continue to receive adalimumab every other week during the screening 
period (if applicable) and the Baseline visit should coincide with the next planned dose of 
ADA.
Adverse Events
AEs will be assessed at every study visit from the first dose of study medication through 
to Week 24 study visit, and during the 70-day safety phone call after the last dose of ADA
(or until the subject begins use of commercially available ADA, whichever comes first). 
In addition, all serious adverse events (SAEs) will be captured from the time the subject 
signs the Informed Consent Form through study completion or Premature Discontinuation 
and at the 70-day safety follow-up. Any new AEs/SAEs reported during the 70-day 
follow-up period should be submitted to AbbVie. The 70-day safety follow-up phone call 


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will be recorded in source documents only and confirmation of the contact will be faxed 
to AbbVie (Refer to Section 5.4.1 and Appendix G for additional information).
ADA Wash-Out 
This is restricted to potentially eligible subjects who on identification by the Investigator,
are receiving ADA at a dose of 40 mg once weekly. These subjects should be initiated on 
ADA 40 mg eow for at least 8 weeks prior to screening. Documentation on date of 
initiation of wash-out and confirmation of all additional inclusion criteria must be 
recorded in the eCRF.
Study Medication Dispensing
ADA and MTX will be dispensed to subjects beginning at Baseline, at Weeks 8 and 16; 
no study medications will be dispensed at Week 24. Refer to Section 5.5 for additional 
information.
Subject Dosing Diary
All subjects will be given a subject dosing diary to record all ADA injection dates and 
times and MTX weekly dosing schedules. Subjects should also record missed ADA and 
MTX doses in their dosing diary.
Unscheduled Visit
If required, an unscheduled visit can be performed according to the visit schedule outlined 
in Table 1. If the unscheduled visit falls within 7 days of the next planned visit, and if all 
the required procedures of the planned visit are performed, the unscheduled visit accounts 
for the planned visit.  The CRF for the planned visit should be completed.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for the measurement of serum ADA concentrations will be collected at 
Baseline, Weeks 8, 16 and 24. Blood samples should be drawn prior to administration of 
both ADA and MTX.
5.3.2.2
Handling/Processing of Samples
The blood samples for PK measurements will be centrifuged within 60 minutes of
collection to separate the serum. The serum samples will be transferred using sterile
plastic pipettes into screw-capped polypropylene vials labeled with the study drug
number, protocol number, subject number, and study week. The serum samples will be 
frozen within 2 hours after collection and will remain frozen in a –20°C or colder freezer
after collection until shipment. Sites that do not have access to a –20°C or colder freezer
must ship the samples the day they are collected.
Sample collection and handling instructions will be provided by the central laboratory to 
the investigative sites.
5.3.2.3
Disposition of Samples
The frozen serum samples will be packed in dry ice (pellet form) sufficient to last 3 days
during transport. Samples will be shipped pursuant to instructions from the central
laboratory. An inventory of the samples will be included in the package for shipment. The 
investigative site will need to identify a dry ice source and will be responsible for
purchasing the necessary amount of dry ice for shipment of frozen samples. Shipping kits 
for the samples will be provided by the central laboratory.
Arrangements will be made with the central laboratory for the transfer of samples.


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5.3.2.4
Measurement Methods
Serum concentrations of ADA will be determined using a validated assay method. All 
methods will be performed under the supervision of the Drug Analysis Department at 
AbbVie.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variable(s)
The primary efficacy endpoints will be: 
x
Based on Investigator assessment, the proportion of subjects (primary and secondary 
sub-optimal responders at baseline) achieving a satisfactory response to ADA + 
MTX treatment after 16 weeks (satisfactory response defined as highly or 
completely satisfied with subject’s therapy based on responses to the satisfaction 
questionnaire);
x
Based on subject self-assessment, the proportion of subjects (primary and secondary 
sub-optimal responders at baseline) achieving a satisfactory response to ADA + 
MTX treatment after 16 weeks (satisfactory response defined as highly or 
completely satisfied with therapy based on responses to the satisfaction 
questionnaire).
5.3.3.2
Secondary Variable(s)
Secondary efficacy endpoints will include:
x
The proportion of subjects (primary and secondary sub-optimal responders at 
baseline) achieving 50%, 75%, 90% and 100% reductions in PASI at 8, 16 and 24 
weeks after initiation of ADA + MTX (change in PASI based on score at initiation 
of ADA + MTX therapy);
x
The proportion of primary sub-optimal responders achieving 50%, 75%, 90% and 
100% reductions in PASI at 8, 16 and 24 weeks after initiation of ADA + MTX 
(change in PASI based on score at initiation of ADA + MTX therapy);


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x
The proportion of secondary sub-optimal responders achieving 50%, 75%, 90% and 
100% reductions in PASI at 8, 16 and 24 weeks after initiation of ADA + MTX 
(change in PASI based on score at initiation of ADA + MTX therapy);
x
The proportion of subjects on ADA 40 mg eow prior to baseline or 40 mg once 
weekly prior to wash-out achieving 50%, 75%, 90% and 100% reductions in PASI 
16 weeks after initiation of ADA + MTX (change in PASI based on score at 
initiation of ADA + MTX therapy);
x
Proportion of primary and secondary sub-optimal responders achieving a clinical 
response defined as a PGA of “Clear” or “Minimal” at 8, 16 and 24 weeks after 
initiation of ADA + MTX;
x
DLQI scores at baseline (at initiation of ADA + MTX) and at weeks 8, 16 and 24;
x
Change and percent change in DLQI from baseline to weeks 8, 16 and 24; 
x
Proportion of subjects with each of the five categories of satisfaction with treatment 
at baseline (at initiation of ADA + MTX) and at weeks 8, 16 and 24 (subject self-
assessment and Investigator assessment using the satisfaction questionnaires);
x
Proportion of primary and secondary sub-optimal responders achieving a DLQI 
score of 0 or 1 at 8, 16 and 24 weeks after initiation of ADA + MTX;
x
Serum levels of ADA in subjects at baseline (at initiation of ADA + MTX) and at
weeks 8, 16 and 24.
5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of ADA 
and MTX. Incidence of AEs and changes in vital signs, physical examination results, and 
clinical laboratory tests (hematology, chemistry and urinalysis) will be assessed.
5.3.5
Pharmacokinetic Variables
ADA trough serum concentrations will be summarized for subjects at each time point 
using descriptive statistics. Data will be provided for all subjects and for subjects 
differentiated on the basis of whether they were primary or secondary sub-optimal 
responders to prior ADA therapy at Baseline.


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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 AE, safety concerns or failure to 
comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following
occurs:
x
Clinically significant abnormal laboratory result(s) or AEs, as determined by the 
Investigator in consultation with the AbbVie Study-Designated Physician.
x
The Investigator believes it is in the best interest of the subject.
x
The subject requests withdrawal from the study.
x
Inclusion and exclusion criteria violation was noted after the subject started study 
drugs, when continuation of the study drugs would place the subject at risk, as 
determined by the AbbVie Medical Monitor (see Section 7.0).
x
Introduction of prohibited medications or dosages when continuation of the study 
drug would place the subject at risk as determined by the AbbVie Study-Designated 
Physician.
x
Subject is non-compliant with TB prophylaxis.
x
The subject becomes pregnant while on study medication.
x
Subject has dysplasia of the gastrointestinal tract or a malignancy, except for
localized non-melanoma skin cancer. Discontinuation for carcinoma in-situ of the 
cervix is at the discretion of the Investigator.
x
Subject is diagnosed with lupus-like syndrome, multiple sclerosis or demyelinating 
disease.
x
Subject is significantly non-compliant with study procedures which would put the 
subject at risk for continued participation in the trial, as determined by the 
Investigator, in consultation with the AbbVie Medical Monitor and the Investigator.
If, during the course of study drugs administration, the subject prematurely discontinues 
either ADA or MTX, the procedures outlined for the Termination Visit must be completed  
within 2 weeks of the last dose of either drug, and preferably prior to the initiation of 


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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 ADA or MTX, the subject will be 
treated in accordance with the Investigator's best clinical judgment.
A final phone call will be made to the subject 70 days after the last dose of ADA to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs 
unless not required, as outlined in Section 5.1.
In the case of subjects who prematurely discontinue ADA or MTX, all attempts must be 
made to arrange a Termination Visit or to contact subjects by telephone. This visit should 
be used to determine the date of the last dose of study drugs and the primary reason for 
premature discontinuation and assessment of AEs. Any necessary laboratory tests and 
physical examinations should also be carried out. The information will be recorded on the 
appropriate eCRF page.
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject. At a minimum, two phone calls must 
be made and one certified letter must be sent. Discontinued subjects 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 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.


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5.5
Treatments
5.5.1
Treatments Administered
ADA will be provided as a sterile, preservative-free solution for injection in 1 mL pre-
filled pens containing ADA 40 mg/0.8 mL. Subjects will be advised to self-administer 
ADA eow starting at the Baseline visit (Week 0) through Week 24; last injection will be 
at Week 22. Subjects will not receive a loading dose of 80 mg ADA at Baseline since all 
subjects should already be receiving a fixed ADA dose of 40 mg eow. Subjects will be 
dispensed 2 ADA kits at baseline (4 pens with 40 mg ADA pens); subjects will inject one 
pen at the site at Baseline and remaining 3 pens will be taken home for eow dosing at 
Weeks 2, 4 and 6. Subjects will return to the site at Week 8 where they will receive 
another 2 ADA kits; this cycle will repeat at Week 16. 
MTX will be provided as 2.5 mg tablets for oral administration. Dose is up to the 
discretion of the Investigator but recommended dose should be between 10 and 25
mg/week, beginning at Week 0 through Week 23. The minimum initial dose of MTX 
should be 10 mg/week. Subjects will be advised by the Investigator as to the appropriate 
dose and the number of pills required to achieve this dose. If dose is > 10 mg/week, dose 
should be split (divided into two doses, administered on the same day). MTX dose can be 
increased at any time over the study period, based on the clinical judgment of the 
Investigator. Subjects will receive sufficient MTX tablets at Baseline for dosing until 
Week 8 Visit; additional MTX tablets will be provided at Week 8 and 16 Visits. All MTX 
dose adjustments, and the reasons for the adjustment, should be recorded in the eCRF.
Allocation of MTX tablets will be adjusted at site visits to reflect any dosing changes.
All subjects will also receive the non-investigational medicinal product oral folic acid as a 
dietary supplement since MTX acts as a folic acid antagonist. The folic acid tablets will 
be provided by the Investigator at a dose of 1.0 mg per day.  The required folic acid dose 
must be taken every day of the week except on the day when MTX is taken. The 
Investigator will provide specific instructions on the number of folic acid tablets each 
subject should take. In the event a subject forgets to take the tablets or takes more or less 


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than is required, they will be instructed to contact the Investigator for guidance. Unused 
folic acid tablets should be returned to the investigative site.
Each site will be responsible for tracking the lot numbers and expiration dates for all non-
investigational medicinal products (e.g. folic acid) that are dispensed.
5.5.2
Identity of Investigational Product(s)
The individual study drug information is presented in Table 3.
Table 3:
Identity of Investigational Products
Drug
Mode of 
administration
Formulation
Manufacturer
Adalimumab
Subcutaneous 
injection
40 mg/0.8 mL solution for injection
Adalimumab/citric acid monohydrate, 
dibasic sodium phosphate dihydrate, 
mannitol, monobasic sodium phosphate 
dihydrate, polysorbate 80, sodium 
citrate, sodium chloride, sodium 
hydroxide (added as necessary to adjust 
pH), and water for injection
AbbVie
Methotrexate
Oral
2.5 mg tablets
Methotrexate/corn starch, lactose, 
magnesium stearate
Hospira
Health Care 
Corporation 
or equivalent
5.5.2.1
Packaging and Labeling
ADA will be provided as a solution for injection (Table 3), packaged as a prefilled pen 
containing 40mg ADA/0.8 mL with two pens in a carton. MTX 2.5 mg tablets will be 
supplied in bottles containing 100 tablets per bottle. Supplies will be labeled in an open-
label format. Each kit label will include all information as required by local regulations. 
All blank spaces on the label will be filled in by site staff prior to dispensing to the 


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subject. The labels must remain affixed to the primary and potential secondary packaging 
material at all times.
Each ADA carton and MTX bottle will contain a unique number that is assigned to a 
subject via an Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS). The type and number of kits dispensed will be managed by the 
IVRS/IWRS. 
5.5.2.2
Storage and Disposition of Study Drug(s)
ADA pre-filled pens 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.
MTX should be stored protected from light and moisture at 15°C to 25°C/59° to 77°F 
according to labeled storage conditions.
A storage temperature log is to be maintained to document proper storage conditions. The 
refrigerated temperature must be recorded on a temperature log to record proper function. 
Malfunctions or any temperature excursion must be reported to the Sponsor immediately. 
Study medication should be quarantined and not dispensed until AbbVie GPRD or 
AbbVie Temperature Excursion Management System (ATEMS) deems the medication as 
acceptable. All clinical supplies must be stored and locked in a secure place until they are 
dispensed for subject use or are returned to AbbVie.
Investigational products are for investigational use only and are to be used only within the 
context of this study.
5.5.3
Method of Assigning Subjects to Treatment Groups
There is no randomization in this study. All subjects will receive the same therapy. All 
subjects will be assigned a subject number by the IVRS/IWRS. Before the study is 
initiated, the telephone number and call-in directions for the IVRS/IWRS will be provided 
to each site.


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5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study medication as outlined in Section 5.5.1.
The kit number(s) to be dispensed, both for ADA and MTX, will be assigned by the 
IVRS/IWRS.  Each ADA carton and MTX bottle will contain a unique number that is 
assigned to a subject via IVRS/IWRS. The number of kits dispensed will be managed by 
the IVRS/IWRS. On dosing days that occur on study visit days, subjects will administer 
ADA drug injection in the office under guidance of study site personnel after all specified 
study tests and procedures have been completed. Although subjects should be familiar 
with sterile subcutaneous injection technique, qualified study site personnel should 
directly observe subject self-injection at the time of all scheduled visits to ensure that it is 
carried out correctly. Site personnel observation of the subject's self-injection technique is 
of particular importance during the Baseline Visit. This supervision will serve as a
confirmation of the use of safe and appropriate drug injection techniques and to answer
any questions related to drug administration. ADA doses that do not occur on study visit 
days should be administered to subject by himself/herself, or by a designee (friend, family 
member or health care professional) throughout the study. For MTX, subjects should be 
instructed to bring their drug with them on study visit days that coincide with subject’s 
MTX dosing schedule so that MTX can be taken in the office. Again, qualified study site
personnel should observe oral MTX dosing, particularly to ensure that the correct number 
of tablets are taken for the prescribed MTX dose.
Each subject's dosing schedule should be closely monitored by the site at each study visit
by careful review of the subject's dosing diary. This will ensure that all subjects enrolled 
into the study maintain their original ADA dosing schedule beginning with the first dose 
of study medication (Baseline/Day 0). Doses of ADA should be taken on the same 
"scheduled dosing day" of each appropriate dosing week. Dosing schedule for MTX 
should also be closely reviewed to ensure that drug is taken at the required dose per week 
and, if the weekly drug dose is split (i.e. > 10 mg/week), that the dose is taken on the same 
day in two equal doses. In addition, dosing diaries should be reviewed to ensure that the 
subject has adjusted dosing to reflect any study-related MTX dose increases. 


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If a subject should forget to administer the ADA injection on their regularly scheduled 
dosing date, they should take the forgotten injection as soon as they remember the dose 
was missed up to the day before their next scheduled dose. The subject should not 
administer two ADA injections on the same day. If a subject should forget to take an 
MTX dose, they should take the forgotten dose as soon as they remember the dose was 
missed up to 3 days before their next scheduled dose. Subjects should be encouraged to 
record incorrect or missed ADA and MTX doses in their dosing diary. 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.  
Doses not administered (e.g. not taken before next dose is scheduled), should be recorded 
as not taken in the source documents. The extra dose should be returned to the study site. 
The subject should resume their regular dosing schedule based on the first dosing date at 
Baseline.
The folic acid tablets will be provided by the Investigator at a dose of 1.0 mg per day.  
The required folic acid dose must be taken every day of the week except on the day when 
the MTX is taken. The Investigator will provide specific instructions on the number of 
folic acid tablets each subject should take.
5.5.5
Blinding
There is no blinding in this study. All subjects will receive the same treatment, except for 
possible variation in the dose of MTX which will not be blinded.
5.5.6
Treatment Compliance
The 
Investigator
or 
his/her 
designated 
and 
qualified 
representatives 
will 
administer/dispense study drugs only to subjects enrolled in the study in accordance with 
the protocol. The study drugs must not be used for reasons other than that described in the 
protocol.


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The subject or their qualified designee will administer all doses of ADA and MTX.
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 ADA and MTX treatment regimens, the subject will be given a 
subject dosing diary to record all ADA injection dates and times and MTX weekly dosing 
schedules. Compliance information will be documented on the appropriate eCRF. 
Subjects will be counseled on missed doses of ADA and MTX. If the subject does not 
return the dosing diary, unused ADA or MTX, empty Investigational Product (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 study medication. The subject should be 
instructed to return all items at the next scheduled visit or sooner if possible. The 
information should be documented on the source documents as per "best recollection" and 
when possible, re-verified when the dosing diary is returned before completing the
applicable eCRF page.
5.5.7
Drug Accountability
The Investigator or designee will verify that drug supplies are received intact, at the 
appropriate temperature and in the correct amounts from the drug depot. This will be 
accomplished by documenting the condition of the shipment, verifying the kit numbers in 
the package against the Proof of Receipt (POR) or similar document included with each 
drug shipment, and documenting this verification by signing and dating the POR and by
registering the arrival of medication through the IVRS/IWRS. The original POR Note and 
the IVRS/IWRS confirmation will be kept in the site files as a record of what was 
received.
In addition, an IVRS/IWRS 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 the identification of person dispensing the drug. All 
empty IP boxes/bottles and used pre-filled pens will be inventoried by the site and verified 
by the CRA. Each subject will be given their own sharps disposal container to store used 
pens. Empty IP boxes/bottles and Sharps containers should be returned by the subject at 


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each visit for accountability and compliance purposes and new containers issued as 
necessary. Empty boxes/bottles and returned Sharps containers will be retained until the 
CRA is on site to confirm the returned medication. CRAs and site staff will complete 
study medication accountability via source documents, subject dosing diaries and empty 
IP boxes/bottles and by visually inspecting the pens in the Sharps container whenever 
possible. Used Sharps containers should never be opened. Once the CRA has verified 
drug accountability at the site, the site staff and CRA will document that the used pens
have been destroyed, using appropriate biohazard precautions, when appropriate. A copy 
of the destruction methodology should be maintained at the site's facility. Unused 
medications should not be destroyed, but will be returned to AbbVie by the CRA once 
drug accountability has been completed at the site.
Non-investigational medicinal product (standard of care) (e.g., generic name and generic 
name) must be obtained commercially.
Unused folic acid tablets should be returned to the investigative site and accounted for to 
assess subject’s compliance.
Investigator must agree not to supply study medication to any persons not enrolled in the 
study.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is a single arm, open label, longitudinal study designed to assess the impact of 
addition of oral MTX to ADA therapy in subjects with Ps who are not responding 
optimally to ADA monotherapy, either as primary or secondary sub-optimal responders. 
Sub-optimal response in this case means subjects with an unsatisfactory response to 
treatment based on an Investigator assessment.  Subjects must also have a PGA > 3 and a 
PASI of > 5 to be eligible for participation in the study. Efficacy is based on the 
proportion of subjects with a satisfactory response to ADA + MTX therapy, based on 
subject self-assessment and an assessment by the Investigator; Ps related clinical 


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outcomes will also be assessed as will the relationship between serum ADA levels and 
degree of clinical response. There is no control group in this study; instead each subject 
serves as their own control and outcomes after addition of MTX are compared to similar 
assessments at Baseline, prior to the addition of MTX to ADA therapy.
5.6.2
Appropriateness of Measurements
The most recent Canadian Ps treatment guidelines recognize the importance of the 
patient’s preferences and priorities in treatment decisions (2). This study incorporates, as a 
primary objective, subject satisfaction with therapy, in order to incorporate this patient-
centered approach, and also includes Investigator assessment of satisfaction with 
treatment response. In addition, the study includes efficacy measurements which are 
standard for assessing disease activity in subjects with Ps. All clinical and laboratory 
procedures in this study are standard and generally accepted. 
5.6.3
Suitability of Subject Population
Adult subjects 18 years of age or older, with a diagnosis of moderate to severe Ps who 
have been receiving ADA monotherapy for at least 16 weeks and who, in the opinion of 
the treating Investigator, have a sub-optimal response to treatment (primary sub-optimal 
responders), or have not maintained an initial positive response (secondary sub-optimal 
responders) and who meet all inclusion criteria and none of the exclusion criteria, will be 
enrolled in this study. The inclusion criteria identify a population who could benefit from 
the addition of MTX to ADA therapy in treatment of Ps, as has been demonstrated in 
other immune-mediated diseases such as RA where some subjects do not respond 
optimally to ADA monotherapy (8,26).
5.6.4
Selection of Doses in the Study
ADA doses for this study are those indicated in the Canadian Product Monograph for 
treatment of Ps (9). The MTX dose (10 to 25 mg/week) is within the range recommended 
for systemic MTX monotherapy in Ps and RA. In addition, a similar MTX dose range 
added to ADA therapy has been shown to be effective in treatment of RA (26) and 


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preliminary studies in Ps show that addition of MTX (10 mg/week) to ADA therapy in 
subjects with insufficient response to ADA alone improves PASI outcomes (27).
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this trial contains both: 
●
Biologic compound(s) and
●
Device component(s) (pen).
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1.
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 AEs on 
a routine basis throughout the study.  The Investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drugs
(causality will be assessed for both ADA and MTX), and any action(s) taken. For SAEs
considered as having "no reasonable possibility" of being associated with study drugs, the 
Investigator will provide an “Other” cause of the event. For AEs to be considered 
intermittent, the events must be of similar nature and severity. AEs, whether in response 
to a query, observed by site personnel, or reported spontaneously by the subject will be 
recorded.
All AEs will be followed to a satisfactory conclusion.


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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 AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any 
worsening of a pre-existing condition or illness is considered an AE. Worsening in 
severity of a reported AE should be reported as a new AE. Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
the study, necessitate therapeutic medical intervention, meets protocol specific criteria
(see Section 6.1.7 regarding toxicity management) and/or if the Investigator considers 
them to be AEs.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
AE 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 AE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.


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Life-Threatening
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g.,
sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the
appropriate case report form.


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6.1.2
Adverse Event Severity
The Investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The AE causes considerable interference with the subject's usual 
activities and may be incapacitating or life-threatening.
6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug(s) (causality will be assessed for both ADA and MTX):
Reasonable 
Possibility
An AE where there is evidence to suggest a causal relationship 
between the study drug and the AE.
No Reasonable 
Possibility
An AE where there is no evidence to suggest a causal 
relationship between the study drug and the AE.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug(s) will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug(s) 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(s) is 
given, an “Other” cause of event must be provided by the Investigator for the SAE.
6.1.4
Adverse Event Collection Period
All AE reported from the time of study drugs administration until 70 days following 
discontinuation of study drugs administration have elapsed will be collected, whether 
solicited or spontaneously reported by the subject. In addition, SAEs and protocol related 




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AbbVie Clinical Pharmacovigilance Team within 24 hours of the site being made aware 
of the AE. 
Email: 
FAX to
For safety concerns, contact the Therapeutic Area Safety Team at:
Immunology Safety Team 
For any subject safety concerns, please contact the physician listed below:
Primary Medical Monitor: 


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In emergency situations involving study subjects when the primary Medical Monitor is 
not available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline 
where your call will be re-directed to a designated backup AbbVie Medical Monitor: 
Phone:
6.1.6
Pregnancy
Pregnancy in a study subject or a partner of study subject must be reported to AbbVie 
within 1 working day of the site becoming aware of the pregnancy. Subjects who become 
pregnant during the study must be discontinued (Section 5.4.1).  
Pregnancies in study subjects and their partners will be collected from the date of the first 
dose through 150 days following the last dose of study drug. 
Information regarding a pregnancy occurrence in a study subject or a study subject’s 
partner and the outcome of the pregnancy will be collected.  
In the event of pregnancy occurring in a subject's partner during the study, written 
informed consent from the partner must be obtained prior to the collection of any such 
information. 
Pregnancy in a study subject is not considered an AE. However, the medical outcome of 
an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a SAE
and must be reported to AbbVie within 24 hours of the site becoming aware of the event. 
6.1.7
Toxicity Management
Subjects who develop a new infection while undergoing treatment with ADA and MTX 
should be monitored closely. Administration of study ADA injections and/or oral MTX 
should be interrupted if a subject develops an infection requiring intravenous (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 Investigator determines that the 


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infection has been successfully treated. Otherwise prohibited concomitant medications 
may be given if medically necessary. Prior to any prohibited medication use, every 
attempt should be made to contact the AbbVie Medical Monitor for direction on re-
introduction of ADA and MTX therapy after prohibited medication administration;
however, these communications should not delay the administration of any necessary 
medication(s), study-prohibited or otherwise, to the subject.
If the subject must undergo elective surgery, the study ADA injections and oral MTX 
must be interrupted 2 weeks prior to the surgery. If the subject must undergo emergency 
surgery, the study ADA injections and oral MTX must be interrupted at the time of the 
surgery. ADA and oral MTX 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. If any subject needs to skip more than two ADA doses or two weekly 
doses of MTX (consecutive or intermittent) over the course of the study, even if for the 
situations described above, further follow-up on the subject's study participation should be 
discussed with the AbbVie Study designated Physician.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.


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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 into the RAVE® electronic data capture (EDC) system or via the back-up
paper form if EDC is unavailable.  Product Complaints occurring during the study will be 
followed-up to a satisfactory conclusion.  All follow-up information is to be reported to 
the Sponsor (or an authorized representative) and documented in source as required by the 
Sponsor.  Product Complaints associated with adverse events will be reported in the study 
summary.  All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (pen, etc.).
In instances where a return is requested, every effort should be 
made by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects. The Principal Investigator is 
responsible for complying with all protocol requirements, and applicable local laws 
regarding protocol deviations. If a protocol deviation occurs (or is identified) after a 
subject has been enrolled, the Principal Investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and their assigned Clinical Monitor or the following AbbVie 
Clinical Monitor(s):


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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study. 
For the purposes of this protocol, reportable deviations are defined as: 
x
Subject entered into the study even though she/he did not satisfy entry criteria
x
Subject who developed withdrawal criteria during the study and was not 
withdrawn
x
Subject who received wrong treatment or incorrect dose 
x
Subject who received excluded or prohibited concomitant treatment 
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The primary objective of the statistical analyses is to determine the proportion of subjects 
with Ps who have a satisfactory response to ADA + MTX treatment, based on a self-
assessment by subjects and an assessment by the treating Investigator. Secondary 
objectives include an evaluation of the efficacy of ADA + MTX in subjects with Ps and 
characterization of the possible relationship between serum levels of ADA and efficacy 
outcomes. The impact of MTX on ADA serum levels will also be assessed by defining the 
change in serum ADA from baseline following the addition of MTX to therapy. Safety of 
ADA + MTX will also be assessed. 


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Complete specific details of the statistical analysis will be described and fully documented 
in the Statistical Analysis Plan (SAP). The SAP will be finalized prior to the database 
lock.
8.1.1
Analysis Population
The intent-to-treat (ITT) population will be used in the assessment of treatment 
satisfaction and in the evaluations of ADA + MTX efficacy. The ITT population is 
defined as:
x
All subjects who received at least one dose of ADA and one dose of MTX.
A per protocol population will not be defined for this qualitative study. 
The safety population is defined as all subjects who received at least one dose of ADA 
and one dose of MTX and will be used to evaluate safety of ADA + MTX.
8.1.2
Planned Methods for Statistical Analysis
Point estimates and 95% confidence intervals (CIs) will be provided for the discrete 
efficacy variables such as the proportion of responders to ADA + MTX. Changes from 
baseline (in PASI, PGA, DLQI and ADA serum levels) will be estimated using an 
appropriate estimation from a Mixed Model and statistical tests of change from baseline 
equal to zero will be carried out at the 0.05 significance level. Descriptive statistics will be 
provided as appropriate. These include the number of observations, mean, and standard 
deviation for continuous variables and counts and percentages for discrete variables. The 
analysis will be performed using SAS® (SAS Institute Inc., Cary, NC, USA).
8.1.3
Demographics and Baseline Characteristics
Demographic and Baseline characteristics of the study subjects will be summarized using 
descriptive statistics. Characteristics will be defined for the ITT population and for 
subjects differentiated on the basis of whether they are primary sub-optimal responders  or 
secondary sub-optimal responders at Baseline.


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8.1.4
Statistical Analysis of Efficacy
The primary and secondary efficacy analyses will be conducted on the ITT population.
The primary efficacy analyses will also be conducted for the following sub-populations:
x
Subjects defined as primary sub-optimal responders at baseline, based on 
Investigator assessment;
x
Subjects defined as secondary sub-optimal responders at baseline, based on 
Investigator assessment.
For the primary and secondary efficacy analyses, sub-optimal responder imputation 
(imputing missing satisfaction data as “dissatisfied”) will be used.  In the event that 
greater than 5% of the satisfaction data are missing, the following will be carried out to 
impute the missing data in sensitivity analyses:
x
Last observation carried forward (LOCF): The LOCF analyses will use the
completed evaluation from the previous visit within the particular period for efficacy 
measures assessed, to impute missing data at later visits;
Additional exploratory efficacy outcomes will be analyzed using available data at each 
assessment point and changes over time for PASI, PGA and DLQI scores will be 
estimated using a Mixed Model. Exploratory analysis to determine associations between 
ADA serum levels and PASI, PGA and DLQI scores will also be carried out. This could
be accomplished using a regression analysis with ADA serum level and visit as 
explanatory variables and either PASI, PGA or DLQI as response variables and 
controlling for within subject measurements. To determine the form of the regression 
model, the exploratory analyses could be carried out using LOESS Regression or general 
additive models. Alternatively, subjects could be grouped according to predetermined 
ranges of PASI, PGA or DLQI and the analysis could concentrate on determining 
differences in ADA serum levels in these groups.


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8.1.5
Statistical Analysis of Safety
All AEs, SAEs, and AEs leading to discontinuation will be collected during the study and
up to 70 days after the last dose of ADA. Safety analyses will be carried out using the
Safety Population. A treatment-emergent AE is defined as an event with onset or 
worsening after the first dose of study drugs (ADA + MTX) and within 70 days after the 
last dose of ADA. The number and percent of subjects experiencing treatment-emergent 
AEs will be tabulated using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA®) system organ class and preferred term. Summaries (including percentages 
and event per 100 patient-years) of SAEs, deaths and AEs leading to discontinuation from 
the study will be provided as well.
8.1.6
Interim Analysis
No interim analysis is planned for this study.
8.2
Determination of Sample Size
This study should have a 30 month recruitment period where it is anticipated that 
approximately 200 subjects will be recruited.  With this sample size the proportion of 
responders, defined as the proportion of subjects with a highly or completely satisfied 
response after 16 weeks of ADA + MTX therapy, based on an Investigator assessment and 
subject self-assessment, can be estimated within ± 4.9% with 95% confidence when the 
point estimate is 15%, within ± 6.4% with 95% confidence when the point estimate is 
30%, or within ± 6.9% with 95% confidence when the point estimate is 50%.  Additional 
accuracy estimates are provided in the Table below.


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Table 4:
Accuracy Estimates with a Sample Size of 200 Subjects
Estimated Proportion of 
Responders
Accuracy 
Estimate
5%
3.0%
10%
4.2%
15%
4.9%
20%
5.5%
25%
6.0%
30%
6.4%
35%
6.6%
40%
6.8%
45%
6.9%
50%
6.9%
Note: Proportion of responders can be estimated with +/- accuracy with 95% confidence. The size of the 95% 
Confidence Interval would be 2×Accuracy
Due to the recent enrollment plan change (enroll 50 patients or as the number of 
enrollment by 31-Dec-2016), Updated accuracy estimates with a sample size of 50 
subjects, about the proportion of subjects with a highly or completely satisfied response 
after 16 weeks of ADA + MTX therapy based on an Investigator assessment and subject 
self-assessment, are provided in the table below.


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Table 5:
Accuracy Estimates with a Sample Size of 50 Subjects
Estimated Proportion of 
Responders
Accuracy 
Estimate
5%
6.0%
10%
8.3%
15%
9.9%
20%
11.1%
25%
12.0%
30%
12.7%
35%
13.2%
40%
13.6%
45%
13.8%
50%
13.9%
Note: Proportion of responders can be estimated with +/- accuracy with 95% confidence. The size of the 95% 
Confidence Interval would be 2×Accuracy
8.3
Statistical Analysis of ADA Serum Levels
ADA serum concentrations will be summarized at each time point using descriptive 
statistics including number of subjects, number of non-missing observations, mean, 
median, standard deviation, coefficient of variation (CV), minimum and maximum as 
appropriate. Mean and median concentration versus time plots will be generated. Data 
will be assessed for the following subgroups:
x
Total recruited subjects;
x
Subjects defined as primary sub-optimal responders at baseline, based on 
Investigator assessment;
x
Subjects defined as secondary sub-optimal responders at baseline, based on 
Investigator assessment
To further characterize the relationship between ADA serum levels and treatment 
response, subjects will be classified as non-responders (< 50% improvement in PASI from 
baseline (baseline defined as addition of MTX to ADA therapy); moderate responders (>
50% to <75% improvement in PASI from baseline) or good responders (> 75% 


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improvement in PASI from baseline) at 8, 16 and 24 weeks. At each visit, median ADA 
serum levels will be evaluated by group and compared between groups.
In addition, exploratory analysis to determine possible associations between MTX dose 
and ADA serum levels will be carried out. 
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, CRFs, subject dosing 
diary, any protocol amendments, the Investigator's Brochure, the informed consent and all 
other forms of subject information related to the study (e.g., advertisements used to recruit 
subjects) and any other necessary documents be reviewed by an IEC/IRB. The IEC/IRB 
will review the ethical, scientific and medical appropriateness of the study before it is 
conducted. IEC/IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design. The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Health Canada. During the conduct of 
the study, the Investigator should promptly provide written reports (e.g., ICH Expedited 
Reports, and any additional reports required by local regulations) to the IEC/IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IEC/IRB should also be provided to AbbVie.


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9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. Responsibilities of the clinical 
Investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study. Prior to any study-related screening
procedures being performed on the subject, the informed consent form will be reviewed 
and signed and dated by the subject, the person who administered the informed consent, 
and any other required signatories. 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. Consent must be obtained before any study-related procedures including completion 
of the Investigator/subject satisfaction assessment. In addition, consent must be obtained 
before wash-out procedures are initiated in subjects who are receiving ADA 40 mg once 
weekly; prior to study enrolment these subjects should be treated with ADA 40 mg eow 
for at least 8 weeks.
Information regarding subject reimbursement for travel expenses and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the study can be found in the informed consent form.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records. This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 


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evaluation checklists, completed satisfaction questionnaires, 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.
The following assessments will be completed by the Investigator (or qualified designee) 
and will be considered source documentation:
x
PASI assessment
x
PGA assessment
x
BSA assessment
x
Treatment satisfaction questionnaire
The following assessments will be completed by the subject and will be considered source 
documentation:
x
Treatment satisfaction questionnaire
x
DLQI
Once collected, these outcome assessments will be entered by AbbVie or the site into the 
EDC system and will be available for viewing by site personnel.
The AE eCRF data segments of: alternate etiology, severity, frequency and relationship to 
ADA + MTX may also be used as source documents and will require Investigator
approval on the eCRF as verification of the accuracy of the information.
10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study. These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable. The CRF data for this study are being 


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collected with an electronic data capture (EDC) system called RAVE® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA. The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11. The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files. These subject 
files will serve as source data for the study. All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system. All data entered into the 
eCRF will be supported by source documentation.
The Investigator, or an authorized member of the Investigator's staff, will make any 
necessary corrections to the eCRF. All changed 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.


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11.0
Data Quality Assurance
Prior to the initiation of the study, an Investigator's meeting and/or a study initiation visit
will be held with the Investigators, their sub-Investigators and study coordinator(s) and
AbbVie personnel and/or their designee. This meeting will include a detailed discussion
of the protocol, performance of study procedures, completion of the eCRFs, subject
questionnaires, subject dosing diary cards, and specimen collection methods.
The CRA will monitor each site throughout the study and source document verification 
will be performed.
All data entered in the database will be verified at AbbVie. Any discrepancies will be
reviewed. The data will be reviewed and computer logic and manual checks will be
created to identify items such as inconsistent study dates. A manual review of selected
line listings will also be performed at the end of the study. Queries will be generated in
the EDC system. Any necessary corrections will be made to the eCRF and documented
via addenda or audit trail. The data from the central laboratory analyses will be 
electronically transferred from the central laboratory to the study database. A final review 
of all laboratory results will be conducted by a physician and clinical review team at 
AbbVie.
12.0
Use of Information
All information concerning ADA and AbbVie's operation, such as AbbVie's patent
applications, formulas, manufacturing processes, basic scientific data, or formulation
information, supplied by AbbVie and not previously published is considered confidential
information.
The information developed during the conduct of this clinical study is also considered
confidential and will be used by AbbVie in connection with the development of ADA.
This information may be disclosed as deemed necessary by AbbVie to other clinical 
Investigators, other pharmaceutical companies, to Health Canada and the FDA and to 
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study and to ensure complete and thorough analysis, the Investigator is obligated to
provide AbbVie with complete test results and all data developed in this study and to
provide direct access to all source data/documents for trial-related monitoring, audits,
IEC/IRB review, and regulatory inspection. This confidential information shall remain 
sole property of AbbVie, shall not be disclosed to others without the written consent of 
AbbVie.
The Investigator will maintain a confidential subject identification code list of all subjects
enrolled in the study (by name and subject number). This list will be maintained at the site 
and will not be retrieved by AbbVie.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie. The Investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements. If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study. Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol. 
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.


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14.0
Investigator's Agreement
1. I have received and reviewed the Investigator's Brochure for adalimumab and the 
product monograph for 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: 
Concomitant longitudinal evaluation of adalimumab with 
methotrexate in the real world: the CLEAR study
Protocol 
Amendment 2
Date:
22 Apr 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1. Menter A, Tyring SK, Gordon K et al.  Adalimumab therapy for moderate to severe 
psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol 
2008;58:106-15.
2. Papp K, Gulliver W, Lynde C et al.  Canadian guidelines for the management of 
plaque psoriasis: Overview.  J Cut Med Surg 2011;15:210-9.
3. Onumah N, Kircik LH.  Psoriasis and its comorbidities.  J Drugs Dermatol 
2012;11(5 Suppl):S5-S10.
4. Optimizing care for patients with moderate to severe psoriasis.  Available at:  
http://www.practicingclinicians.com/2011hs2/pdf/psoriasis.pdf. Accessed November 
8, 2013.
5. Menter A, Gordon KB, Leonardi CL et al.  Efficacy and safety of adalimumab 
across subgroups of patients with moderate to severe psoriasis. J Am Acad Dermatol 
2010;63:448-56.
6. Gladman DD, Antoni C, Mease P et al.  Psoriatic arthritis:  epidemiology, clinical 
features course, and outcome.  Ann Rheumatic Dis 2005;64 (Suppl)  ii14-7.
7. Reich K, Burden AD, Eaton JN, Hawkins NS.  Efficacy of biologics in the treatment 
of moderate to severe psoriasis:  a network meta-analysis of randomized controlled 
trials.  Brit J Dermatol 2012;166:179-88.
8. Garces S, Demengeot J, Benito-Garcia E.  The immunogenicity of anti-TNF therapy 
in immune-medicated inflammatory diseases:  a systematic review of the literature 
with a meta analysis.  Ann Rheum Dis 2013;72:1947-55.
9. Humira Product Monograph. AbbVie Corporation. February 26, 2016.
10. Mrowietz U, Kragballe K, Reich K et al.  An assessment of adalimumab efficacy in 
three Phase III clinical trials using the European Consensus Programme criteria for 
psoriasis treatment goals.  Br J Dermatol 2013;168:374-80.
11. Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from the 
randomized controlled comparative study of adalimumab vs. methotrexate vs. 
placebo in patients with psoriasis (CHAMPION).  Br J Dermatol 2008; 158:558–66.
12. Thaci D, Ortonne JP, Chimenti S et al. A phase IIIb, multicentre, randomized, 
double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with 
and without calcipotriol⁄betamethasone topical treatment in patients with moderate 
to severe psoriasis: the BELIEVE study. Br J Dermatol 2010; 163: 402–11.
13. Gordon K, Papp K, Poulin Y et al.  Long-term efficacy and safety of adalimumab in 
patients with moderate to severe psoriasis treated continuously over 3 years:  results 


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from an open-label extension study for patients from REVEAL.  J Am Acad 
Dermatol 2012;66:241-51.
14. Mahil SK, Arkir Z, Richards G et al.  Predicting treatment response in psoriasis
using serum levels of adalimumab and etanercept:  a single-centre, cohort study.  Br 
J Dermatol 2013;169:306-13.
15. De Simone C, Americo P, Amoruso G et al.  Immunogenicity of anti-TNFα therapy 
in psoriasis:  a clinical issue?  Expert Opin Biol Ther 2013;13:1673-82.
16. Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Clinical response to 
adalimumab: relationship with anti-adalimumab antibodies and serum adalimumab 
concentrations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:921–6.
17. Bartelds GM, Krieckaert CLM, Nurmohamed MT et al. Development of antidrug 
antibodies against adalimumab and association with disease activity and treatment 
failure during long-term follow-up. JAMA 2011; 305:1460–8.
18. West RL, Zelinkova Z, Wolbink GJ et al. Immunogenicity negatively influences the 
outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther 
2008; 28:1122–6.
19. van Kuijk AWR, de Groot M, Stapel SO et al. Relationship between the clinical 
response to adalimumab treatment and serum levels of adalimumab and anti-
adalimumab antibodies in patients with psoriatic arthritis. Ann Rheum Dis 2010; 
69:624–5.
20. Karmiris K, Paintaud G, Noman M et al. Influence of trough serum levels and 
immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. 
Gastroenterology 2009; 137:1628–40.
21. Papp K, Crowley J, Ortonne JP et al. Adalimumab for moderate to severe chronic 
plaque psoriasis: efficacy and safety of retreatment and disease recurrence following 
withdrawal from therapy. Br J Dermatol 2011; 164:434–41.
22. Lecluse LL, Driessen RJ, Spuls PI et al. Extent and clinical consequences of 
antibody formation against adalimumab in patients with plaque psoriasis. Arch 
Dermatol 2010; 146:127–32.
23. Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Plasma trough levels of
adalimumab and infliximab in terms of clinical efficacy during the treatment of 
psoriasis. J Dermatol 2013; 40:39-42.
24. Leonardi C, Sobell JM, Crowley JJ et al.  Efficacy, safety and medication cost 
implications of adalimumab 40 mg weekly dosing in patients with psoriasis with 
suboptimal response to 40 mg every other week dosing:  results from an open-label 
study.  Br J Dermatol 2012;167:658-67.


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25. Weinblatt ME, Keystone EC, Furst DE et al.  Adalimumab, a fully human anti-
tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid 
arthritis in patients taking concomitant methotrexate: the ARMADA trial.  Arthritis 
Rheum 2003;48:35-45.
26. Krieckaert CL, Nurmohamed MT, Wolbink GJ.  Methotrexate reduces 
immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose 
dependent manner.  Ann Rheum Dis 2012; 71:1914-15.
27. Van den Reek JMPA, van Lumig PPM, Kievit W et al.  Effectiveness of 
adalimumab 
dose 
escalation, 
combination 
therapy 
of 
adalimumab 
with 
methotrexate, or both in patients with psoriasis in daily practice.  J Dermatolog Treat 
2013;24:361-8.
28. Christophers E, Segaert S, Milligan G et al. Clinical improvement and satisfaction 
with biologic therapy in patients with severe plaque psoriasis: results of a European 
cross-sectional observational study. J Dermatolog Treat 2013;24:193-8.
29. Pouw MF, Krieckaert CL, Nurmohamed MT et al. Key findings towards optimizing 
adalimumab treatment: the concentration-effect curve. Ann Rheum Dis 2013: ePub.
30. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI). April 1992.
31. Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. 
Dermatologica. 1978;157(4):238-44.
32. Marks R, Barton SP, Shuttleworth D, et al. Assessment of disease progress in 
psoriasis. Arch Dermatol. 1989;125(2):235-40.


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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.


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8. Maintaining records demonstrating that an ethics committee reviewed and approved 
the initial clinical investigation and all amendments.
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 C.
Satisfaction Questionnaire
Subject #:____________
Date: _______________
Satisfaction Questionnaire – Investigator
Overall, at this point in time, how satisfied are you with the Ps control provided by the 
subject’s current treatment regimen?
 Completely dissatisfied
 Moderately dissatisfied
 Slightly satisfied
 Highly satisfied
 Completely satisfied


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Subject #:____________
Date:________________
Satisfaction Questionnaire – Subject
Overall, how satisfied are you with your current treatment for Ps?
 Completely dissatisfied
 Moderately dissatisfied
 Slightly satisfied
 Highly satisfied
 Completely satisfied


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Appendix D.
Psoriasis Area Severity Index (PASI) Scoring Instructions
PASI Scoring 31-32
Four anatomic sites – head, upper extremities, trunk, and lower extremities – are assessed
for erythema, induration (plaque thickness), and desquamation (scaling) as seen on the
day of the examination. The severity of each sign is assessed using a 5-point scale:
x
0 = No symptoms 
x
1 = Slight 
x
2 = Moderate
x
3 = Marked 
x
4 = Very marked 
The table below outlines the characteristics of each category.
The area affected by psoriasis within a given anatomic site is estimated as a percentage of
the total area of that anatomic site and assigned a numerical value according to the degree
of psoriatic involvement as follows:


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x
0 = no involvement 
x
1 = < 10% 
x
2 = 10% to < 30% 
x
3 = 30% to < 50% 
x
4 = 50% to < 70% 
x
5 = 70% to < 90% 
x
6 = 90% to 100% 
Assignments for the following body regions are as follows:
x
Neck: include with the head 
x
Buttocks: include with the lower extremities 
x
Axillae: include with the trunk 
x
Genitals: include with the trunk 
x
The inguinal canal separates the trunk and legs anteriorly
The PASI score for each body region is obtained by multiplying the sum of the severity
scores by the area score, then multiplying the result by the constant weighted value
assigned to that body region. Since the head, upper extremities, trunk, and lower
extremities correspond to approximately 10%, 20%, 30%, and 40% of BSA, 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 degree.


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Appendix E.
Physician Global Assessment of Skin (PGA-S)
The Physician's Global Assessment (PGA) is a 6-point scale used to measure the severity 
of skin disease at the time of the qualified investigator's evaluation of the subject. The 
degree of overall lesion severity will be evaluated using the following categories:


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Appendix F.
Dermatology Life Quality Index (DLQI) 
The aim of this questionnaire is to measure how much your skin problem has affected  
your life OVER THE LAST WEEK.  Please tick √ one box for each question.
Question
Response
1.
Over the last week, how itchy, sore, painful or 
stinging has your skin been?
Very much
A lot
A little
Not at all
2.
Over the last week, how embarrassed or 
self-conscious have you been because of your skin?
Very much
A lot
A little
Not at all
3.
Over the last week, how much has your skin 
interfered with you going shopping or looking after 
your home or garden?
Very much
A lot
A little
Not at all
Not relevant
4.
Over the last week, how much has your skin 
influenced the clothes you wear?
Very much
A lot
A little
Not at all
Not relevant
5.
Over the last week, how much has your skin 
affected any social or leisure activities?
Very much
A lot
A little
Not at all
Not relevant
6.
Over the last week, how much has your skin made it 
difficult for you to do any sport?
Very much
A lot
A little
Not at all
Not relevant


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Question
Response
7.
Over the last week, has your skin prevented you 
from working or studying?
If "No," over the last week how much has your skin 
been a problem at work or studying?
Yes
No
A lot
A little
Not at all
Not relevant
8.
Over the last week, how much has your skin created 
problems with your partner or any of your close 
friends or relatives?
Very much
A lot
A little
Not at all
Not relevant
9.
Over the last week, how much has your skin caused 
any sexual difficulties?
Very much
A lot
A little
Not at all
Not relevant
10. Over the last week, how much of a problem has the 
treatment for your skin been, for example by 
making your home messy, or by taking up time?
Very much
A lot
A little
Not at all
Not relevant
Please check you have answered EVERY question.  Thank you.


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Appendix G.
70-Day Follow-Up (Phone Call)
Study W14-406 
Day 70 Follow-Up (Phone Call)
Site Name/Number: ________ 
Subject Number: ________ 
Please contact all Subjects 70 days following last study drug injection (ADA) 
________________________________________________________________________
Date of Call/Visit: ____________ 
 
Call not needed as subject is continuing on commercial adalimumab. 
 
Lost to Follow-Up (Please check this box if subject was not willing to 
provide any follow-up information or you were unable to speak to the subject 
following at least one attempt).
 
No Events Reported
AE/SAE Reported
List any Adverse Events (AE) and/or Serious Adverse Events (SAE) that occurred since 
the subject was last seen in clinic for this study.  Please document all adverse events on a 
500 AE CRF in the EDC system.  (Please report all SAEs to AbbVie within 24 hours of 
being made aware of the event).  In addition, please note stop dates to any adverse 
events that were ongoing at the last study visit.
Please fax this form to AbbVie at 


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Appendix H.
Adalimumab injection instructions
Subject Injection Instructions
0.8 mL dose
(Administered as a single dose Pen or pre-filled syringe)
Protocol W14-406
Tables of Contents
Dosing Schedule 
General Information 
Injection Procedures


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STUDY DRUG DOSING SCHEDULE
During the study, you will receive subcutaneous (SC) injections and you will take 
methotrexate tablets.
Methotrexate (MTX):
MTX will be provided as a 2.5 mg tablets for oral administration.  MTX tablets will be 
taken once a week during the study.  Your study doctor will let you know how many pills 
per week need to be taken.
You will be dispensed a bottle of MTX at the Baseline (Day -0) visit.  This bottle will 
contain sufficient MTX tablets for dosing until the Week 8 visit.  The first dose will be 
taken at the clinic at the Baseline (Day – 0) visit.  Your study doctor will let you know 
how many pills you have to take every week.  A new bottle of MTX will be dispensed at 
the Week 8 and 16 visits.  You will continue to take MTX once a week.  Your study 
doctor will let you know what dose needs to be taken every week.  The last dose of MTX 
will be at the Week 23.  There is no dose taken at the Week 24 visit.
In the event a MTX dose is missed or an incorrect dose is taken, please contact the clinic 
for instructions.  Please return the bottle with the unused tablets at your next visit (Weeks 
8, 16 and 24).
Please remember to complete the dosing diary after each dose is taken and call the clinic 
if you are having difficulties.
Adalimumab (ADA) injections:
You will receive the following number of injections during the study:
x
Baseline (Day – 0) Visit (the first visit to receive study medication for this study): 
1 injection at the clinic.
x
Starting at Week 2: 1 injection every other week (EOW) through Week 22.  Unless 
the injection is the same week as a clinic visit, you will receive these injections at 
home.


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You will be dispensed 2 ADA kits at the Baseline (Day – 0) Visit (4 Pens or syringes with 
40 mg ADA/ Pen or syringe); 1 Pen/syringe from the first kit will be used for the dose 
administered at the clinic and the remaining 3 Pens/syringes will be taken at home for 
every other week dosing at Weeks 2, 4 and 6.  At the week 8 Visit, 2 ADA kits will be 
dispensed; 1 Pen/syringe from the first kit will be used for the dose administered at the 
site and the 3 remaining Pens/syringes will be taken at home at Weeks 10, 12 and 14.  At 
the Week 16 visit, 2 kits will be dispensed; 1 Pen/syringe from the first kit will be used for 
the dose administered at the clinic and the remaining 3 Pens/syringes will be taken at 
home at Weeks 18, 20 and 22.  The Week 22 dose is the last dose of injectable study 
medication.  There is no dose taken at Week 24.
Please return all used and unused Pens/syringes, the sharp container and empty boxes to 
the clinic at your next visit.  Used Pens/syringes should be placed in the special sharps 
container provided.  All unused Pens/ syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
please contact the clinic immediately for further instructions.  Please record any missed 
doses on your dosing diary.
Remember to complete your dosing diary after each injection and to call the clinic if you 
are having problems administering your study medication.
Folic Acid (vitamin) Pills:
The folic acid (vitamin) pills will be provided to you by the clinic.  You will take folic 
acid every day of the week except on the day you take the MTX tablet(s).  The clinic staff 
will provide specific instructions on the number of pills you should take.
In the event you forget to take the pills or takes more or less than is required, please 
contact the clinic for guidance.  At the end of the study or if you discontinue from the 
study, all unused folic acid pills should be returned to the clinic.  
GENERAL INFORMATION
x
Pens or pre-filled syringes will be labeled "Adalimumab 40mg/0.8mL Solution for 
Injection”.
x
Bottles with tablets will be labeled “Methotrexate”.


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x
Store all adalimumab Pens or pre-filled syringes in your refrigerator NOT in the 
freezer. Should the Pens or syringes accidentally become frozen, call your study 
doctor's office.
x
Store all bottles with Methotrexate tablets at room temperature.
x
Store the bottle of folic acid at room temperature.
x
Study medication should be taken at about the same time of day, on the same day of 
the week as directed by your study doctor.
x
USE A NEW PEN/SYRINGE EVERY INJECTION DAY. There may be 
medication left in the Pen or syringe. DO NOT RE-USE.
x
Save all study medications. Pens or pre-filled syringes (used and unused) & empty 
boxes must be returned to the study center at each visit. Used Pens or syringes will 
be disposed of in a sharps container provided to you.
x
Call your doctor IMMEDIATELY if you experience any itching, hives, shortness of 
breath, or any symptom that has you concerned. If you are unable to reach your doctor 
or if you experience life-threatening symptoms call, ______________________ or 
proceed to your nearest emergency room.
 


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INJECTION PROCEDURES 
1. Setting up for an injection
x
Find a clean flat surface.
x
Do not use if seals on the carton are broken or missing.  Contact your study doctor’s 
office if the seals are broken.
x
Take one kit with the Pen or pre-filled syringe(s) of adalimumab from the refrigerator.  
Do not use a Pen or pre-filled syringe that has been frozen or if it has been left in 
direct sunlight. 
x
Return any unused Pen(s) or syringe(s) to the refrigerator.
x
If you are using the Pen, only remove the caps immediately before injection.
You will need the following items for each dose:
x
Study medication in Pen
x
Alcohol prep(s)
x
Cotton ball or gauze pad(s)
 
 
 
OR
x
Study medication in pre-filled syringe 
x
Alcohol prep(s)
x
Cotton ball or gauze pad(s)
 
 
 


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If you do not have all of the items you need to give yourself an injection, call your study 
physician.  Use only the items provided in the box your adalimumab comes in.
x
Make sure the liquid in the Pen or pre-filled syringe is clear and colorless.  Do not use 
a Pen or pre-filled syringe if the liquid is cloudy or discolored or has flakes or 
particles in it.
x
Have a special sharps (puncture proof) container nearby for disposing of used Pen, 
needles and syringe.
For your protection, it is important that you follow these instructions.
2. Choosing and preparing an injection site
x
Wash your hands well.
x
Choose a site on the front of your thighs or your stomach area (abdomen).  If you 
choose your abdomen, you should avoid the area 5 cm (2 in) around your belly 
button (navel).
x
Choose a different site each time you give yourself an injection.  Each new 
injection should be given at least 2.5 cm (1 in) from a site you used before.  Never 
inject into areas where the skin is tender, bruised, red or hard or where you have 
scars or stretch marks.
x
You should try not to inject directly into any raised, thick, red or scaly skin 
patches or lesions.
x
You may find it helpful to keep notes on the location of your injection sites.
x
Wipe the site where adalimumab is to be injected with an alcohol prep (Swab), 
using a circular motion.  Do not touch this area again until you are ready to inject.
 
3. How to prepare your adalimumab dose for injection 
Pen
x
Hold the Pen with the gray cap pointing up. 


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x
Check the appearance of the solution through the windows on the sides of the Pen to 
make sure the liquid is clear and colourless. 
x
Do not use the Pen if the liquid is cloudy or discoloured or has flakes or particles in it. 
x
Do not use if frozen or if it has been left in direct sunlight. 
 
       
 
 
Pre-filled Syringe
x
Hold the syringe upright with the needle facing down.  Check to make sure that the 
amount of liquid in the syringe is the same or close to the 0.8 mL line for the 40 mg 
pre-filled syringe.  The top of the liquid may be curved.  If the syringe does not have 
the correct amount of liquid, do not use that syringe.  Call your study doctor.
x
Remove the needle cover taking care not to touch the needle with your fingers or 
allow it to touch any surface.
x
Turn the syringe so the needle is facing up and slowly push the plunger in to push the 
air in the syringe out through the needle.  If a small drop of liquid comes out of the 
needle that is okay.
x
Do not shake the syringe.
4. Injecting Adalimumab
Pen
x
Only remove the caps immediately before injection. 
x
Hold the gray body of the Pen with one hand. 
x
Place your hand on the middle of the Pen so that neither the gray cap (Cap 1) nor the 
plum cap (Cap 2) is covered. 
x
Hold the Pen with the gray cap (Cap 1) pointing up. 
x
With your other hand, pull the gray cap (Cap 1) straight off (without twisting) and 
discard the cap. 
x
Check that the small needle cover of the syringe has been removed with the cap. 
x
If a few small drops of liquid come out of the needle, this is okay. 
x
The white needle sleeve, which covers the needle, will now be exposed. Do not try to 
touch the needle housed in the barrel. 


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x
DO NOT RECAP as you may damage the needle.
x
Care should be taken to avoid dropping or crushing the product as it contains a glass 
syringe. 
x
Pull the plum safety cap (Cap 2) straight off (without twisting) to expose the plum-
coloured activation button. The Pen is now ready to use. 
x
Please note that the Pen is activated after removing Cap 2 and that pressing the button 
under Cap 2 will immediately result in discharge of medication. 
x
Do not press the plum-coloured activation button until properly positioned. 
x
DO NOT RECAP as this could cause the unit to discharge.
x
Hold the Pen so that the window is in view. The presence of one or more bubbles in 
the window is normal. 
x
With your free hand, gently squeeze a sizable area of the cleaned skin at the injection 
site and hold firmly. You will inject into this raised area of skin. 
x
Place the white end of the Pen straight (a 90° angle) and flat against the raised area of 
skin. Position the Pen so that it will not inject the needle into your fingers. 
x
With your index finger or thumb, press the plum-coloured button to begin the 
injection. 
x
Try not to cover the window. 
x
Note that you will hear a loud ‘click’ when you press the button, which indicates the 
start of the injection. You will feel a small prick as the needle advances. 
x
Keep pressing and continue to hold the Pen with steady pressure in place for about 10
seconds to ensure complete injection. (A way to remember is simply ‘click and 
count to 10’.) Do not remove the Pen while the injection is being given. 
x
It is important to maintain steady pressure at the injection site for the entire period of 
time. 
 
        
             
 
x
You will see a yellow indicator move into the windows during the injection. The 
injection is complete when the yellow indicator stops moving.


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x
Lift the Pen straight up from the injection site. The white needle sleeve will move 
down over the needle and lock into place over the needle tip. Do not try to touch the 
needle. The white needle sleeve is there to protect you from touching the needle. 
 
       
 
 
x
Press a cotton ball or gauze pad over the injection site and hold it for 10 seconds. Do 
NOT rub the injection site. If you have slight bleeding, this is normal. 
x
Dispose of the Pen immediately into your special sharps container. 
Pre-filled Syringe
x
With your other hand, gently squeeze an area of the cleaned area of skin and hold it 
firmly.
x
You will inject into this raised area of skin.  Hold the syringe like a pencil at about 45° 
angle (see picture) to the skin.
x
With a quick, short, “dart-like motion”, push the needle into the skin.
x
After the needle is in, let go of the skin.  Pull back slightly on the plunger.  If blood 
appears in the syringe it means that you have entered a blood vessel.  Do not inject 
adalimumab.  Pull the needle out of the skin and repeat the steps to choose and clean a 
new injection site.  Do not use the same syringe.  Dispose of it in your special sharps 
container.  If no blood appears, slowly push the plunger all the way in until all of the 
adalimumab is injected.
x
When the syringe is empty, remove the needle from the skin keeping it at the same 
angle it was when it was pushed into the skin.
x
Press a cotton ball or gauze pad over the injection site and hold it for 10 seconds.  Do 
not rub the injection site.  You may have slight bleeding.  This is normal.
x
Dispose of the syringe right away into your special sharps container.
        
         

SAP_001.pdf: 
Adalimumab
W14-406 – Statistical Analysis Plan
Version 1.0 – 29 Mar 2017
1
1.0
Title Page
Statistical Analysis Plan
Study W14-406
Concomitant Longitudinal Evaluation of Adalimumab 
with Methotrexate in the Real World:  the CLEAR 
Study
Date:  29 March 2017
Version 1.0
NCT02196701


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2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 8
4.4
Interim Analysis..................................................................................... 9
5.0
Analysis Populations .............................................................9
5.1
Definition of Analysis Populations ......................................................... 9
6.0
Analysis Conventions .......................................................... 10
6.1
Definition of Baseline........................................................................... 10
6.2
Definition of Final Observation ............................................................ 10
6.3
Definition of Rx Days (Days Relative to the First Dose of Study 
Drug).................................................................................................... 10
6.4
Definition of Analysis Windows and Data Handling Conventions ........ 11
6.5
Missing Data Imputation ...................................................................... 13
6.6
Rounding of Numeric Results............................................................... 13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............14
7.1
Demographic and Baseline Characteristics ........................................... 14
7.2
Medical History.................................................................................... 16
7.3
Prior Treatment and Concomitant Medications ..................................... 17
7.4
Protocol Deviation................................................................................ 17
7.5
Inclusion/Exclusion Criteria ................................................................. 17
8.0
Patient Disposition............................................................... 17
9.0
Study Drug Exposure and Compliance.............................. 18
10.0
Efficacy Analysis .................................................................19
10.1
General Considerations......................................................................... 19
10.2
Efficacy Variables................................................................................ 20
10.2.1
Primary Efficacy Variable .................................................................... 20


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10.2.2
Secondary Efficacy Variables............................................................... 20
10.3
Handling of Multiplicity....................................................................... 21
10.4
Efficacy Subgroup Analyses................................................................. 21
11.0
Safety Analysis.....................................................................21
11.1
General Considerations......................................................................... 21
11.2
Analysis of Adverse Events.................................................................. 22
11.2.1
Treatment-Emergent Adverse Events.................................................... 22
11.2.1.1
Adverse Event Overview...................................................................... 22
11.2.1.2
Adverse Events by System Organ Class and Preferred Term ................ 23
11.2.1.3
Adverse Events by Maximum Severity................................................. 24
11.2.1.4
Adverse Events by Maximum Relationship .......................................... 24
11.2.1.5
Adverse Events by "Reasonable Possibility" of Being Related to 
Study Drug........................................................................................... 24
11.2.1.6
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation................................................ 24
11.2.1.7
Adverse Events of Special Interests...................................................... 25
11.2.1.8
Adverse Events by 100 Patient Years ................................................... 25
11.3
Analysis of Laboratory Data................................................................. 25
11.3.1
Variables and Criteria Defining Abnormality........................................ 25
11.3.2
Statistical Methods ............................................................................... 26
11.3.2.1
Analysis for Continuous Laboratory Data............................................. 26
11.3.2.2
Shift Table Analyses............................................................................. 26
11.3.2.3
Potentially Clinically Significant Laboratory Values ............................ 27
11.4
Analysis of Vital Signs......................................................................... 28
11.4.1
Variables and Criteria Defining Abnormality........................................ 28
11.4.2
Statistical Methods ............................................................................... 28
11.5
Analysis of ECG Parameters ................................................................ 29
11.6
Analysis for Other Safety Variables...................................................... 29
11.7
Safety Subgroup Analyses.................................................................... 29
12.0
Special Statistical Topics..................................................... 29
13.0
List of Tables, Figures and Data Listings that Are to 
Be Programmed................................................................... 29
14.0
Summary of Changes .......................................................... 29


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List of Tables
Table 1.
Accuracy Estimates with a Sample Size of 200 Subjects......................... 8
Table 2.
Accuracy Estimates with a Sample Size of 50 Subjects........................... 9
Table 3.
Windows for High-Sensitivity C-Reactive Protein (hs-CRP; 
Safety Population) ................................................................................ 12
Table 4.
Windows for All Other Efficacy and Safety Analyses (ITT/Safety 
Populations) ......................................................................................... 12
Table 5.
Windows for ADA Injection (Safety Population).................................. 13
Table 6.
Windows for MTX Administration (Safety Population)........................ 13
Table 7.
Clinical Laboratory Tests ..................................................................... 26
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Findings ......... 28
List of Figures
Figure 1.
Study Design Schematic......................................................................... 7


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3.0
Introduction
This analysis plan describes the statistical analyses to be completed for Study 
Protocol W14-406 dated 22 April 2016, which incorporates protocol Amendments 1 and 
2.
This statistical analysis plan (SAP) provides details to further elaborate statistical methods 
as outlined in the protocol and describes analysis conventions to guide the statistical 
programming work.  Pharmacokinetics analysis will be described in separate documents.
The SAP will be signed off before the study database is locked.  Analyses will be 
performed using SAS® version 9.4 (SAS Institute, Inc., Cary, NC  27513) or higher on a 
Hewlett Packard workstation using the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to determine the proportion of primary and 
secondary sub-optimal responders to adalimumab (ADA) monotherapy (sub-optimal 
responders defined as subjects with an unsatisfactory response to treatment based on 
investigator assessment) with a PGA ≥ 3 and a PASI ≥ 5 who have a satisfactory response 
(defined as highly or completely satisfied with subject's therapy using the satisfaction 
questionnaire) after 16 weeks of treatment with adalimumab and methotrexate 
(ADA/MTX) combination therapy, based on investigator and subject satisfaction 
assessments.
The secondary objective of this study includes:
●
To determine the proportion of primary and secondary sub-optimal responders 
to ADA monotherapy (sub-optimal responders defined as subjects with an 
unsatisfactory response to treatment based on investigator assessment) with a 
PGA ≥ 3 and a PASI ≥ 5 who reach PASI 50, PASI 75 and PASI 90 16 weeks 
after initiation of ADA/MTX combination therapy.


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●
To define the demographic and clinical profile of subjects benefiting from 
ADA/MTX combination therapy.
●
To determine the magnitude, timing, and maintenance of the benefit of adding 
MTX to ADA by assessing investigator/subject satisfaction with treatment, 
PGA, PASI, and Dermatology Life Quality Index (DLQI) at 8, 16, and 
24 weeks after addition of MTX to therapy.
●
To determine change in DLQI from baseline in subjects initiated on 
ADA/MTX treatment.
●
To determine change in serum levels of ADA following addition of MTX and 
to characterize a possible correlation with changes in investigator/subject 
satisfaction with treatment, PGA, PASI and DLQI over the study period.  
Serum levels will be evaluated at baseline (initiation of ADA/MTX) and at 
Weeks 8, 16 and 24.
4.2
Design Diagram
This is a multicenter, single arm, open label longitudinal study.  The study entails a 
screening period up to 35 days, a 24-week treatment period and a 70-day safety follow-up 
period.
At screening, subjects who provide written consent will complete a satisfaction 
questionnaire.  PGA and PASI will be determined, and inclusion/exclusion criteria will be 
assessed.  Data collected at a screening visit will include:  subject demographics, disease 
history, vital signs, laboratory investigations and PGA, PASI and DLQI scores.
A 24-week single arm, open label treatment period during which subjects are treated by 
ADA/MTX.  Starting at the baseline visit (Day 0), subjects will continue to self-
administer ADA (40 mg eow) and will have oral MTX added to their treatment at a dose 
to be defined by the investigator (between 10 mg and 25 mg per week).  All subjects will 
also receive the non-investigational medicinal product oral folic acid as a dietary 
supplement since MTX acts as a folic acid antagonist.  The folic acid tablets will be 
provided by the investigator at a dose of 1.0 mg per day.  The required folic acid dose 


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must be taken every day of the week except on the day when MTX is taken.  The 
investigator will provide specific instructions on the number of folic acid tablets each 
subject should take.  At site Visits 8, 16 and 24 weeks after initiation of ADA/MTX, the 
following parameters will be assessed:  investigator assessment of disease status (using a 
satisfaction questionnaire); subject self-assessment of disease status (using a satisfaction 
questionnaire); PGA; PASI; DLQI; AEs; serum levels of ADA.  A schematic of the study 
design is shown in Figure 1:
Figure 1.
Study Design Schematic


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The 70-day safety follow-up period begins from the last dose of ADA, except those 
subjects that continue on ADA therapy after the end of study participation.  Subjects will 
be discontinued from the study if they withdraw consent or if they are deemed unsuitable 
to continue for any reason by the investigator in consultation with the AbbVie Medical 
Monitor.
4.3
Sample Size
This study was planned to have a 30 month recruitment period where it was anticipated 
that approximately 200 subjects will be recruited.  With this sample size the proportion of 
responders, defined as the proportion of subjects with a highly or completely satisfied 
response after 16 weeks of ADA/MTX therapy, based on an investigator assessment and 
subject self-assessment, can be estimated within ± 4.9% with 95% confidence when the 
point estimate is 15%, within ± 6.4% with 95% confidence when the point estimate is 
30%, or within ± 6.9% with 95% confidence when the point estimate is 50%.  Additional 
accuracy estimates are provided in the table below.
Table 1.
Accuracy Estimates with a Sample Size of 200 Subjects
Estimated Proportion of Responders (%)
Accuracy Estimate (%)
5
3.0
10
4.2
15
4.9
20
5.5
25
6.0
30
6.4
35
6.6
40
6.8
45
6.9
50
6.9
Note:
Proportion of responders can be estimated with ± accuracy with 95% confidence.  The size of the 95% 
Confidence Interval would be 2× Accuracy.


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Due to the enrollment plan change (enroll 50 patients or as the number of enrollment by 
31 December 2016), updated accuracy estimates with a sample size of 50 subjects, about 
the proportion of subjects with a highly or completely satisfied response after 16 weeks of 
ADA/MTX therapy based on an investigator assessment and subject self-assessment, are 
provided in the table below.
Table 2.
Accuracy Estimates with a Sample Size of 50 Subjects
Estimated Proportion of Responders (%)
Accuracy Estimate (%)
5
6.0
10
8.3
15
9.9
20
11.1
25
12.0
30
12.7
35
13.2
40
13.6
45
13.8
50
13.9
Note:
Proportion of responders can be estimated with ± accuracy with 95% confidence.  The size of the 95% 
Confidence Interval would be 2× Accuracy.
4.4
Interim Analysis
No interim analysis is planned for this study.
5.0
Analysis Populations
5.1
Definition of Analysis Populations
Intent-to-Treat (ITT) Populations
The Intent-to-Treat population will be used for all efficacy analyses, which is defined as 
all subjects who receive at least one dose of study ADA and at least one dose of MTX 
during the study.


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The primary efficacy analyses will also be conducted for the following sub-populations:
●
ITT Subjects who are defined as primary sub-optimal responders at baseline 
based on Investigator assessment.
●
ITT Subjects who are defined as secondary sub-optimal responders at baseline 
based on Investigator assessment.
Safety Populations
The Safety Population will be used for all safety analysis, which is defined as all subjects 
who received at least one dose of study ADA and one dose of MTX during the study.  In 
this study, the safety population is the same as the ITT Population.
Notations for Treatment Groups
●
ADA/MTX:  Subjects who received ADA and MTX as study drugs.
6.0
Analysis Conventions
6.1
Definition of Baseline
The last non-missing measurement collected on or before the maximum date of either the 
first dose of ADA or the first dose of MTX will be used as baseline for the summary of 
demographics and disease characteristics, the safety analyses, and the efficacy analyses.
6.2
Definition of Final Observation
Final observation is defined as the last non-missing observation collected within 70 days 
following the last dose of study ADA.
6.3
Definition of Rx Days (Days Relative to the First Dose of 
Study Drug)
We define the maximum date of either the first dose of study ADA or the first dose of 
MTX during the study as Rx Day 1 (RxDY 1).  Other Rx days (RxDY) are calculated for 
each time point as the number of days between Rx Day 1 and the specific time point.  Rx 


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days are positive values when the time point of interest is after Rx Day 1.  Rx days are 
negative values when the time point of interest is prior to Rx Day 1.  For example, the day 
prior to Rx Day 1 is defined as Rx Day –1 (there is no Rx Day 0).  Rx days will be 
calculated and displayed in all presentations of data in listing format.
6.4
Definition of Analysis Windows and Data Handling 
Conventions
All time points and corresponding time windows are defined based on Rx Days.
For visit-wise efficacy analyses, analysis time windows are constructed using the 
following algorithm:
1.
Determine the nominal Rx day for each scheduled visit (e.g., Week 8 [8 weeks 
after baseline visit] equals Rx Day 57);
2.
Determine the window around a specific nominal Rx day by adding or subtracting 
half of the interval between adjacent scheduled visits (e.g., days between Baseline 
and Week 8 is 56).  The threshold between adjacent scheduled visits is determined 
by splitting the interval evenly between the visits.
3.
If more than one assessment is included in a time window the assessment closest to 
the nominal day will be used.  If there are two observations equidistant to the 
nominal day, the latest one will be used in analyses.  If more than one assessment is 
included on the same day, then the worst assessment on that day will be used in 
analyses.
4.
If a subject does not have an assessment in a particular visit window due to the 
inability to follow the visit schedule, but has assessments in the same study period 
both before and after the visit window, then the worst of the two will be used for 
the visit.  Of note, this convention will be applied to the non-responder imputation 
method only.


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Analysis windows have been specified for the analysis of efficacy, laboratory parameters, 
study drug injections and vital signs for efficacy and safety populations in Table 3, 
Table 4, Table 5 and Table 6.  In order to include all post baseline data, the first post 
baseline interval starts on the day after the date of first study drug injection in each period 
(Rx Day 2) for all efficacy variables.
Table 3.
Windows for High-Sensitivity C-Reactive Protein (hs-CRP; Safety 
Population)
Scheduled Week
Nominal Day (Rx Day)
Interval
Baseline
1
≤ 1
Week 24
169
2 ~ 337a
a.
Minimum of Rx Day 337 and 70 days after the last dose of study ADA.
Rx day relative to the maximum date of either the first dose of study ADA or the first dose of MTX during the study.
Table 4.
Windows for All Other Efficacy and Safety Analyses (ITT/Safety 
Populations)
Scheduled Week
Nominal Day (Rx Day)
Interval
Baseline
1
≤ 1
Week 8
57
2 ~ 85
Week 16
113
86 ~ 141
Week 24
169
142 ~ 197a
a.
Minimum of Rx Day 197 and 70 days after the last dose of study ADA.
Rx day relative to the maximum date of either the first dose of study ADA or the first dose of MTX during the study.


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Table 5.
Windows for ADA Injection (Safety Population)
Scheduled Week
Nominal Day (Rx Day)
Interval
Baseline
1
≤ 1
Week 2
15
2 ~ 22
Week 4
29
23 ~ 36
Week 6
43
37 ~ 50
…
…
…
Week K
K × 7 + 1
K × 7 – 5 ~ K × 7 + 8
Week 22
155
149 ~ 162
Rx day relative to the first dose date of study ADA during the study.
Table 6.
Windows for MTX Administration (Safety Population)
Scheduled Week
Nominal Day (Rx Day)
Interval
Baseline
1
≤ 1
Week 1
8
2 ~ 11
Week 2
15
12 ~ 18
Week 3
22
19 ~ 25
…
…
…
Week K
K × 7 + 1
K × 7 – 2 ~ K × 7 + 4
Week 23
162
159 ~ 165
Rx day relative to the first dose date of MTX during the study.
6.5
Missing Data Imputation
No global imputation is taking place at the database level.  Efficacy and safety related 
imputations, as applicable, are outlined in Section 10.1 and Section 11.1, respectively.
6.6
Rounding of Numeric Results
Rounding will be performed for presentation of results.  No rounding will be performed 
before or during analyses. 
The mean and median will be rounded for presentation to 1 decimal more than the data 
were entered into the database.  The standard deviation will be rounded to 2 decimal 


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places more than the data that were entered into the database.  The minimum and 
maximum values will be presented as entered into the database. 
Probabilities will be rounded to 3 decimal places before assignment of statistical 
significance and will be presented in rounded format.  Probabilities that round to zero or 
are reported by SAS as zero will be presented as "< 0.001."
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
All demographic and baseline variables will be described with summary statistics.  
Categorical data will be summarized using the frequency and percentage; continuous data 
will be summarized using the mean, standard deviation, median, first quartile, 
third quartile, minimum, and maximum.  The number of non-missing values will also be 
summarized.
All summaries will be presented for the ITT Population.  No statistical tests will be 
performed.
The following demographic and baseline parameters will be summarized.
Demographic
●
Sex [male, female]
●
Age [years]
●
Age category [< 40, 40 – 64, ≥ 65]
●
Body weight [kg] – overall and by gender
●
Height [cm]
●
Body mass index [kg/m2]
●
BMI Category [< 25 , 25 – < 30, ≥ 30]
●
Race
●
Ethnicity


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Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [current, former, never, unknown]
●
Alcohol Use [current, former, never, unknown]
Baseline Characteristics 
●
Duration of Ps:  The duration of Ps will be calculated relative to the date of 
screening visit (i.e., duration = [date of screening visit – date of onset] + 1.  
Duration of Ps will be expressed in years, by dividing the result in days by 
365.25.
●
Psoriatic arthritis (PsA) status [yes, no]
●
Duration of Psoriatic arthritis (PsA):  The duration of PsA will be calculated 
relative to the date of screening visit (i.e., duration = [date of screening visit –
date of onset] + 1.  Duration of PsA will be expressed in years, by dividing the 
result in days by 365.25.
●
Family history of psoriasis [yes, no]
Baseline Characteristics – Efficacy Assessments
●
Psoriasis Area and Severity Index (PASI)
●
Physician's Global Assessment of Skin Psoriasis (PGA-S)
●
Dermatology Life Quality Index (DLQI)
●
Body Surface Area affected by Psoriasis (BSA)
●
Satisfaction Questionnaire – Investigator
●
Satisfaction Questionnaire – Subject
●
Hi-sensitivity C-reactive Protein (hs-CRP)
Vital Signs
●
Systolic blood pressure (mmHg)
●
Diastolic blood pressure (mmHg)
●
Pulse (bpm)


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●
Respiratory rate (rpm)
●
Body temperature (°C)
●
ECG (Normal, Abnormal – not clinically significant, Abnormal – clinically 
significant, Unable to evaluate)
Chest X-Ray, TB Test and BCG Vaccination History
●
Chest x-ray (Normal, Abnormal, Missing)
●
Calcified granulomas (Absent, Present, Missing)
●
Pleural scarring (Absent, Present, Missing)
●
Pleural thickening (Absent, Present, Missing)
●
Signs of active TB (No, Yes, Missing)
●
PPD TB test (< 5 mm, ≥ 5 mm, missing)
●
Quantiferon TB test (Negative, Indeterminate, Positive, Missing)
●
Enrolled on TB Prophylaxis (No, Yes, Missing)
●
TB History – at higher risk (No, Yes, Missing)
●
BCG immunization (No, Yes, Unknown)
●
Active or latent TB (No, Yes, Missing)
The following variables will be presented in listing format:
●
Physical Examination
●
Pregnancy Test
7.2
Medical History
Medical history will be summarized using body systems and condition/diagnosis as 
captured on the eCRF.  The body systems will be presented in alphabetical order and the 
conditions/diagnoses will be presented in alphabetical order within each body system.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized.  Subjects reporting more than one condition/diagnosis within a body system 
will be counted only once for that body system.


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7.3
Prior Treatment and Concomitant Medications
The number and percent of subjects who received a prior or concomitant medication will 
be tabulated by the generic name assigned by the World Health Organization (WHO) 
Dictionary.
A prior medication is defined as any medication taken prior to the maximum date of either 
the first dose of study ADA or the first dose of MTX during the study.  A concomitant 
medication is defined as any medication that started prior to the aforementioned date and 
continued to be taken after the maximum date of either the first dose of study ADA or the 
first dose of MTX or any medication that started on or after the date of the first dose of 
study drug, but not after the last study ADA dose date during the study.
Prior Ps treatment received and discontinued (including reason for discontinuation) prior 
to screening will be summarized as well.
7.4
Protocol Deviation
Number and percentage of subjects who reported at least 1 of the following protocol 
deviation categories will be provided:
●
Inclusion/exclusion criteria deviations
●
Developed withdrawal criteria but was not withdrawn
●
Received wrong treatment or incorrect dose
●
Received excluded concomitant treatment
7.5
Inclusion/Exclusion Criteria
Number and percentage of subjects who did not meet inclusion/exclusion criteria will be 
reported. 
8.0
Patient Disposition
The summary of subject disposition for the ITT Population will include:


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●
Number of subjects in the ITT population 
●
Number and percentage of subjects who complete the entire study
●
Number and percentage of subjects who prematurely discontinue from study
●
Number and percentage of subjects who remain on ADA/MTX combo after 
completion from study
●
Number and percentage of subjects who remain ADA only after completion 
from study
In addition, the reasons for premature discontinuation (primary reason and all reasons) 
will be summarized with frequencies and percentages.  Subjects with multiple reasons for 
premature discontinuation will be counted once in the calculation of the number and 
percentage of total discontinuations ("Premature Discontinuation").
9.0
Study Drug Exposure and Compliance
Summary of study drug exposure and compliance will be provided.
The study drug exposure (days) will be summarized with the mean, standard deviation, 
minimum, first quartile, median, third quartile and maximum, for ADA and for MTX.  
Study drug exposure will be summarized as follows.
Study Drug Exposure (in Days) for ADA:
●
Date of last study ADA injection – Date of first study ADA injection 
+ 14 days. 
Study Drug Exposure (in Days) for MTX:
●
Date of last dose of MTX – Date of first dose of MTX + 7 days.
Compliance (%), which is defined as the number of injections received divided by the 
number of injections planned for ADA, and as the doses received divided by the doses 
planned for MTX, during the subject's participation in the study (rounded to 0.1%), will 
be summarized separately.  In addition, at each scheduled time point, the number of ADA 


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injections and MTX doses received and compliance will be summarized with frequencies 
and percentages.
When computing compliance at each scheduled time point, the denominator for each 
week will include all subjects in each analysis population who have not prematurely 
discontinued prior to the scheduled study drug injection.  The date of prematurely 
discontinuation will be taken from vital sign dataset.
10.0
Efficacy Analysis
10.1
General Considerations
Point estimates and 95% confidence intervals (CIs) based on normal approximation will 
be provided for the discrete efficacy variables such as the proportion of responders to 
ADA/MTX.  Change and percent change from baseline variables will be estimated using 
an appropriate estimation from a Mixed Model and statistical tests of change from 
baseline equal to zero will be carried out at the 0.05 significance level; 95% confidence 
intervals will also be provided.
Descriptive statistics will be provided.  These include the number of observations, mean, 
and standard deviation for continuous variables and counts and percentages for discrete 
variables.  Baseline and visit means at each scheduled visit will also be provided for 
change and percent change from baseline continuous variables.
Missing data will be imputed using the following methods for the efficacy analyses:
●
Non-Responder Imputation (NRI):  The NRI analysis will categorize any 
subject who has missing value at a specific visit as non-responder (or 
"dissatisfied" in satisfaction variables) for that visit.  NRI will be the primary 
approach in analyses of categorical variables.
●
Mixed-effect Model Repeat Measurement (MMRM):  A mixed-effect model 
will be developed for continuous endpoint repeated measured at Baseline, 
Week 8, 16, and 24; controlling for time and subject ID.  The fixed effects will 
be used to report the visit means at corresponding visits.  Change and percent 


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change from baseline will be determined accordingly.  MMRM will be the 
primary approach in analyses of continuous variables.
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the 
completed evaluation from the previous visit to impute missing data at later 
visits.  Baseline efficacy evaluations will not be carried forward.  LOCF will 
be a sensitivity approach in analyses of continuous variables and categorical 
variables.
All efficacy variables will be analyzed for the ITT population overall, and separately by 
primary sub-optimal responders and secondary sub-optimal responders at baseline.
10.2
Efficacy Variables
10.2.1
Primary Efficacy Variable
The primary efficacy endpoints will be:
●
Based on investigator assessment, the proportion of subjects achieving a 
satisfactory response at Week 16 (satisfactory response is defined as highly or 
completely satisfied with therapy based on responses to the satisfaction 
questionnaire).
●
Based on subject self-assessment, the proportion of subjects achieving a 
satisfactory response at Week 16 (satisfactory response defined as highly or 
completely satisfied with therapy based on responses to the satisfaction 
questionnaire).
10.2.2
Secondary Efficacy Variables
Secondary efficacy variables included:
●
Based on investigator assessment, the proportion of subjects achieving a 
satisfactory response at scheduled visits other than Week 16
●
Based on subject self-assessment, the proportion of subjects achieving a 
satisfactory response at scheduled visits other than Week 16
●
Proportion of subjects achieving PASI 50/75/90/100 at all scheduled visits


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●
Change and percent change from baseline in PASI at all scheduled visits.
●
Proportion of subjects achieving a clinical response defined as a PGA of 
"Clear" or "Minimal" at all scheduled visits
●
Change and percent change from baseline in DLQI at all scheduled visits
●
Based on investigator assessment, the proportion of subjects at each of the 
five categories of satisfaction at all scheduled visits
●
Based on subject self-assessment, the proportion of subjects at each of the 
five categories of satisfaction at all scheduled visits
●
Proportion of subjects achieving a DLQI score of 0 or 1 at all scheduled visits
●
Change and percent change from baseline in BSA at all scheduled visits.
●
Change from baseline in hs-CRP at all scheduled visits.
10.3
Handling of Multiplicity
No multiplicity adjustment will be applied to the efficacy analyses.
10.4
Efficacy Subgroup Analyses
PASI 50/75/90/100 endpoints will also be analyzed in the following subgroup:
●
Subjects on ADA 40 mg eow prior to baseline or 40 mg once weekly prior to 
wash-out.
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital sign 
measurements.  Safety analyses with group comparison will be carried out using the 
Safety Population.
Mean changes from baseline in all continuous laboratory parameters and vital signs 
variables to post-baseline visits will be summarized for the Safety Population.  No 


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statistical tests will be applied.  The number of non-missing values will be given.  Missing 
safety data will not be imputed.
11.2
Analysis of Adverse Events
Treatment-emergent adverse events (TEAEs) will be tabulated. 
Adverse events that start more than 70 days after the last study ADA injection during the 
study will not be included in the summaries; however, if reported, these adverse events 
will be included in the adverse event data listings.  A summary of all pretreatment 
(i.e., event start date is prior to the date of the first study drug injection) serious adverse 
events will be provided.  Adverse events will be summarized by patient year as well.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAE) are defined as following:
TEAEs are defined as any event with an onset date that is on or after the maximum date of 
either the first dose of study ADA or the first dose of MTX and no more than 70 days 
after the last study ADA injection during the study.
If an incomplete onset date is collected for an adverse event, the event will be assumed to 
be treatment-emergent unless there is other evidence that confirms that the event is not 
treatment-emergent (e.g., the event end date is prior to the study drug start date).
Adverse event data will be summarized and presented using the Medical Dictionary for 
Drug Regulatory Activities (MedDRA®) system organ class (SOCs) and preferred terms 
(PTs).
11.2.1.1
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized for the 
following AE categories:
●
Any AE


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●
Any AE with a Reasonable Possibility of being related to study drug by the 
investigator
●
Any severe AE
●
Any serious AE
●
Any serious AE with a Reasonable Possibility of being related to study drug 
by the investigator
●
Any AE leading to discontinuation of study drug 
●
Any AE of special interest
●
Any AE Leading to Death
●
Any Deaths
Additional AEs may be considered for tabulation/summary based on recommendations for 
Clinical and Safety as deemed appropriate.  Any event with an unknown severity will be 
considered as severe and any AE with an unknown relationship will be considered as 
drug-related.
11.2.1.2
Adverse Events by System Organ Class and Preferred Term
TEAEs will be summarized and presented using primary Medical Dictionary for
Regulatory Activities (MedDRA version 16.1 or later version) system organ classes 
(SOCs) and preferred terms (PTs).  The SOCs will be presented in alphabetical order, and 
the PTs will be presented in alphabetical order within each SOC.
A subject who reports more than 1 AE in different SOCs will be counted only once in the 
overall total.  A subject who reports more than 1 AE in different PTs, which are in the 
same SOC, will be counted only once in the SOC total.  A subject who reports more than 
1 AE with the same PT will be counted only once for that PT using the most extreme 
incident (i.e., most severe for the severity tables and most related for the relationship 
tables).


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11.2.1.3
Adverse Events by Maximum Severity
TEAEs will also be summarized by maximum severity. If a subject has an adverse event 
with unknown severity, then the subject will be counted in the severity category of 
"unknown," even if the subject has another occurrence of the same event with a severity 
present.  The only exception is if the subject has another occurrence of the same adverse 
event with the most extreme severity "Severe."  In this case, the subject will be counted 
under the "Severe" category.
11.2.1.4
Adverse Events by Maximum Relationship
TEAEs will also be summarized by maximum relationship to study drug, as assessed by 
the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same event with a relationship present.  The only exception is if 
the subject has another occurrence of the same adverse event with a relationship 
assessment of "Reasonable Possibility."  In this case, the subject will be counted under the 
"Reasonable Possibility" category.
11.2.1.5
Adverse Events by "Reasonable Possibility" of Being 
Related to Study Drug  
TEAEs will also be summarized by relationship defined by "Reasonable Possibility" of 
being related to study drug, as assessed by the investigator.  If a subject has an AE with an 
unknown relationship, then the subject will be counted in as with "Reasonable 
Possibility."
11.2.1.6
Serious Adverse Events (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.


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11.2.1.7
Adverse Events of Special Interests
The Adverse Events of Special Interests (AESI) categories following the most updated 
PSAP will be summarized and presented using primary MedDRA system organ classes 
(SOCs) and preferred terms (PTs).
11.2.1.8
Adverse Events by 100 Patient Years
TEAEs will be summarized by event rate per 100 patient years, defined as
,
where total patient years is defined as the sum of the study drug exposure of all subjects 
normalized by 365.25, and rounded to one decimal place.
11.3
Analysis of Laboratory Data
11.3.1
Variables and Criteria Defining Abnormality
Clinical laboratory tests conducted in the study are listed in the table below.  Laboratory 
parameters will be reported using the standard international (SI) units.
Note:  For urinalysis, only specific gravity and pH will be summarized.
Years
Patient 
Total
TEAEs
of
Number 
100!


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Table 7.
Clinical Laboratory Tests
Chemistry
Hematology
Urinalysis
Quantiferon TB Gold
Other
Albumin
Alkaline
Phosphatase
ALT
AST
Calcium
Cholesterol
Creatinine
Enzymatic
Glucose, Random, 
Serum
Phosphate
Potassium
Sodium
Total Bilirubin
Total Protein
Triglycerides
Urea (BUN)
Uric Acid
Basophils
Eosinophils
HCT
HGB
Lymphocytes
Monocytes
Neutrophils
Platelets
RBC
WBC
Blood
Glucose, Urine
Ketones
Leukocytes
Nitrite
pH
Protein, Urine
Specific Gravity
Urine 
Microscopic
Quantifeton Mit. 
Minus NIL
Quantiferon NIL
Quantiferon TB Gold
Quantiferon TB minus 
NIL
ANA Pattern
Anti-ds DNA
Antinuclear
Antibody
Hs-CRP
HBV DNA PCR
Taqman
HCG, 
Quantitative
11.3.2
Statistical Methods
11.3.2.1
Analysis for Continuous Laboratory Data
Mean changes from baseline to post-baseline visits and to the final visit will be 
summarized with the baseline mean, the visit mean, change from baseline mean, standard 
deviation, and median.
11.3.2.2
Shift Table Analyses
The laboratory data will be categorized as low, normal, or high based on the normal 
ranges of the laboratory used in this study.  The shift tables will tabulate the number and 
percentage of subjects with baseline values below/within/above the normal range versus 
minimum/maximum/final values below/within/above the normal range.


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Shift tables for changes from baseline according to the normal range will be provided for 
each hematology, clinical chemistry and urinalysis (specific gravity and pH only) 
parameter.  Shifts from baseline to the following endpoints will be considered:  minimum 
value, maximum value and final value.  Categories of "low or normal" and "high or 
normal" will be included at baseline in addition to the categories of "low," "normal," 
"high" and "missing."
11.3.2.3
Potentially Clinically Significant Laboratory Values
Frequencies and percentages of subjects with post baseline lab values that are Grade 3 or 
above according to the CTC toxicity criteria will be summarized.  A separate listing will 
be provided that presents all of the subjects and values that are CTC toxicity Grade 3 or 
above.  For each of these subjects, the whole course of the respective parameter will be 
listed.
Additional summaries will be presented for liver function tests including ALT or serum 
glutamic-pyruvic transaminase (SGPT), AST or serum glutamic-oxaloacetic transaminase 
(SGOT), alkaline phosphatase, and total bilirubin.  Each laboratory value will be 
categorized as follows:
●
< 1.5 × ULN
●
≥ 1.5 × ULN – < 3.0 × ULN
●
≥ 3.0 × ULN – < 5.0 × ULN
●
≥ 5.0 × ULN – < 8.0 × ULN
●
≥ 8.0 × ULN
where ULN is the upper normal limit.
Shift tables of baseline to the maximum values, and from baseline to final value will be 
presented using these five categories.  
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following four criteria:


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●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
Alkaline phosphatase ≥ 2.5 × ULN, or
●
Total bilirubin ≥ 1.5 × ULN
11.4
Analysis of Vital Signs
All analyses will be conducted for subjects in the Safety Population.
11.4.1
Variables and Criteria Defining Abnormality
The following vital sign parameters will be assessed:  Systolic blood pressure [mmHg], 
Diastolic blood pressure [mmHg], Pulse [beats per minute], Respiratory rate [breaths per 
minute], Body Temperature [°C], Weight [kg].  The following table presents the Criteria 
for Potentially Clinically Significant Vital Sign Findings.
Table 8.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic Blood Pressure
Low
Value ≤ 90 mmHg and/or decrease ≥ 20 mmHg from baseline
High
Value ≥ 180 mmHg and/or increase ≥ 20 mmHg from baseline
Diastolic Blood Pressure
Low
Value ≤ 50 mmHg and/or decrease ≥ 15 mmHg from baseline
High
Value ≥ 105 mmHg and/or increase ≥ 15 mmHg from baseline
Pulse
Low
Value ≤ 50 bpm and/or decrease ≥ 15 bpm from baseline
High
Value ≥ 120 bpm and/or increase ≥ 15 bpm from baseline
11.4.2
Statistical Methods
Mean changes from baseline to post-baseline visits and to the final visit in vital sign 
parameters will be summarized with the baseline mean, the visit mean, change from 
baseline mean, standard deviation, median.
Vital signs results satisfying the criteria for potentially clinically significant values will be 
identified in a listing.  For each of these subjects, the whole course of the respective 


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parameter will be listed.  The number and percentage of subjects who have at least 
one value meeting criteria for potentially clinically significant values will be provided for 
each selected vital sign parameter.
11.5
Analysis of ECG Parameters
ECG results will be listed in the data listings.
11.6
Analysis for Other Safety Variables
Not applicable.
11.7
Safety Subgroup Analyses
No safety subgroup analyses will be performed.
12.0
Special Statistical Topics
Not applicable.
13.0
List of Tables, Figures and Data Listings that Are to 
Be Programmed
To be provided in a separate document.
14.0
Summary of Changes
Not applicable now.