Conditions: Generalized Pustular Psoriasis (GPP) Adalimumab Japanese
Keywords: efficacy safety
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study was to investigate the efficacy, safety, and pharmacokinetics of adalimumab in Japanese participants with generalized pustular psoriasis (GPP) who did not have an adequate response to their currently approved treatment.

Detailed description:
This was a Phase 3, multicenter, open-label, single-arm study of adalimumab in Japanese participants with generalized pustular psoriasis (GPP). The study included a 30-day screening period, a 52-week treatment period, and a 70-day follow-up period. The dose regimen of adalimumab used in this study was 80 mg at Week 0 by subcutaneous (SC) injection, followed by 40 mg every other week (eow) on and after Week 2 until Week 50. Dose escalation to 80 mg eow was allowed for participants who did not have adequate response on or after Week 8.

Arms:
arm 1: 80 mg at Week 0 by subcutaneous (SC) injection, followed by 40 mg every other week (eow) on and after Week 2 until Week 50. Dose escalation to 80 mg eow was allowed for participants who did not have adequate response on or after Week 8.

Interventions: intervention 1: Adalimumab
Intervention descriptions: intervention 1: Adalimumab pre-filled syringe, administered by subcutaneous injection

Protocol document:
Prot_001.pdf: 
Adalimumab 
M14-193 Protocol
1
1.0
Title Page
Clinical Study Protocol M14-193
A Multicenter, Open-Label Study of Adalimumab in 
Japanese Subjects with Generalized Pustular 
Psoriasis
AbbVie Investigational
  Product:
Adalimumab
Date:
08 June 2015
Development Phase:
3
Study Design:
This is a multicenter, open-label study of adalimumab in 
Japanese subjects with Generalized Pustular Psoriasis.
Investigator:
Multicenter:  Investigator information is on file at AbbVie
Sponsor*:
AbbVie GK (Japan)
Sponsor/Emergency
  Contact:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
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.
/$5


Adalimumab 
M14-193 Protocol
2
1.1
Synopsis
AbbVie Inc.
Protocol Number:  M14-193
Name of Study Drug:  Adalimumab
Phase of Development:  3
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  08 June 2015
Protocol Title:  A Multicenter, Open-label Study of Adalimumab in Japanese Subjects with Generalized 
Pustular Psoriasis
Objective:
The primary objective is to investigate efficacy, safety and pharmacokinetics of adalimumab in Japanese 
subjects with Generalized Pustular Psoriasis (GPP).
Investigators:  Multicenter Trial (Investigator information on file at AbbVie).
Study Sites:  Approximately 10 sites in Japan
Study Population:  Male and female Japanese subjects ≥ 15 and ≤ 75 years of age with a diagnosis of 
GPP.  GPP patients with previous infliximab exposure can be enrolled.
Number of Subjects to be Enrolled:  10 subjects
Methodology:
This study is a 52-week trial.  The study will include a 30-day screening period, 52-week open-label 
active treatment period, and a subsequent 70-day follow-up period after the last dose.
Subjects will be Japanese patients diagnosed as GPP with total skin score of at least 3 and erythema with 
pustule (skin score of at least 1) in Japan Dermatology Association (JDA) severity index of GPP in GPP 
Medical Care Guideline 2014.
Subjects who meet all the inclusion criteria and none of the exclusion criteria will be enrolled and treated 
subcutaneously with adalimumab 80 mg at the Baseline for initial dose and then 40 mg eow on and after 
Week 2 until Week 50.  Dose-escalation to 80 mg eow is allowed if subjects have inadequate response 
(i.e., minimal improvement, unchanged or worsened) on or after Week 8. Dose reduction is not allowed 
throughout the study period for the dose-escalated subjects.
The primary efficacy variable is the proportion of subjects achieving Clinical Response (CR) at 
Week 16.  CR is defined as the reduction of skin score of 1 (if the subject's Baseline skin score is 3) or 2 
(if the subject's Baseline skin score is 4 or higher) relative to Baseline, according to JDA severity index 
of GPP in GPP Medical Care Guideline 2014.
Study visits will occur at Baseline (Week 0), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52, 
and at the Premature Discontinuation visit if the subject discontinues prior to Week 52.  No open label 
extension (OLE) study is planned after this 52-week study.


Adalimumab 
M14-193 Protocol
3
Methodology (Continued):
Adverse events will be collected throughout the study.  Subjects who complete this study or who decide 
to withdraw the study participation will have a Day 70 follow-up phone call following their last dose of 
study drug to determine the status of any ongoing adverse events (AEs) or serious adverse events 
(SAEs), or the occurrence of any new AEs or SAEs.
Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion criteria are for subjects enrolled in this study.
Main Inclusion:
1.
Subject must be able and willing to provide written informed consent and comply with the 
requirements of this study protocol.  If the subject is < 20 years old, a subject's parent or legal 
guardian must be willing to give written informed consent.
2
Male or female ≥ 15 and ≤ 75 years of age at the Baseline visit.
3.
Subject must have a diagnosis of Generalized Pustular Psoriasis (GPP) for at least 60 days prior to 
Screening and determined by the Investigator through subject interview and review of medical 
history during the Screening Period.
4.
Subject must have had an inadequate response to, or demonstrated intolerance to, or have a 
contraindication to the currently approved treatment for their GPP (excluding infliximab).
5.
Subject must have total skin score of at least 3 and erythema with pustules (skin score of at least 1) 
in Japan Dermatology Association (JDA) severity index of GPP in GPP Medical Care Guideline 
2014 in Japan at Baseline.
6.
Subject may be included if they have previously experienced a benefit for their GPP from 
infliximab and discontinued its use due to a subsequent loss of response (i.e., judged by the 
Investigator to have responded to infliximab in the past and subsequently experienced an overall 
lack of improvement or worsening of GPP related symptoms, "infliximab secondary failure") or 
intolerance (i.e., in the opinion of the investigator therapy was discontinued as a result of a 
significant acute or delayed infusion/administration reaction to the medication).  Confirmed 
documentation indicating loss of response or lack of tolerability will be required.
7.
If female, subject is either not of childbearing potential, defined as postmenopausal for at least 
1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy and/or hysterectomy) or 
is of childbearing potential who must have negative result of pregnancy test performed at the 
Screening and at the Baseline.  Female subject of childbearing potential is practicing an approved 
method of birth control throughout the study and for 150 days after last dose of study drug.  


Adalimumab 
M14-193 Protocol
4
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
8.
If female, subject is not breast-feeding throughout the study and for 150 days after last dose.
9.
Subject has a negative TB Screening Assessment (including a PPD test and/or Quantiferon-TB 
Gold test, or equivalent) and negative chest x-ray (CXR) (posterior anterior [PA] and lateral view).  
If the subject has evidence of a latent TB infection, the subject must initiate and complete a 
minimum of 2 weeks of an ongoing TB prophylaxis or have documented completion of a full 
course of TB prophylaxis prior to Baseline.
10. Subject is judged to be in good general health, as determined by the Principal Investigator based 
upon the results of a medical history, physical examination, laboratory profile, chest x-ray, and a 
12-lead electrocardiogram (ECG) performed during the Screening.
Main Exclusion:
1.
Subject has erythrodermic psoriasis, guttate psoriasis, or subcorneal pustular dermatosis at 
Screening.
2.
Subject diagnosed drug-induced GPP.
3.
Total score of 14 or more in JDA severity index of GPP in GPP Medical Care Guideline 2014 in 
Japan.
4.
Subject has other active skin disease (e.g., urticarial, atopic dermatitis) or skin infections (bacterial, 
fungal, or viral) that may interfere with evaluation of GPP, with the exception of footpad 
trichophytosis (athlete's foot).
5.
Subject who cannot taper off cyclosporine until Week 8 after the Baseline and during the study.  
Subject who cannot taper etretinate to 20 mg/day at the maximum dose prior to the Baseline.
6.
Subjects who is receiving oral corticosteroid more than 10 mg/day at the Baseline, and cannot taper 
off until Week 4 after the Baseline and during study.
7.
Subject who received granulocyte and monocyte adsorption apheresis (GMA) therapy for at least 
28 days prior to the Baseline and cannot avoid this therapy during the study.
8.
Subjects who received any investigational agents of chemical or biologic nature (including 
anti-IL17 agents), which would be efficacious to GPP or psoriasis-related skin disease for at least 
28 days or 5 half-lives of the drug prior to the Baseline, whichever is longer, and during the study.
9.
Subjects who received ustekimumab for at least 84 days prior to the Baseline and during the study.
10. Subject who cannot avoid PUVA or narrow-band UVB phototherapy for at least 14 days prior to 
the Baseline and during the study.
11. Subject who cannot avoid "Strongest" corticosteroid in Japanese classification of topical therapy for 
at least 14 days prior to the Baseline and during the study.  The other topical therapies including 
corticosteroids ("Very strong," "Strong," "Medium" and "Weak" in Japanese classification), 
vitamin D3 and topical tacrolimus can be allowed to use concomitantly.
12. Subject who cannot avoid anti-tumor necrosis factor (TNF) agent other than infliximab and 
adalimumab (including but not limited to etanercept [Enbrel], golimumab [Simponi] or 
certolizumab pegol [Cimzia]) for at least 28 days prior to the Baseline and during the study.
13. Prior exposure to adalimumab.


Adalimumab 
M14-193 Protocol
5
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
14. Subject who has previous used infliximab:
!
and has not clinically responded at any time ("primary non-responder") unless subject 
experienced a treatment limiting reaction, or
!
who used infliximab ("secondary treatment failure") within 42 days prior to the Baseline.
15. Prior exposure to medications that have a potential or known association with progressive 
multifocal leukoencephalitis (PML) (i.e., natalizumab [Tysabri], rituximab [Rituxan], efalizumab 
[Raptive]).
16. Subject with any active viral infection that makes the subject an unsuitable candidate for the study 
based on the investigator's clinical assessment.
17. Hepatitis B:  HBs Ag positive (+) or detected sensitivity on the HBV-DNA PCR qualitative test for 
HBc Ab/HBs Ab positive subjects.
18. Subject with known hypersensitivity to the excipients of adalimumab.
19. Positive pregnancy test at the Screening (serum) or the Baseline (urine).
20. Female who is breast-feeding or considering becoming pregnant during the study.
21. History of clinically significant drug or alcohol abuse in the last 12 months.
22. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease.
23. History of moderate to severe congestive heart failure (NYHA class III or IV), recent 
cerebrovascular accident and/or any other condition which, in the opinion of the investigator, would 
put the subject at risk by participation in the study.
24. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other 
than a successfully treated non-metastatic cutaneous squamous cell carcinoma, basal cell carcinoma 
or localized carcinoma in situ of the cervix.
25. Chronic recurring infections or active TB.
26. Infection(s) requiring treatment with intravenous (IV) anti-infectives (antibiotics, antivirals, 
antifungals) within 30 days prior to Baseline or oral anti-infectives (antibiotics, antivirals, 
antifungals) within 14 days prior to Baseline.
27. History of invasive infection (listeriosis, histoplasmosis), human immunodeficiency virus (HIV). 
28. Screening laboratory and other analysis show any of the following abnormal results:
!
AST, ALT > 1.75 × upper limit of the reference range;
!
WBC count < 3.0 × 109/L;
!
Electrocardiogram (ECG) – with clinically significant abnormalities 
!
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert syndrome;
!
Serum creatinine > 1.6 mg/dL.
29. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the 
study.


Adalimumab 
M14-193 Protocol
6
Investigational Products:
Adalimumab
Doses:
80 mg starting at Baseline (Week 0) and 40 mg eow on and after 
Week 2 until Week 50.  Dose escalation to 80 mg eow is allowed for 
subjects who do not have appropriate response and meeting dose 
escalation criteria on or after Week 8.  Dose reduction is not allowed 
after dose escalation until the study end.  Treatment of study drug will 
not occur at Week 52.
Mode of Administration:
Subcutaneous injection (SC)
Duration of Treatment:  52 weeks
Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of subjects achieving Clinical Response (CR) at 
Week 16.  CR is defined as reduction of skin score of 1 (if the subject's Baseline skin score is 3) or 2 (if 
the subject's Baseline skin score is 4 or higher) relative to Baseline, according to JDA severity index of 
GPP in GPP Medical care guideline 2014 in Japan.
Pharmacokinetic:
Blood samples will be collected for the measurement of serum adalimumab concentrations at the 
Baseline and Weeks 2, 4, 8, 12, 16, 24, 36, and 52 or at the Premature Discontinuation visit.  Blood 
samples will be collected for the measurement of anti-adalimumab antibody (AAA) at the Baseline, 
Weeks 8, 16, 24, 36, and 52 or at the Premature Discontinuation visit.  Blood samples will be also 
collected prior to dose escalation.
Safety:
Adverse events, laboratory data and vital signs will be assessed throughout the study.
Statistical Methods:
Efficacy:
The primary efficacy variable is the proportion of subjects achieving Clinical Response (remission and 
improvement) at Week 16;
Secondary variables, to be analyzed at each scheduled visit, include:
!
Proportion of subjects achieving Clinical Response (except Week 16, which is the primary 
endpoint).
!
Proportion of subjects achieving remission.
!
Change from the Baseline in total GPP score (skin and systemic/laboratory test).
!
Change from the Baseline in JDA severity index of GPP.
!
Change and Percent change from the Baseline in total skin score.
!
Change from the Baseline in total systemic/laboratory test score.
!
Change from the Baseline in score of erythema area (overall) and BSA (BSA of GPP).
!
Change from the Baseline in score of erythema area with pustule and BSA.
!
Change from the Baseline in score of edema area and BSA.


Adalimumab 
M14-193 Protocol
7
Statistical Methods (Continued):
Efficacy:
!
Change from the Baseline in Body temperature.
!
Change from the Baseline in WBC.
!
Change from the Baseline in hs-CRP.
!
Change from the Baseline in serum Albumin.
!
Proportion of subjects achieving "Mild" in JDA severity index of GPP for patients with 
"Moderate" or "Severe" at Baseline.
!
Proportion of subjects achieving Treatment Success in PGA (reduction of 2 grades).
!
Change from the Baseline in PGA grade.
!
Proportion of subjects achieving PGA 0/1 for patients with PGA grade at least 2 at Baseline.
!
Proportion of subjects achieving PASI 90.
!
Proportion of subjects achieving PASI 75.
!
Proportion of subjects achieving PASI 50.
!
Change and Percent change from the Baseline in PASI score.
!
Proportion of subjects achieving DLQI = 0.
!
Change from the Baseline in DLQI score.
!
Change from the Baseline in SF-36 score.
!
Proportion of subjects taking systemic co-medication for GPP (etretinate, MTX).
!
Proportion of subjects taking topical co-medication for GPP (corticosteroid, vitamin D3, 
tacrolimus).
Determination of the Sample Size:
GPP is designated as the specified rare and intractable disease in Japan and patient number is quite 
limited.  Assuming the Clinical Response rate of adalimumab in GPP is similar to PASI 75 response in 
plaque psoriasis, 50% to 60% as expected response rate in adalimumab treatment and 10% as a threshold 
response rate is hypothesized.
A sample size of 6 to10 provides over 90% power to detect the difference between expected Clinical 
Response rate (50% to 60%) and threshold response rate (with no medication, 10%) in GPP, using a 
one sample Chi-square test with 2.5% one-sided significance level.  Using Fisher's exact test, an exact 
binomial test with a nominal 0.025 one-sided significance level will have 82% power to detect the 
difference between the threshold proportion of 10% and the expected proportion of 50%.
Therefore, the target number of subjects is set 10 subjects, taking the study feasibility into consideration.
Statistical Methods (Continued):
Determination of the Sample Size (Continued):
Threshold Response Rate
Expected Response Rate
Actual Power
No of Subjects
10%
50%
91.2%
10
10%
55%
91.6%
8
10%
60%
90.3%
6


Adalimumab 
M14-193 Protocol
8
Pharmacokinetic:
Adalimumab trough serum concentrations will be reported at each time point using descriptive statistics.  
The relationship between adalimumab concentrations and Clinical Response improvement will be 
determined as appropriate.
Immunogenicity:
AAA will be evaluated for each subject and rates of AAA positive will be calculated.  As appropriate, 
the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and treatment emergent 
adverse events may be evaluated.
Safety:
Adverse events (AEs), laboratory data and vital signs are the safety parameters in this study.  
Treatment-emergent AEs are defined as events that begin or worsen either on or after the first dose day 
of the study medication and within 70 days after the last dose of the study medication.  
Treatment-emergent AEs will be summarized separately for the first half period (Week 0 to Week 24), 
the second half period (Week 24 to Week 52), and entire period (Week 0 to Week 52).
An overview of treatment-emergent AEs, including AEs of special interest, AEs leading to death and 
AEs leading to PD, AEs by Medical Dictionary for Drug Regulatory Activities (MedDRA) preferred 
term and system organ class, AEs by maximum relationship to study drug, and AEs by maximum 
severity will be summarized by number and percentage.  Other safety variables like laboratory data will 
be described by descriptive statistics.  In addition, shift tables and listings will be provided for abnormal 
values, whereby the normal range of the analyzing laboratory will be used.


Adalimumab 
M14-193 Protocol
9
1.2
List of Abbreviations and Definition of Terms
Abbreviations
AAA
Anti-adalimumab Antibody
ADA
Adalimumab
AE
Adverse event
ALT
Alanine Transaminase
ANA
Antinuclear Antibody
AST
Aspartate Transaminase
BCG
Bacillus Calmette-Guérin
BUN
Blood Urea Nitrogen
CDC
Centers for Disease Control and Prevention
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
dsDNA
Double-stranded Deoxyribonucleic Acid
ECG
Electrocardiogram
EU
European Union
eCRF
Electronic Case Report Form 
eow
every other week
ew
every week
FDA
Food and Drug Administration
FAS
Full Analysis Set
GCP
Good Clinical Practice
GMA 
Granulocyte and Monocyte absorbent Apheresis
GPP
Generalized Pustular Psoriasis
hs-CRP
high-sensitivity C-Reactive Protein
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IRB
Institutional Review Board
JDA
Japanese Dermatological Association
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Activities


Adalimumab 
M14-193 Protocol
10
MTX
Methotrexate
NRI
Non-Responder Imputation
PA
Posterior-anterior
PASI
Psoriasis Area and Severity Index
PD
Premature Discontinuation
PGA
Physician's Global Assessment
PK
Pharmacokinetics
POR
Proof of Receipt
PML
Progressive Multifocal Leukoencephalopathy
PPD
Purified Protein Derivative
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SDP
Study Designated Physician
TB
Tuberculosis
TNF
Tumor Necrosis Factor


Adalimumab 
M14-193 Protocol
11
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Synopsis .....................................................................................................2
1.2
List of Abbreviations and Definition of Terms..........................................9
2.0
Table of Contents...................................................................11
3.0
Introduction ...........................................................................15
3.1
Benefits and Risks....................................................................................17
3.2
Adalimumab Overview............................................................................18
3.3
Safety Information ...................................................................................18
4.0
Study Objective......................................................................19
5.0
Investigational Plan...............................................................19
5.1
Overall Study Design and Plan:  Description ..........................................19
5.2
Selection of Study Population..................................................................22
5.2.1
Inclusion Criteria .....................................................................................23
5.2.2
Exclusion Criteria ....................................................................................25
5.2.3
Prior and Concomitant Therapy...............................................................28
5.2.3.1
Prior Therapy ...........................................................................................28
5.2.3.2
Concomitant Therapy...............................................................................29
5.2.3.3
Prohibited Therapy...................................................................................30
5.3
Efficacy, Pharmacokinetic, and Safety Assessments/Variables ..............31
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................31
5.3.1.1
Study Procedures .....................................................................................36
5.3.2
Drug Concentration Measurements .........................................................49
5.3.2.1
Collection of Samples for Analysis .........................................................49
5.3.2.2
Handling/Processing of Samples .............................................................50
5.3.2.3
Disposition of Samples ............................................................................50
5.3.2.4
Measurement Methods.............................................................................50
5.3.3
Efficacy Variables....................................................................................50
5.3.3.1
Primary Variable......................................................................................50
5.3.3.2
Secondary Variables ................................................................................51
5.3.3.3
Safety Variables .......................................................................................52
5.3.4
Pharmacokinetic Variables ......................................................................52


Adalimumab 
M14-193 Protocol
12
5.4
Removal of Subjects from Therapy or Assessment .................................53
5.4.1
Discontinuation of Individual Subjects....................................................53
5.4.2
Discontinuation of Entire Study...............................................................54
5.5
Treatments................................................................................................54
5.5.1
Treatments Administered.........................................................................54
5.5.2
Identity of Investigational Product...........................................................55
5.5.2.1
Packaging and Labeling...........................................................................55
5.5.2.2
Storage and Disposition of Study Drugs..................................................56
5.5.3
Method of Assigning Subjects to Treatment Groups...............................57
5.5.4
Selection and Timing of Dose for Each Subject......................................57
5.5.5
Treatment Compliance.............................................................................58
5.5.6
Drug Accountability.................................................................................58
5.6
Discussion and Justification of Study Design..........................................59
5.6.1
Discussion of Study Design and Choice of Control Groups....................59
5.6.2
Appropriateness of Measurements...........................................................59
5.6.3
Suitability of Subject Population .............................................................60
5.6.4
Selection of Doses in the Study ...............................................................60
6.0
Complaints .............................................................................60
6.1
Medical Complaints.................................................................................61
6.1.1
Definitions................................................................................................61
6.1.1.1
Adverse Event..........................................................................................61
6.1.1.2
Serious Adverse Events ...........................................................................62
6.1.2
Adverse Event Severity............................................................................63
6.1.3
Relationship to Study Drug......................................................................64
6.1.4
Adverse Event Collection Period.............................................................64
6.1.5
Adverse Event Reporting.........................................................................65
6.1.6
Pregnancy.................................................................................................67
6.2
Product Complaint ...................................................................................67
6.2.1
Definition .................................................................................................67
6.2.2
Reporting..................................................................................................68
6.3
Toxicity Management ..............................................................................68
7.0
Protocol Deviations................................................................69


Adalimumab 
M14-193 Protocol
13
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................70
8.1
Statistical and Analytical Plans................................................................70
8.1.1
Analysis Population .................................................................................70
8.1.2
Planned Methods of Statistical Analysis..................................................71
8.1.3
Demographics and Baseline Characteristics............................................71
8.1.4
Statistical Analyses of Efficacy ...............................................................71
8.1.4.1
Primary Efficacy Variable .......................................................................71
8.1.4.2
Secondary Efficacy Variables..................................................................71
8.1.5
Statistical Analyses of Safety...................................................................72
8.1.6
Other Statistical Analyses of Efficacy .....................................................72
8.1.7
Interim Analysis.......................................................................................73
8.1.8
Pharmacokinetic Analyses .......................................................................73
8.2
Determination of Sample Size .................................................................73
9.0
Ethics.......................................................................................74
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................74
9.2
Ethical Conduct of the Study ...................................................................75
9.3
Subject Information and Consent.............................................................75
9.3.1
Informed Consent Form and Explanatory Material .................................75
9.3.2
Revision of the Consent Form and Explanatory Material .......................76
10.0
Source Documents and Case Report Form 
Completion .............................................................................76
10.1
Source Documents ...................................................................................76
10.2
Case Report Forms...................................................................................77
11.0
Data Quality Assurance........................................................79
12.0
Use of Information.................................................................79
13.0
Completion of the Study .......................................................80
14.0
Investigator's Agreement......................................................82
15.0
Reference List ........................................................................83


Adalimumab 
M14-193 Protocol
14
List of Tables
Table 1.
Study Activities........................................................................................32
Table 2.
Clinical Laboratory Tests.........................................................................43
Table 3.
Study Drugs .............................................................................................55
List of Figures
Figure 1.
Study Schematic.......................................................................................20
Figure 2.
Adverse Event Collection ........................................................................65
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ............................................84
Appendix B.
List of Protocol Signatories......................................................................86
Appendix C.
Clinical Expense and Compensation .......................................................87
Appendix D.
Screening Log – Sample ..........................................................................89
Appendix E.
Eligibility Assessment Form for Enrollment ...........................................90
Appendix F.
Injection Instructions – Sample Pre-Filled Syringe .................................95
Appendix G.
Subject Dosing Sheet for Self-Injection – Sample ................................103
Appendix H.
Severity Assessment Criteria from the Medical Care Guideline for 
Pustular Psoriasis (Generalized) ............................................................104
Appendix I.
Efficacy Assessment Criteria.................................................................105
Appendix J.
Observation of Skin Lesions – Example................................................106
Appendix K.
Skin Lesion Evaluation Form (GPP) and Scoring Form for 
Systemic Symptoms – Example.............................................................107
Appendix L.
PGA Scale for Generalized Pustular Psoriasis.......................................108
Appendix M.
Psoriasis Area and Severity Index (PASI) .............................................110
Appendix N.
Work Sheet for PASI score....................................................................113
Appendix O.
Dermatology Life Quality Index (DLQI)...............................................114
Appendix P.
SF-36......................................................................................................116
Appendix Q.
Guidelines to Evaluate Loss of Response and Intolerance to 
Infliximab...............................................................................................121
Appendix R.
70-Day Follow-Up Phone Call – Sample ..............................................122


Adalimumab 
M14-193 Protocol
15
3.0
Introduction
Generalized Pustular Psoriasis (GPP) is severe form of psoriasis and inflammatory disease 
of undetermined cause, which is characterized by generalized cutaneous erythema along 
with acute pyrexia as well as multiple sterile pustules.  This disease has a very low 
incidence in Japan, and the effective treatments are limited.  Therefore, it is designated as 
a specified rare and intractable disease by the Ministry of Health, Labour and Welfare 
(MHLW).
GPP may either be preceded by plaque psoriasis, or arise without a prior history of plaque 
psoriasis, classically after withdrawal of systemic glucocorticosteroids,1 and recently the 
studies for disease pathogenesis have been identified specific gene region susceptible to 
GPP.2  GPP is characterized by pyrexia with chills and extensive skin erythema, where 
tender pustules form and then coalesce into lakes of pus.  Desquamation from the pustules 
occurs thereafter, which is accompanied by nail plate changes (thickening and 
onycholysis), complaint of general malaise, and with a high frequency, mucosal 
symptoms, arthritis, and eye symptoms.  These symptoms significantly impair quality of 
life (QOL) and markedly affect daily living.  GPP is also characterized by multiple 
recurrences, and rarely, patients experience capillary leak syndrome, respiratory failure, or 
secondary amyloidosis, and are also at risk for death from cardiac or circulatory failure, 
general debility, and infections.
In the acute phase of the disease, GPP requires intense management of the general 
condition.  Once the symptoms are relatively stable, management of skin symptom is 
important.  In Japan, some systemic treatments are approved:  etretinate, cyclosporine, 
and infliximab.  All these treatments are demonstrated to be effective for GPP, and 
improve skin symptom and patient QOL.  However, etretinate is teratogenic and causes 
liver disorder, while cyclosporine sometimes causes renal disorder and hypertension.  For 
these reasons, their use cannot be continued for long-term disease management in some 
patients from the safety point of view.  Infliximab, which contains murine protein, may 
rarely cause anaphylactic symptoms.  Loss of response (secondary failure patients) has 


Adalimumab 
M14-193 Protocol
16
been also observed during treatment for the long-term use, and actions to be taken for 
such reduced response are clinically significant.  These limitations of current treatments 
highlight the need for new therapeutic options for GPP.
Adalimumab (genetical recombination), a fully human anti-human tumor necrosis factor-α 
(TNFα) monoclonal antibody, exhibits the efficacy by inhibiting action of TNFα which 
plays an important role in the pathology of psoriasis.  Since adalimumab contains no 
murine protein, neutralizing antibodies to the drug is less likely to be produced, and it is 
less of a risk for occurrence of the anaphylactic symptom and expected to cause fewer 
cases of reduced response by continued use.  In Japan, adalimumab has been approved for 
indications of rheumatoid arthritis, plaque psoriasis, arthritic psoriasis, Crohn's disease, 
ankylosing spondylitis, juvenile idiopathic arthritis, ulcerative colitis, and intestinal 
Behcet's disease.
In Japan, the Medical care guideline for GPP 20143 recommends the following systemic 
treatments for GPP:  etretinate, cyclosporine, methotrexate (not approved for GPP in 
Japan), and TNFα inhibitors such as infliximab and adalimumab as the committee's 
opinion.  The report from the overseas experts meeting (Medical Board of the National 
Psoriasis Foundation)4 and the psoriasis treatment guideline in the United Kingdom5 also 
recommend the use of anti-TNFα preparations (e.g., infliximab and adalimumab) for GPP.
While adalimumab has not been investigated in overseas or Japanese clinical studies in 
GPP patients, case reports6-10 for clinical use of adalimumab in GPP patients and results 
of the post-marketing surveillance (all-case surveillance) conducted in Japan suggest the 
effectiveness of adalimumab in GPP patients.
As described above, adalimumab was expected to be an effective treatment for GPP 
patients who have no adequate response to the existing treatments (except for biologics) 
and secondary failures with infliximab treatment.  In 2011, the Japanese Dermatological 
Association submitted a request for an indication of an unapproved drug to MHLW to 
propose GPP as an additional indication of adalimumab.  In response to this request, 
MHLW invited company opinions about use of adalimumab for GPP on 15 November.  In 


Adalimumab 
M14-193 Protocol
17
January 2012, AbbVie submitted an opinion that Public Domain Submission is 
appropriate for the approval of additional indication.  On 23 March 2012, however, such 
application was not adopted by the Study Group on Unapproved and Off-label Drugs of 
High Medical Need for the following reasons:  infliximab, a similar drug with the same 
indication, had been already approved; adalimumab was not considered to be positioned 
as a standard treatment in overseas because it had not been approved for treatment of GPP 
in 6 major foreign countries (e.g., major European countries and the United States) and 
there had been no clinical study globally.  Therefore, the sponsor planned to conduct a 
clinical study in Japan for the approval of an indication for GPP to meet the unmet 
medical needs.
The purpose of this study is to evaluate efficacy, safety and pharmacokinetics of 
adalimumab dose regimen approved for plaque Ps in Japan (80 mg at Week 0 by 
subcutaneous injection, followed by 40 mg every other week [eow] on and after Week 2, 
and dose escalation to 80 mg eow is allowed if the adequate response is not obtained) in 
Japanese GPP patients who had an inadequate response to the currently approved 
treatment.
3.1
Benefits and Risks
This study is the first clinical trial in patients diagnosed with generalized pustular 
psoriasis on adalimumab in the world, and expected clinical use of this drug in Japan.  
The dose regimen planned in this study is 80 mg for initial loading dose subcutaneously 
followed by 40 mg every other week (eow) on and after Week 2 until study end, which is
the same dose regimen in Ps approved in Japan.  Dose escalation to 80 mg eow is allowed 
if subjects have inadequate response on or after Week 8 and meet the dose escalation 
criteria.  Reasonable efficacy is expected not only in the patients who had inadequate 
response to the existing therapies, but also in the infliximab-secondary failures, which 
have been reported to being increased in Japan.  The safety of this dose regimen is 
supported by the safety data of clinical studies in plaque psoriasis (Studies M04-688 and 
M04-702).


Adalimumab 
M14-193 Protocol
18
3.2
Adalimumab Overview
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody 
containing only human peptide sequences.  Adalimumab is produced by recombinant 
deoxyribonucleic acid (DNA) technology in a mammalian cell expression system.  It 
consists of 1330 amino acids and has a molecular weight of approximately 
148 kilodaltons.  Adalimumab is composed of fully human heavy and light chain variable 
regions, which confer specificity to human TNF, and human IgG1 heavy chain and kappa 
light chain sequences.  Adalimumab binds with high affinity and specificity to soluble 
TNF-α but not to lymphotoxin-α (TNF-β).
TNF is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses.  Elevated levels of TNF play an important role in pathologic 
inflammation.  Adalimumab binds specifically to TNF and neutralizes the biological 
function of TNF by blocking its interaction with the p55 and p75 cell surface TNF 
receptors.  Adalimumab also modulates biological responses that are induced or regulated 
by TNF.  After treatment with adalimumab, levels of acute phase reactants of 
inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and 
serum cytokines rapidly decrease.
Adalimumab was first approved in US and EU for the treatment of Rheumatoid Arthritis 
in 2002 and 2003, respectively, and subsequently the Pharmaceuticals and Medical 
Devices Agency in Japan in 2008.  Additional indications have been approved in the US 
and EU including Psoriasis, Psoriatic Arthritis, Axial Spondylitis, Crohn's Disease, 
Juvenile Arthritis, and Ulcerative Colitis.  Additional updates regarding approved 
indications can be found in the current edition of the Humira Investigational Drug 
Brochure.
3.3
Safety Information
Adalimumab therapy has a well-established and well-described safety profile based on 
extensive post-marketing experience and continued clinical trial subject exposure since 
the first approved indication in 2002 for rheumatoid arthritis.  A detailed discussion of the 


Adalimumab 
M14-193 Protocol
19
pre-clinical toxicology, metabolism, pharmacology, and safety experience with 
adalimumab can be found in the current Investigator's Brochure.  AbbVie is committed to 
continue to collect safety information including those events that may occur in this trial in 
order to confirm this established safety profile and to identify any unknown potential 
adverse reactions, rare events and those events with a long latency.  AbbVie is 
participating in a Food and Drug Administration (FDA)-requested, TNF inhibitor class 
wide exploration of the rare appearance of malignancy in subjects who are 30 years old or 
younger at the time of diagnosis.  The risk of malignancy in this age group has not been 
established and is difficult to study due to its rarity.  AbbVie appreciates your attention to 
the additional reporting requirements needed in this unlikely event, outlined in 
Section 6.1.5 under Adverse Event Reporting.
4.0
Study Objective
The primary study objective is to investigate efficacy, safety and pharmacokinetics of 
adalimumab in Japanese patients with generalized pustular psoriasis (GPP).
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, multicenter, open-label, single-arm study of adalimumab dosing 
regimens (80 mg at Week 0 by subcutaneous injection, followed by 40 mg every other 
week [eow] on and after Week 2 until Week 50) in Japanese patients with generalized 
pustular psoriasis with total skin score of at least 3 and erythema with pustule (skin score 
of at least 1) in Japan Dermatology Association (JDA) severity index of GPP in GPP 
Medical Care Guideline 2014.  Dose escalation to 80 mg eow is allowed for subjects who 
do not have adequate response on or after Week 8.
The study is designed to enroll 10 subjects at approximately 10 sites in Japan to meet 
scientific and regulatory objectives in alignment with ethical considerations.
This study will include:


Adalimumab 
M14-193 Protocol
20
●
A 30-day Screening Period
●
A 52-Week Treatment Period
●
A 70-Day Follow-Up Period
A subject's participation in the study is anticipated to be up to 66 weeks.  There is a 
± 7-day window for all study visits.  An effort will be made to bring subjects back to their 
original scheduled visit (calculated from Baseline) if they are out of the visit window.
Study visits for clinical and safety assessments will be performed at Baseline (Week 0), 
Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52, and at the Premature 
Discontinuation visit if the subject discontinues prior to Week 52.  No open label 
extension (OLE) study is planned after this 52-week study.  Blood samples will be 
collected for clinical laboratory test, adalimumab serum concentrations, anti adalimumab 
antibody (AAA) levels, as indicated in Table 1.  In addition, photography of skin lesion 
will be performed in subjects who consent to it in pre-selected sites. 
A schematic of the study design is presented in Figure 1.
Figure 1.
Study Schematic
Screening Period
The Screening Period begins at the Screening Visit and continues through to Baseline 
Visit (Week 0).  Screening Assessments will include medical history, physical 


Adalimumab 
M14-193 Protocol
21
examination, chest x-ray, electrocardiogram (ECG), laboratory results including 
pregnancy testing, all of which will be reviewed by the study site to confirm selection 
criteria are met prior to enrolling the subject.
Subjects who meet all eligibility criteria during the Screening Period (Section 5.2.1 and 
Section 5.2.2) will enter the 52-Week Treatment Period.  The length of time between 
Screening and the Baseline Visits must allow time for lab results.  The Screening period 
(30 days, ± 7 days is granted around all study visits) may be extended as necessary for 
subjects who require initiation of prophylactic anti-tuberculosis (TB) therapy, or in case of 
external, not subject-related circumstances (e.g., due to delay of availability of screening 
test results).
Subjects who initially screen fail for the study may be permitted to re-screen following 
re-consent.  There is no minimum period of time a subject must wait to re-screen for the 
study.  The subject must meet all inclusion and none of the exclusion criteria at the time 
of re-screening in order to qualify for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold or 
equivalent), chest x-ray, and ECG, these tests will not be required to be repeated for 
re-screening provided the conditions noted in Section 5.3.1.1 are met and no more than 
90 days have passed.  All other screening procedures will be repeated.  As appropriate, 
sites should contact the AbbVie SDP to confirm if subjects may be re-screened.
52-Week Treatment Period
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the 52-Week Treatment Period.
All subjects enrolled in the study will be allocated at Baseline (Week 0) to the same 
adalimumab dose regimen at the investigation site.  The dose regimen will be 80 mg at 
Baseline (Weeks 0) by subcutaneous injection followed by 40 mg eow on and after Week 
2 until Week 50 as shown in Figure 1.  Dose-escalation to 80 mg eow will be allowed for 


Adalimumab 
M14-193 Protocol
22
subjects who do not have adequate response (e.g., minimal improvement, unchanged or 
worsened) on or after Week 8.  No dose reduction is allowed after dose escalation.
Subjects will return to the study site at scheduled visits and complete study procedures for 
each visit as outlined in Section 5.3.1.1.
For subjects who are on oral steroids at the Baseline, their steroid dose must be tapered off 
for 4 weeks (until Week 4) and withdrawn for the rest of the study period.  For subjects 
who are on cyclosporine at the Baseline, the treatment must be tapered off for 8 weeks 
(until Week 8) and withdrawn for the rest of the study period.
Throughout the study, subjects who are on etretinate (maximum dose of 20 mg/day at the 
Baseline), MTX, azathioprine, or salazosulfapyridine will be continued on their stable 
dose or have their dose of GPP-specific concomitant medications decreased as specified 
in Section 5.2.3.2.  Dose escalation is not allowed for these treatments.
No study drug will be administered at the final visit.
70-Day Follow-Up/Premature Discontinuation
Subjects may discontinue adalimumab treatment at any time during study participation 
(Section 5.4).  Subjects who end study participation early will have a premature 
discontinuation (PD) Visit.  All subjects will have a follow-up phone call approximately 
70 days after the last administration of study drug to obtain information on any new or 
ongoing AEs.
5.2
Selection of Study Population
Ten subjects will be enrolled at approximately 10 investigation sites in Japan.
Male and female subjects who meet all of the inclusion criteria specified in Section 5.2.1
and none of the exclusion criteria specified in Section 5.2.2 of the protocol are eligible to 
be enrolled into the study.


Adalimumab 
M14-193 Protocol
23
5.2.1
Inclusion Criteria
1.
Subject must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol.  If the subject is < 20 years old, a 
subject's parent or legal guardian must be willing to give written informed consent.
2.
Male or female ≥ 15 and ≤ 75 years of age at the Baseline visit.
3.
Subject must have a diagnosis of Generalized Pustular Psoriasis (GPP) for at least 
60 days prior to Screening and determined by the Investigator through subject 
interview and review of medical history during the Screening Period.
4.
Subject must have had an inadequate response to, or demonstrated intolerance to, 
or have a contraindication to the currently approved treatment for their GPP 
(excluding infliximab).
5.
Subject must have total skin score of at least 3 and erythema with pustules (skin 
score of at least 1) in JDA severity index of GPP in GPP Medical Care Guideline 
2014 in Japan at Baseline. 
6.
Subject may be included if they have previously experienced a benefit for their 
GPP from infliximab and discontinued its use due to a subsequent loss of response 
(i.e., judged by the Investigator to have responded to infliximab in the past and 
subsequently experienced an overall lack of improvement or worsening of GPP 
related symptoms, "infliximab secondary failure"), or intolerance (i.e., in the 
opinion of the investigator therapy was discontinued as a result of a significant 
acute or delayed infusion/administration reaction to the medication).  Confirmed 
documentation indicating loss of response or lack of tolerability will be required, 
see Section 10.1 and Appendix Q.
7.
If female, subject is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral 
oophorectomy and/or hysterectomy) or is of childbearing potential who must have 
negative result of pregnancy test performed at the Screening and at the Baseline.  
Female subject of childbearing potential is practicing an approved method of birth 


Adalimumab 
M14-193 Protocol
24
control throughout the study and for 150 days after last dose of study drug.  
Examples of approved methods of birth control which result in a low failure rate 
when used consistently and correctly are:
●
Condoms, sponge, foams, jellies, diaphragm, intrauterine devices (IUDs), or 
intrauterine hormone releasing system (IUS);
●
Sexual abstinence (when in line with preferred and usual lifestyle of the 
subject);
●
A vasectomized partner;
●
Hormonal contraceptives for at least 90 days prior to study drug administration.
Note:  low-dose progestin-only oral contraceptives are not considered adequate.
8.
If female, subject is not breast-feeding throughout the study and for 150 days after 
last dose.
9.
Subject has a negative TB Screening Assessment (including a PPD test and/or 
Quantiferon TB Gold test, or equivalent) and negative chest x-ray (CXR) (posterior 
anterior [PA] and lateral view).  If the subject has evidence of a latent TB infection, 
the subject must initiate and complete a minimum of 2 weeks of an ongoing TB 
prophylaxis or have documented completion of a full course of TB prophylaxis 
prior to Baseline (Section 5.3.1.1).
10.
Subject is judged to be in good general health, as determined by the Principal 
Investigator based upon the results of a medical history, physical examination, 
laboratory profile, chest x-ray, and a 12 lead electrocardiogram (ECG) performed 
during the Screening.
Rationale for the Inclusion Criteria
1
In accordance with good clinical practice (GCP)
2 – 10
In order to select the appropriate subject population with a disease status 
representative of the target population for evaluation


Adalimumab 
M14-193 Protocol
25
5.2.2
Exclusion Criteria
1.
Subject has erythrodermic psoriasis, guttate psoriasis, or subcorneal pustular 
dermatosis at Screening.
2.
Subject diagnosed drug-induced GPP.
3.
Total score of 14 or more in JDA severity index of GPP in GPP Medical Care 
Guideline 2014 in Japan.
4.
Subject has other active skin disease (e.g., urticarial, atopic dermatitis) or skin 
infections (bacterial, fungal, or viral) that may interfere with evaluation of GPP, 
with the exception of footpad trichophytosis (athlete's foot).
5.
Subject who cannot taper off cyclosporine until Week 8 after the Baseline and 
during the study.  Subjects who cannot taper etretinate to 20 mg/day at the 
maximum dose prior to the Baseline.
6.
Subject who is receiving oral corticosteroid more than 10 mg/day at the Baseline, 
and cannot taper off until Week 4 after the Baseline and during study.
7.
Subject who received granulocyte and monocyte adsorption apheresis (GMA) 
therapy for at least 28 days prior to the Baseline and cannot avoid this therapy 
during the study.
8.
Subjects who received any investigational agents of chemical or biologic nature 
(including anti-IL17 agents), which would be efficacious to GPP or 
psoriasis-related skin disease for at least 28 days or 5 half-lives of the drug prior to 
the Baseline, whichever is longer, and during the study.
9.
Subjects who received ustekimumab for at least 84 days prior to the Baseline and 
during the study.
10.
Subject who cannot avoid PUVA or narrow-band UVB phototherapy for at least 
14 days prior to the Baseline and during the study.
11.
Subject who cannot avoid "Strongest" corticosteroid in Japanese classification of 
topical therapy for at least 14 days prior to the Baseline and during the study.


Adalimumab 
M14-193 Protocol
26
12.
Subject who cannot avoid anti-tumor necrosis factor (TNF) agent other than 
infliximab and adalimumab (including but not limited to etanercept [Enbrel], 
golimumab [Simponi] or certolizumab pegol [Cimzia]) for at least 28 days prior to 
the Baseline and during the study.
13.
Prior exposure to adalimumab.
14.
Subject who has previous used infliximab:
●
and has not clinically responded at any time ("primary non-responder") unless 
subject experienced a treatment limiting reaction, or
●
who used infliximab ("secondary treatment failure") within 42 days prior to the 
Baseline.
15.
Prior exposure to medications that have a potential or known association with 
progressive multifocal leukoencephalopathy (PML) (i.e., natalizumab [Tysabri®], 
rituximab [Rituxan®], efalizumab [Raptiva®]).
16.
Subject with any active viral infection that makes the subject an unsuitable 
candidate for the study based on the investigator's clinical assessment.
17.
Hepatitis B:  HBs Ag positive (+) or detected sensitivity on the HBV-DNA PCR 
qualitative test for HBc Ab/HBs Ab positive subjects.
18.
Subject with known hypersensitivity to the excipients of adalimumab.
19.
Positive pregnancy test at the Screening (serum) or the Baseline (urine).
20.
Female who is breast-feeding or considering becoming pregnant during the study.
21.
History of clinically significant drug or alcohol abuse in the last 12 months.
22.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
23.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and/or any other condition which, in the opinion of 
the investigator, would put the subject at risk by participation in the study.


Adalimumab 
M14-193 Protocol
27
24.
Current evidence of dysplasia or history of malignancy (including lymphoma and 
leukemia) other than a successfully treated non-metastatic cutaneous squamous cell 
carcinoma, basal cell carcinoma or localized carcinoma in situ of the cervix.
25.
Chronic recurring infections or active TB.
26.
Infection(s) requiring treatment with intravenous (IV) anti-infectives (antibiotics, 
antivirals, antifungals) within 30 days prior to Baseline or oral anti-infectives 
(antibiotics, antivirals, antifungals) within 14 days prior to Baseline.
27.
History of invasive infection (e.g., listeriosis, histoplasmosis), human 
immunodeficiency virus (HIV).
28.
Screening laboratory and other analysis show any of the following abnormal 
results:
●
AST, ALT > 1.75 × upper limit of the reference range;
●
WBC count < 3.0 × 109/L;
●
Electrocardiogram (ECG) – with clinically significant abnormalities;
●
Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of 
indirect bilirubin relating to Gilbert syndrome;
●
Serum creatinine > 1.6 mg/dL.
29.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
Rationale for the Exclusion Criteria
1, 2
To avoid medical conditions that may compromise the ability to 
identify subjects with the correct diagnosis or to interpret medical 
importance of clinical results
3, 18, 21
To exclude subjects who maybe at increased risk for protocol 
non-adherence or premature discontinue
4 – 15
To avoid bias for the evaluation of efficacy and safety by concomitant 
or prior use of other medications or treatments


Adalimumab 
M14-193 Protocol
28
16, 17, 19, 20, 
22 – 28
To reduce the risk to subjects or others and/or to exclude underlying 
conditions that would compromise the subject's safety
29
To maintain the integrity of other aspects of study conduct, including, 
subject sampling, treatment procedures, etc.
5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any non-GPP medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, mineral supplements, and herbal supplements) that the subject is 
receiving within 30 days prior to Baseline, is receiving at the time of Enrollment, and/or 
receives during the study, must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency on the appropriate electronic case report form (eCRF).  Medication for 
PPD test and injection solvents does not need to record as far as adverse events derived 
from these drugs are not occurred.
GPP-specific medications and therapies (including but not limited to cyclosporine, 
etretinate, MTX, oral or topical corticosteroids, topical vitamin D3, phototherapy, or 
GMA) that the subject has received within 90 days of Baseline should be recorded on the 
appropriate page of the eCRF and should include the date(s) of administration and 
dosages, and reason(s) for termination of the treatment (if appropriate).  Subjects who 
failed to respond (within the past 1 year) or were intolerant (within the past 5 years) to 
treatment will have date(s) of administration, dosages including maximum dose, and 
reasons for discontinuation recorded in appropriate eCRF, as long as these information is 
available in the medical records.
For subjects previously treated with infliximab, the infliximab history will be recorded, 
including the duration of therapy, maximum dose, reason for use and reason(s) for 
termination of treatment.


Adalimumab 
M14-193 Protocol
29
The AbbVie SDP identified in Section 6.1.5 should be contacted if there are any questions 
regarding concomitant or prior therapies.
In addition for subjects age ≤ 30 with a reported malignancy adverse event, prior exposure 
to, or current use of, antineoplastics, or other drugs which have a risk of malignancy as 
stated in their labels and other relevant dosing information to estimate total exposure will 
be collected in the source documents and appropriate eCRF pages.  At the time of the 
reported malignancy adverse event, sites will be asked if any of the prior and concomitant 
medications contributed to the event.  Any medications used prior to the study will be 
captured on the appropriate eCRF.  Information on the reason for use, date(s) of 
administration including start and end dates, highest maintained dose, dosage information 
including dose, route and frequency, and reason for stopping the medication will be 
collected in the source documents and appropriate eCRF pages.
5.2.3.2
Concomitant Therapy
Doses of etretinate (tapered to 20 mg/day at maximum dose prior to the Baseline), MTX, 
azathioprine, or salazosulfapyridine taken at Baseline will be continued and remain stable 
throughout the study.  Doses may be decreased or terminated in the event of 
moderate-to-severe treatment-related toxicities or improvement of GPP skin lesion 
according to the discretion of the investigator.  Dose escalation of these treatments will 
not be allowed.
Doses of topical corticosteroids ("Very strong," "Strong," "Medium" and "Weak" in 
Japanese classification), topical vitamin D3, or topical tacrolimus taken at the Baseline 
will be continued without dose escalation.  Dose escalation (increase of amount for use) of 
topical corticosteroids is allowed only to use lower classes of drugs.  Doses may be 
decreased or terminated in the event of moderate-to-severe treatment-related toxicities or 
improvement of GPP skin lesion according to the discretion of the investigator.
For subjects who are on oral steroids at the Baseline, their steroid dose must be tapered off 
for 4 weeks (until Week 4) and withdrawn for the rest of the study period.  For subjects 


Adalimumab 
M14-193 Protocol
30
who are on cyclosporine at the Baseline, the treatment must be tapered off for 8 weeks 
(until Week 8) and withdrawn for the rest of the study period.
Changes in all concomitant medications will be assessed at each study visit from Baseline 
(Week 0) through Week 52/PD Visits.  Any changes will be documented, including the 
reason for the change of dose will be documented in the source documents and captured 
on the appropriate eCRF page.
Prophylaxis treatment with isoniazid for TB will be recorded.  Even if a subject 
prematurely discontinues the study, isoniazid treatment should be continued for 9 months 
considering the best interest of the subject at the discretion of the investigator.
Any vaccine (except for live vaccines) administered during the study will be recorded in 
the eCRF as a concomitant medication.
5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:
●
All biologic therapy with a potential therapeutic impact on the disease being 
studied including but not limited to the following:
○
Etanercept (Enbrel®);
○
Infliximab (Remicade®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Golimumab (Simponi®);
○
Certolizumab pegol (Cimzia®);
○
Ustekinumab (Stelara®);
○
Belimumab (Benlysta®);


Adalimumab 
M14-193 Protocol
31
○
Vedolizumab (Entyvio®).
●
Anti-IL-17 agents (Secukinumab, Ixekizumab, Brodalumab), including 
28 days prior to Baseline and during the study. 
●
GMA, including 28 days prior to Baseline and during the study.
●
Live vaccines, during the study and for 70 days after the last dose of study 
drug.
●
Tofacitinib (Xeljanz®).
●
Recreational or medical marijuana use 14 days prior to Baseline and during the 
study.
●
Intravenous corticosteroid use or topical "Strongest" corticosteroid in Japanese 
Classification is prohibited within 14 days prior to Baseline and during the 
study.
●
Investigational drugs of a chemical or biologic nature or investigational 
procedures are prohibited within 28 days or 5 half-lives (whichever is longer) 
of the drug prior to Baseline and during the study.
The AbbVie SDP identified in Section 6.1.5 should be contacted if there are any questions 
regarding prohibited therapy.
5.3
Efficacy, Pharmacokinetic, and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures will be performed as summarized in Section 5.3.1.1.  All subjects must 
meet the study selection criteria outlined in Section 5.2.1 and Section 5.2.2 in order to be 
enrolled into the study.


Adalimumab 
M14-193 Protocol
32
Table 1.
Study Activities
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Informed Consent
X
Assign Subject ID 
Number
X
Subject Background
X
Inclusion/Exclusion 
Criteria
X
Xb
Medical/Surgical History
X
Xb
Prior and Concomitant 
Therapy Assessment
X
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol Use
X
Tobacco Use
X
Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-Rayd/12-Lead 
ECGe
X
Xf
Xg
TB Screeningh
X
Vital Signs
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Tests
Xj
Xk
Xk
General Labsl:  Blood 
Chemistry and 
Hematology
X
Xm
X
X
X
X
X
X
X
X
Xs


Adalimumab 
M14-193 Protocol
33
Table 1.
Study Activities (Continued)
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Urinalysisn
X
X
X
X
X
X
X
HIV Screeno
X
Hepatitis B Screenp
X
Hepatitis C Screen
X
Antinuclear Antibody 
(ANA)/Anti-Double-
Stranded DNA (dsDNA)q
X
Photographyr
X
X
X
X
X
X
X
X
X
GPP Skin Score and BSA,
Systemic/Laboratory 
Score
X
X
X
X
X
X
X
X
X
X
Xs
PGA
X
X
X
X
X
X
X
X
X
X
Xs
PASI Score
X
X
X
X
X
X
X
X
X
X
Xs
DLQI
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
Administer Study Drugt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
PK Measurementsu
X
X
X
X
X
X
X
X
X
Xs
AAA Measurementsu
X
X
X
X
X
X
Xs


Adalimumab 
M14-193 Protocol
34
Table 1.
Study Activities (Continued)
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Monitor Adverse Eventsv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Follow-Up Phone Call
Xw
Footnote for Table 1;
a.
The Baseline visit date will serve as the reference for all subsequent visits.  A ± 7-days window is permitted around scheduled study visits.
b.
Update inclusion/exclusion, medical/surgical history, and prior and concomitant therapy information to assure subject eligibility.
c.
Physical examinations performed at Screening, Week 24 and Week 52/PD Visits will be full physical examinations.  Physical exams performed at all other visits will be 
symptom-based.
d.
Chest x-ray (CXR) includes posterior-anterior [PA] and lateral views.  Subjects with normal chest x-ray within 90 days of Screening will not require a repeat chest x-ray, if 
documentation is available.
e.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.
f.
Subjects will have a repeat CXR or ECG at Week 52 or the appropriate Premature Discontinuation visit, only if in the opinion of the investigator, clinically significant AEs 
develop during the study that warrant a repeat.
g.
Subjects can have a repeat CXR/ECG at any time during the study as warranted based on the opinion of the Investigator.
h.
Subjects with negative latent TB test(s) (In case a subject received both a PPD test and IGRA, both must be negative) within 90 days of Screening will not require a repeat 
latent TB test, if documentation is available.  PPD skin test is to be read 48 to 72 hours after placement.
i.
Height will be measured at the Screening only.
j.
All females of childbearing potential will have a serum pregnancy test at the Screening that is performed at the central laboratory.
k.
All females of childbearing potential will have a urine pregnancy test at the Baseline and Week 52 or Premature Discontinuation visits at the central laboratory.  Any subject 
with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior to start of the treatment in the study.  Urine pregnancy test at the 
Baseline will be performed also at site to confirm negative result on site.  If the result at site is positive, treatment with study drug should not be started until the serum 
pregnancy test at the central laboratory is confirmed negative.
l.
Subject should be fasting.  Please refer to the laboratory manual for further instructions.


Adalimumab 
M14-193 Protocol
35
Table 1.
Study Activities (Continued)
m.
Laboratory assessments will only need to be repeated at the Baseline if the time between blood sampling for Screening and Baseline is greater than 14 days, or if the subject's 
health status has changed to warrant a repeat test.
n.
Dipstick urinalysis will be conducted by the central laboratory at all required study visits.  A microscopic analysis will beperformed in the event the dipstick results show 
protein, ketones or blood greater than negative or glucose greater than normal.
o.
Subjects will be tested for HIV and documented that the test has been performed.  This testing is to be done at the central laboratory.  A subject will not be eligible for study 
participation if test results indicate a positive HIV infection.  AbbVie will not receive results from the testing and not bemade aware of any positive result.
p.
Subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc 
Ab Total (+) require PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection sensitivity will be exclusionary.
q.
Anti-dsDNA will be measured if ANA is positive.
r.
Photographs of skin lesion will be taken at the time points above in subjects who agree to do in the pre-selected sites.
s.
When dose escalation is decided on unscheduled visit or on any visit when the data collection is not planned, the investigator must assess skin lesion (GPP skin score, BSA, 
PGA and PASI score), and perform blood sampling for laboratory test and PK/AAA prior to dose escalation.  Body temperature will come from Vital Signs.  Additional study 
drug dispense may be necessary, if appropriate.
t.
Administration of study drug will be performed after all assessments and examinations scheduled for that day have been completed.  Study drug will be administered every 
other week in the investigator's office or at subject's home after training of self-injection to ensure proper technique.
u.
Blood samples for the measurement of adalimumab and AAA concentrations will be collected prior to dosing.
v.
All AEs reported from the time of study drug administration until 70 days following discontinuation of study drug administration will be collected.  SAEs and protocol-related 
nonserious AE will be collected from the time the subject signed the study-specific informed consent until 70 days following discontinuation of study drug administration.
w.
Site personnel will contact all subjects by phone 70 days after the last dose of study drug to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AE/SAEs.


Adalimumab 
M14-193 Protocol
36
5.3.1.1
Study Procedures
The study procedures outlined in Table 1 are discussed in detail in this section, with the 
exception of drug concentration and antibody measurements (discussed in Section 5.3.2), 
and the collection of adverse event (AE) information (discussed in Section 6.1.4).  All 
study data will be recorded in source documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study specific, Institutional Review 
Board (IRB) approved, informed consent form before any study procedures are performed 
or any medications are withheld from the subject.  Details regarding how informed 
consent will be obtained and documented are provided in Section 9.3.
Assignment of Subject Identification Number
After obtaining the informed consent, the investigator will assign a subject identification 
number to each subject and record it in the subject screening/registration sheet (Screening 
Log, Appendix D).  This record will be used for the management of the subjects.
The subject identification number consists of 4 digits; the first 2 digits refer to the 
investigation site (presented in the site list) and the last 2 digits refer to specific subjects 
(ascending number) within each site.  The unique number will be used repeatedly, if the 
subject is re-screened for this study.
Subject Background
Year of birth, sex, race and ethnicity will be recorded at the Screening Visit.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and none of the 
exclusion criteria at both the Screening and Baseline Visits.


Adalimumab 
M14-193 Protocol
37
Assessment of Eligibility at the Screening Visit
The investigator will assess the eligibility of each subject according to the inclusion and 
exclusion criteria.  The following information will be sent by email or facsimile to the 
sponsor's CRA within 3 days;
●
Subject identification number,
●
IC signed date,
●
sex,
●
age,
●
total skin score,
●
next scheduled visit date.
Assessment of Eligibility at the Baseline Visit (Prior to the Initiation of Treatment)
The investigator will make the final assessment of eligibility according to the inclusion 
and exclusion criteria based on the latest information obtained during the Screening 
period.  The results of the eligibility assessment and GPP skin scores will be sent within 
5 days by email or facsimile to the sponsor's CRA.  The worksheet for the eligibility 
assessment and the scores of skin lesions will be kept as the source document.
Medical (including Medication) and Surgical History
A complete medical and surgical history, as well as history of alcohol and tobacco use, 
will be obtained from each subject during the Screening Period.  Medical history will 
include GPP-related medical history (which includes GPP-onset date) and 
non-GPP-related medical history.  An updated medical history will be obtained at the 
Baseline Visit to ensure that the subject still qualifies for enrolling in the study.
All previous therapies used for GPP within 90 days prior to Baseline will be recorded in 
the appropriate eCRF.  Information on any treatment failure (failure to respond within the 
past 1 year and/or intolerant within the past 5 years) will be also recorded in the eCRF, 
see Section 5.2.3.1.


Adalimumab 
M14-193 Protocol
38
A detailed history with respect to loss of response and/or intolerance to infliximab will be 
documented in the subject's source documents.  Documentation will include the 
investigator's judgment based on the conditions defined in Appendix Q.
A detailed medical history with respect to TB exposure also needs to be documented.  
This information needs to include Bacillus Calmette-Guérin (BCG) vaccination, 
cohabitation with individuals who have had TB, and/or residence or work in TB-endemic 
locations.
Physical Examination
A physical exam will be performed at the designated study visits as outlined in Table 1.  
Physical examinations performed at Screening, Week 24 and Week 52/PD Visits will be 
full physical examinations, whereas physical examinations performed at all other visits 
will be symptom-based.
Physical examination findings that are related to subject's medical history will be captured 
on the appropriate medical history eCRF.
Chest X-Ray
All subjects will undergo a standard chest x-ray (PA and lateral views) at the Screening 
Visit to rule out the presence of TB or other clinically relevant findings.  The chest x-ray 
will not be required if the subject had a previous normal chest x-ray within 90 days of 
Screening, provided all protocol required documentation is available at the site (as 
outlined below).  A computerized tomography will be performed for more precise 
assessment, if necessary.
In the assessment of the chest x-ray, a radiologist/physician must note the presence or 
absence of (1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of 
active TB.  The Principal Investigator will indicate the clinical significance of any 
findings and will sign and date the report.  The CXR reports require the signature of both 
the radiologist/physician who read the films and the Principal Investigator.  If it is the 


Adalimumab 
M14-193 Protocol
39
site's policy that the radiologist/physician does not sign the final report, the report must 
include the date of the procedure, the name of the interpreting radiologist/physician and at 
a minimum must be signed and dated by the Principal Investigator.
Subjects can have a repeat chest x-ray at any time during the study as warranted based on 
the opinion of the investigator.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the designated study visits as outlined in 
Table 1.  A qualified physician will interpret the clinical significance of any abnormal 
finding, sign, and date each ECG.  Any clinically significant findings will be documented 
in the source documents and later transcribed on to the appropriate eCRF using the 
following conventions as appropriate:
●
Normal
●
Abnormal – not clinically significant
●
Abnormal – clinically significant
●
Unable to evaluate
The original ECG tracing, signed and dated by a qualified physician or local reader and 
the investigator, will be retained in the subject's record at the study site and monitored by 
the responsible sponsor's CRA.
For subjects with a normal ECG taken within 90 days of screening, a repeat ECG at 
screening will not be required, provided all protocol required documentation is available.  
If there are other findings that are clinically significant, the Principal Investigator must 
contact the SDP before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the investigator.


Adalimumab 
M14-193 Protocol
40
TB Screening
Subjects should be screened for TB using either PPD or IGRA.  A PPD skin test (known 
as tuberculin skin test) will be placed in each investigation site or an Interferon-Gamma 
Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test or T SPOT TB test) will be 
performed in the central laboratory during the Screening Period for all subjects including 
those with a prior history of BCG administration.  If a subject had a negative PPD or 
IGRA test within 90 days prior to screening, and all protocol required documentation is 
available, this test does not need to be repeated, provided nothing has changed in the 
subject's medical history to warrant a repeat test.  In case a subject received both a PPD 
test and IGRA, both must be negative.
Subject will be required to have the PPD test read by a licensed healthcare professional 48 
to 72 hours 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."  
Subjects who have had an ulcerating reaction to a PPD skin test in the past should not be 
re-exposed and should not be tested at Screening but will be considered PPD-positive.
If the IGRA test is indeterminate, the site should repeat the test with another blood sample 
or perform a PPD test.  If the second IGRA test is also indeterminate, the subject is 
considered to be positive and should initiate TB prophylaxis.
If the PPD or the IGRA test is positive or the subject has a chest x-ray indicative of latent 
TB, the subject will be required to initiate and have taken at least 2 weeks of an ongoing 
course of Center for Disease Control (CDC) recommended prophylaxis or prophylaxis per 
local guidelines prior to starting study therapy.
Subjects with a prior history of latent TB that have a documented completion of the CDC 
recommended or local guideline recommended prophylaxis may be permitted to enroll.  If 


Adalimumab 
M14-193 Protocol
41
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 before enrolling into the study.
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.
Vital Signs
Vital sign determinations of diastolic and systolic blood pressure in the sitting position, 
pulse rate (counted for at least 30 seconds), respiratory rate, body temperature (oral), and 
body weight will be obtained at each visit prior to blood draws.  Weight measurements of 
subjects (with clothes on) will be obtained at each visit using the same measuring 
instrument.  Height will be measured at the Screening Visit only.  All measurements will 
be recorded in metric units.
Pregnancy Tests
A serum pregnancy test will be performed on all women of childbearing potential at 
Screening by the central laboratory.  Urine pregnancy tests will be performed at the 
Baseline Visit (prior to start of treatment with test drug), and at the Week 52/PD for all 
women of childbearing potential by the central laboratory.
If any urine pregnancy test is positive, a serum pregnancy test will be performed by the 
central laboratory.  A lactating or pregnant female will not be eligible for participation or 
continuation in this study.
Urine pregnancy test at the Baseline will be performed also at the investigation site to 
confirm negative result on site.  If the result at site is positive, treatment with study drug 
must not be started until the serum pregnancy test at the central laboratory is confirmed 
negative.


Adalimumab 
M14-193 Protocol
42
Laboratory Assessments
Samples obtained for the laboratory tests will be collected as indicated in Table 1.  
Laboratory assessments will only need to be repeated at the Baseline if the time between 
blood sampling for Screening and Baseline is greater than 14 days, or if the subject's 
health status has changed to warrant a repeat test.
Blood draws should be performed in fasting status after completion of questionnaires 
(DLQI and SF-36), efficacy assessments and vital sign determinations during a study 
visit, but before study drug administration, if applicable.  Additional laboratory tests may 
be obtained when clinically warranted.  All laboratory test results that are considered 
clinically significant by the investigator will be followed to a satisfactory resolution.
A certified central laboratory chosen for the study will provide instructions regarding the 
collection, processing, and shipping of sample for the clinical laboratory tests indicated in 
Table 2.  The laboratory results will be reported by the central laboratory to the 
investigation site where they will be reviewed, signed and dated by the investigator.
The last clinical laboratory test value obtained prior to the first treatment will serve as the 
baseline laboratory test values.  Laboratory abnormalities are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events.


Adalimumab 
M14-193 Protocol
43
Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysisa
Hematocrit
Hemoglobin
Red Blood Cell count
White Blood Cell count
Neutrophils (Stab, Seg)
Bands (Stab)
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase/alanine 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase/aspartate 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
hs-CRP
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Additional Blood Samples Collected
β-hCG (serum pregnancy test)
QuantiFERON-TB Gold or T-SPOT TB (IGRA)
HIV 
HBV
HCV
ANA
anti-dsDNA – if ANA positive
Pharmacokinetic, Anti-adalimumab antibody
a.
A microscopic analysis will be performed by the central laboratory, in the event the dipstick results show protein, 
ketones or blood greater than negative or glucose greater than normal.
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits as 
listed in Table 2.  A microscopic analysis will be performed by the central laboratory, in 


Adalimumab 
M14-193 Protocol
44
the event the dipstick results show protein, ketones or blood greater than negative or 
glucose greater than normal.
HIV Screen
All subjects will be tested for antibodies to the Human Immunodeficiency Virus (HIV) at 
Screening and documented that the test has been performed.  This testing will be done at 
the central laboratory.  A subject will not be eligible for study participation if test results 
indicate a positive HIV infection.  AbbVie will not receive results from the testing and 
will not be made aware of any positive result.
Hepatitis B Screen
All subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  
A positive result for the hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and 
core antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab 
Total (+) require PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that 
meets or exceeds detection sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require 
HBV DNA PCR qualitative testing, and can be eligible to the study;
●
HBs Ab (–) and HBc Ab Total (–)
●
HBs Ab (+) and HBc Ab Total (–)
●
HBs Ab (+) and HBc Ab Total (+)
Hepatitis C Screen
All subjects will be tested for the presence of the Hepatitis C Virus (HCV) at Screening.  
A positive result for the hepatitis C will be exclusionary.


Adalimumab 
M14-193 Protocol
45
Antinuclear Antibody and Anti-Double-Stranded DNA
ANA will be performed and if positive, anti-dsDNA will be performed at Screening as 
indicated.
Photography
Photography of skin lesions will be recorded for subjects who agree to be taken in the 
pre-selected sites at the time points noted in Table 1.  Photography will be used for 
referring changes of skin lesions from the Baseline over time, for the selected skin lesions 
at the discretion of the investigator. When photography is conducted, it will be recorded 
in the medical record appropriately. 
Skin Lesions Outcome Assessments
The assessor must be a dermatologist or experienced physician.  The site will make every 
attempt to have the same investigator perform the assessment of skin lesions throughout 
the study for each subject.
GPP Skin Score and BSA (Body Surface Area)
Skin lesion will be observed and assessed BSA for each skin symptom (erythema, 
erythema with pustule, and edema [Appendix J]) and to calculate skin score (Appendix H) 
at the time points indicated in Table 1.  BSA of GPP is relevant to BSA of erythema in 
GPP.
BSA, a proportion of skin lesion area in the total body surface area will be determined.  
The following should be taken into account for the assessment that four anatomic sites –
the head, upper extremities, trunk, and lower extremities correspond to approximately 
10%, 20%, 30%, and 40% of body surface area, respectively, and the palm corresponds 
approximately 1% of BSA.  BSA below 1% should be round up to integer number in the 
assessment.


Adalimumab 
M14-193 Protocol
46
Systemic Symptom/Laboratory Test Score
Systemic symptom/Laboratory test score in JDA severity index of GPP will be calculated 
from the result of Vital signs (body temperature) and Laboratory test (WBC, hs-CRP and 
serum Albumin) at the time points indicated in Table 1 (Appendix K).
PGA (Physician's Global Assessment) 
A Physician's Global Assessment (PGA) of disease severity will be performed by the 
investigator at the time points indicated in Table 1.  The PGA is static and refers to the 
subject's disease state at the time of the assessment and is not a comparison with the 
subject's previous disease state, whether at the Baseline or at the previous visits 
(Appendix L).
Psoriasis Area and Severity Index Score (PASI Score)
A qualified investigator will assess the PASI score (Appendix M) at the time points 
indicated in Table 1.  All raw data used to determine the PASI score will be recorded on a 
worksheet (Appendix N) and entered to eCRF.  The PASI score will be calculated on the 
EDC system automatically.
DLQI (Dermatology Life Quality Index)
Subjects will complete a DLQI questionnaire (Appendix O) at the Baseline, Weeks 8, 16, 
24, 36 or 52/PD visit.  The subject will complete the questionnaire by oneself or with the 
aid of site personnel, if necessary, before the investigator performs any clinical 
assessment to avoid biasing the subject's response.  Sites will review the subject's 
questionnaires/assessments to make sure that they are complete before the subject 
completes the study visit and clarify any discrepancies with the subject before the visit is 
over to ensure accuracy.
SF-36v2™ Health Status Survey
The SF-36v2™ form contains 36 total questions targeting a subject's functional health and 
well-being, as well as his/her psychometric physical and mental health.  Subjects will 


Adalimumab 
M14-193 Protocol
47
complete the SF-36 at the visits indicated in Table 1 (Appendix P).  The subject will 
l complete the questionnaire by oneself or with the aid of site personnel, if necessary, 
before the investigator performs any clinical assessment to avoid biasing the subject's 
response.  Sites will review the subject's questionnaires/assessments to make sure that 
they are complete before the subject completes the study visit and clarify any
discrepancies with the subject before the visit is over to ensure accuracy.
Study Drug Dispensing/Administration
Study drug will be administered to subjects by study site medical staff, by him/herself or 
by a designee (friend, family member or health care professional) throughout the study.  
The date and time (the nearest minute) that study drug is dosed will be recorded after 
injection.
When subjects hope for self-injection, he/she or a designated family member or friend 
will be trained to administer study medication during the first visit or appropriate times of 
visit, under the supervision of trained medical personnel to reinforce proper aseptic SC 
injection technique including the management of study drug at home.  This training must 
be documented in the subject's source document.  Detailed instructions and training for 
the administration of adalimumab are provided in Appendix F.
A ± 7-day dosing window is allowable for scheduled study dosing dates.  For subjects 
who deviate from the dosing schedule, every effort should be made to bring the subject 
back to the original dosing schedule as soon as possible.
Subjects will maintain a Subject Dosing Sheet for all study medication administered 
outside of the study visit (i.e., at home).  The Subject Dosing Sheet will be reviewed and 
verified for compliance at each site visit by the study personnel.  All relevant dosing 
information will be retained by study personnel.  Additionally, any discernible departure 
from the protocol regarding study drug administration will be documented appropriately.  
A sample of the Subject Dosing Sheet is presented in Appendix G.


Adalimumab 
M14-193 Protocol
48
The site staff will maintain all the information of study drug medication including those 
performed at the investigation site, and record appropriately for each subject.
For subjects who cannot/will not self-administer study drug or do not have adequate 
support (family member, friend or healthcare professional) at home, administration will 
occur in the investigation site.
At all office visits, subjects should be observed after study drug administration until 
judged clinically stable by the study personnel.  If an anaphylactic reaction or other 
serious allergic reaction occurs, administration of study medication should be 
discontinued immediately and appropriate therapy initiated.  When dosing at home, 
subjects should be instructed to contact the site immediately with any signs or symptoms 
of a reaction.  If subjects are unable to reach his/her study site or experience 
life-threatening symptoms, they will be instructed to call an emergency number or 
proceed to the nearest emergency room and then inform the site as soon as possible.
Study drug is dispensed by the site staff or pharmacists in the site following the subject's 
treatment schedule.  The first two doses of study drug will be administered on site at the 
Baseline Visit.  On and after Week 2, necessary number of study drug packages will be 
prescribed and dispensed to the subjects to take home who hope for self-injection.
The site staff will remind the subject to take the syringe(s) in the correct order before 
opening a new package, when applicable.  Subjects must be reminded to take correct 
number of the syringe in the order dispensed by the site staff.  The site staff should count 
all remaining on site visits to dispense the correct number of study drug.
The subject must be instructed to return all used and unused study drug (syringes), sharp 
containers and empty boxes at each visit for the purpose of compliance assessment and 
drug accountability as detailed in Section 5.5.5 and Section 5.5.6.


Adalimumab 
M14-193 Protocol
49
Adverse Events
Adverse events will be assessed at every study visit from Baseline through the Final/Early 
Termination visit, and during the 70-day phone call or clinic visit (if applicable).  For 
those subjects who terminate the study early, a phone call or routine clinic visit should 
occur approximately 70 days after last dose of study medication to obtain follow-up 
information on any ongoing or new AEs.  In addition, serious adverse events and 
protocol-related non-SAE will be collected from the time the subject signs the 
study-specific informed consent.  Refer to Section 6.0 and Appendix R for additional 
information.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for adalimumab and anti-adalimumab antibody (AAA) assays will be
obtained at the time points as indicated in Table 1.
The date and time that each blood sample is collected will be recorded to the nearest 
minute in the source document and on the appropriate eCRF.
Collection of Samples for Adalimumab and AAA Assays
Blood samples for adalimumab and AAA assays will be collected by venipuncture into 
appropriately labeled 4 mL evacuated serum collection tubes (one tube for adalimumab 
and one tube for AAA) without gel separator immediately prior to dosing.  Sufficient 
blood will be collected to provide approximately 2 mL serum for adalimumab assay and 
2 mL serum for AAA assay.  Please refer to the laboratory manual for further instructions.  
Serum for assay will be frozen and transferred to the central laboratory for storage until 
the shipment to the measurement facilities.
A maximum of 15 samples (not including unscheduled visit sample collections) are 
planned to be collected per subject for adalimumab (9 samples) and AAA (6 samples) 
assays.  The total number of samples planned (not including unscheduled visit sample 


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collections) will not exceed 90 (9 samples × 10 subjects) for the adalimumab assay and 
60 (6 samples × 10 subjects) for the AAA assay.
Additional blood sample for measurement of adalimumab and AAA assays will be 
collected prior to dosing and whenever a subject is scheduled to be dose escalated.
5.3.2.2
Handling/Processing of Samples
The blood samples for adalimumab and AAA assays will be labeled with the type of 
sample, the protocol number, the subject number, the week and the assay type 
(pharmacokinetic [PK]-Adalimumab or AAA).  Additional detailed instructions for the 
handling and processing of samples will be provided from the central laboratory.
5.3.2.3
Disposition of Samples
Frozen samples will be packed in dry ice (pellet form) sufficient to last 7 days during 
transport.  Samples will be shipped by the central laboratory pursuant to instructions from 
the sponsor.  An inventory of the samples will be included in the package for shipment.
5.3.2.4
Measurement Methods
Serum concentrations of adalimumab and AAA will be determined using a validated 
ligand binding assay (LBA) method under the supervision of the Bioanalysis Department 
at AbbVie.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variable
The primary efficacy variable is the proportion of subjects achieving Clinical Response 
(remission and improvement) at Week 16.
For the efficacy assessment criteria, see Appendix I.


Adalimumab 
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5.3.3.2
Secondary Variables
Secondary efficacy variables, to be analyzed at each scheduled visit, include:
1.
Proportion of subjects achieving Clinical Response (expect Week 16, which is the 
primary endpoint).
2.
Proportion of subjects achieving remission.
3.
Change from the Baseline in total GPP score (skin and systemic/laboratory test).
4.
Change from the Baseline in JDA severity index of GPP.
5.
Change and Percent change from the Baseline in total skin score.
6.
Change from the Baseline in total systemic/laboratory test score.
7.
Change from the Baseline in score of erythema area (overall) and BSA (BSA of 
GPP).
8.
Change from the Baseline in score of erythema area with pustule and BSA.
9.
Change from the Baseline in score of edema area and BSA.
10.
Change from the Baseline in Body temperature.
11.
Change from the Baseline in WBC.
12.
Change from the Baseline in hs-CRP.
13.
Change from the Baseline in serum Albumin.
14.
Proportion of subjects achieving "Mild" in JDA severity index of GPP for patients 
with "Moderate" or "Severe" at the Baseline.
15.
Proportion of subjects achieving Treatment Success in PGA (reduction of 2 grades).
16.
Change from the Baseline in PGA grade.
17.
Proportion of subjects achieving PGA 0/1 for patients with PGA grade at least 2 at 
Baseline.
18.
Proportion of subjects achieving PASI 90.


Adalimumab 
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52
19.
Proportion of subjects achieving PASI 75.
20.
Proportion of subjects achieving PASI 50.
21.
Change and Percent change from the Baseline in PASI score.
22.
Proportion of subjects achieving DLQI = 0.
23.
Change from the Baseline in DLQI score.
24.
Change from the Baseline in SF-36 score.
25.
Proportion of subjects taking systemic co-medication for GPP (etretinate, MTX).
26.
Proportion of subjects taking topical co-medication for GPP (corticosteroid, 
vitamin D3, tacrolimus).
5.3.3.3
Safety Variables
Safety will be assessed by adverse events, laboratory data and vital signs during the entire 
study period.
5.3.4
Pharmacokinetic Variables
Pharmacokinetic
Serum concentrations of adalimumab at each scheduled sampling time will be reported.  
Changes in serum adalimumab concentration in subjects who get dose-escalated will also 
reported.
Immunogenicity
The number and percentage of subjects who develop AAA will be determined.


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an adverse event, safety concerns or 
failure to comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:
●
Clinically significant abnormal laboratory result(s) or adverse event(s), as 
determined by the Investigator in consultation with the AbbVie SDP.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie SDP (Section 5.2 and Section 7.0).
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie SDP.
●
Subject is non-compliant with TB prophylaxis.
●
The subject becomes pregnant while on study medication.
●
Subject has dysplasia of the gastrointestinal tract or a malignancy, except for 
localized non-melanoma skin cancer.  Discontinuation for carcinoma in situ of 
the cervix is at the discretion of the Investigator.
●
Subject is diagnosed with lupus-like syndrome, multiple sclerosis or 
demyelinating disease.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial, as determined by the 
Investigator, in consultation with the AbbVie SDP.
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the PD Visit must be completed within 


Adalimumab 
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2 weeks of the last dose of study drug, and preferably prior to the initiation of another 
therapy.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the Investigator feels are necessary to treat the 
subject's condition.  Following discontinuation of the study drug, the subject will be 
treated in accordance with the Investigator's best clinical judgment.
A final phone call will be made to the subject approximately 70 days after the last dose of 
study drug to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs.
All attempts must be made to determine the date of the last dose of study drug and the 
primary reason for PD.  The information will be recorded on the appropriate eCRF page.
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Subjects will receive adalimumab 80 mg (2 syringes) at Baseline (Week 0) by 
subcutaneous injection.  At and after Week 2, subjects will receive 40 mg (1 syringe) 


Adalimumab 
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every other week (eow) subcutaneously until Week 50.  No study drug administration will 
occur at Week 52. 
Dose Escalation
For subjects who meet dose escalation criteria on or after Week 8, 80 mg (2 syringes) 
doses will be administered subcutaneously every other week until study end.  No dose 
reduction will be allowed after dose escalation throughout the study.  The dose escalation 
criteria are defined as the subjects who do not achieve Clinical Response (i.e., minimal 
improvement, unchanged or worsened) on or after Week 8 (Appendix I).
Prior to dose escalation, the observation result of skin lesions (GPP skin score, PGA and 
PASI score) will be recorded.  Blood draw for the laboratory test (including WBC, 
hs-CRP and serum albumin for systemic/laboratory score) and measurement of 
pharmacokinetics and AAA will be also performed, prior to dose escalation.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 3.
Table 3.
Study Drugs
Drug
Dosage Form
Device
Formulation
Manufacturer
Adalimumab
Parenteral
Pre-filled 
syringe
40 mg/0.8 mL solution for injection 
Adalimumab/Mannitol, Citric acid 
monohydrate, Sodium citrate, Disodium 
phosphate dihydrate, Sodium 
dihydrogen phosphate dihydrate, 
Sodium chloride, Polysorbate 80, Water 
for injections, Sodium hydroxide added 
as necessary to adjust pH
AbbVie
5.5.2.1
Packaging and Labeling
Investigational product will be packaged in 0.8 mL syringe containing adalimumab 
40 mg/0.8 mL.  Each dosing package contains 2 pre-filled syringes.  The carton label will 
contain the following information as required per country requirements.


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●
Sponsor's name and address
●
Study protocol number
●
Study drug name
●
Storage conditions
●
Manufacturing number
●
Expiry date
●
Display of "for clinical trial"
All labels must remain affixed to study medication at all times, and should never be 
removed for any reason.
Detailed instructions and training for the administration of study drug supplies are 
provided in Appendix F.
5.5.2.2
Storage and Disposition of Study Drugs
Adalimumab pre-filled syringes are to be stored protected from light at 2° to 8°C/36° to 
46°F.  Study medication drug must not be frozen at any time.  A storage temperature log 
is to be maintained to document proper storage conditions.  The refrigerator temperature 
must be recorded on a temperature log to record proper function.  Malfunctions or any 
temperature excursion must be reported to the sponsor immediately.  Study medication 
should be quarantined and not dispensed until AbbVie GPRD 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.


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5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be assigned a unique identification number by the Investigator at the site 
at the Screening visit.  Subjects who meet all entry criteria in Section 5.2.1 and none of 
the exclusion criteria in Section 5.2.2 will be assigned to the treatment arm.  Subjects will 
be referred to using the subject identification number assigned at the Screening.
Study drug will be dispensed and/or administered at the study visits summarized in 
Table 1.  The investigator will record the number of study drug and the date of initial 
dosing in the subject's screening/registration sheet.  The site will send the results of the 
eligibility assessment and GPP skin score within 5 days by email or facsimile to the 
sponsor's CRA.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study medication as outlined in Section 5.5.1.
If a subject should forget to administer the injection of study medication on his/her 
regularly scheduled dosing date, they should take the forgotten injection as soon as they 
remember the dose was missed up to the day of his/her next scheduled dose.  The subject 
should not administer two doses on the same day except the first dose at the Baseline visit 
and after dose escalation.
In the event the incorrect dose is taken or a dose is missed, the subject should be 
instructed to contact the site to determine how to proceed with dosing.  The subject must 
record all self-dosing information on the Subject Dosing Sheet (Appendix G).
Doses not administered (e.g., not taken before next dose is scheduled), should be recorded 
as not taken in the source.  The extra syringe(s) should be returned to the study site full.  
The subject should resume his/her regular dosing schedule based on the first dosing date 
at Baseline.


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5.5.5
Treatment Compliance
The investigator or his/her designated and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than that described in the protocol.
The subject or his/her qualified designee, or site personnel will administer all doses of 
study drug.  In order to document compliance with treatment regimen for subjects 
conducting self-injection, the subject will be given a Subject Dosing Sheet (Appendix G) 
to record necessary dosing information including injection dates and times.  Compliance 
information will be verified at every site visit and documented on the appropriate eCRF
by making a dosing performance record per subject. Subjects will be counseled on missed 
doses of medication.  If the subject does not return IP boxes and sharp containers (when 
applicable), the site should question the subject and obtain as much information as 
possible as to the dosing of the study drug.
The information should be documented on the source documents as per "best recollection" 
and when possible, re-verified when the dosing sheet is returned before completing on the 
applicable eCRF page.
5.5.6
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact, at the 
appropriate temperature, and in the correct amounts.  This will be accomplished by 
documenting the condition of the shipment, verifying the manufacturing number in the 
package against the Proof of Receipt (POR) or similar document included with each drug 
shipment, and documenting this verification by signing and dating the POR or similar 
document.  The original POR Note or similar document will be kept in the site files as a 
record of what was received.
In addition, an accurate running inventory of study drug will be kept by the site on a Site 
Drug Accountability log including date received, the manufacturing number, date 


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59
dispensed, subject number, and the identification with date of the person dispensing the 
drug.
For Subjects Dosing at Home
Each subject will be given his/her own Sharps disposal container to store used pre-filled 
syringes.  Empty IP boxes and Sharps containers should be returned by the subject at each 
visit for accountability and compliance purposes and new containers issued as necessary.  
Empty Boxes and returned Sharps containers will be retained until the sponsor's CRA is 
on site to confirm the returned medication.  CRAs and site staff will complete study 
medication accountability via study medication logs, source documents, empty IP boxes 
and by visually inspecting the syringes in the Sharps container whenever possible.  Used 
Sharps containers should never be opened.  
The unused pre-filled syringes will be returned by the CRA and used pre-filled syringes 
will be discarded by the site, after drug accountability has been completed at the site.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Study M14-193 is a multicenter, open-label, single arm study of adalimumab dosing 
regimen of adalimumab in Japanese subjects with generalized pustular psoriasis (GPP).  
No placebo arm is planned due to limited GPP patient number in Japan and the purpose of 
this study is to investigate whether efficacy is achieved with the approved dose regimen in 
plaque psoriasis and to detect any safety concerns in GPP patients.  This study design was 
endorsed by PMDA.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  The 
clinical efficacy measurement used in this study (JDA severity index of GPP, BSA, and 
PASI score) has been used in multiple clinical trials in assessing disease activity in 


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subjects with GPP.  PGA was newly established by AbbVie, and this was endorsed by 
clinical experts and PMDA.
5.6.3
Suitability of Subject Population
Subjects with GPP who meet all inclusion criteria and none of the exclusion criteria are 
eligible for this study.  The specific subject population chosen was based on unmet 
medical needs of currently available medical therapies as well as previous anti-TNF 
therapy (infliximab) that demonstrated effectiveness in GPP.  This was endorsed by 
PMDA.
5.6.4
Selection of Doses in the Study
Dose regimen was determined based on efficacy and safety data from the adult Ps 
population from Study M04-688, and observed long-term safety data from Ps study 
(Study M04-702) in Japan, according to the PMDA's advice.
Dose Escalation Criteria
When the enrolled subject would respond inappropriately during the course of the study, 
dose can be escalated to 80 mg eow on or after Week 8.  The safety of 80 mg eow was 
confirmed in Studies M04-688/M04-702 Japanese Ps studies.  The dose escalation 
criterion is when efficacy of subjects does not achieve the clinical response (i.e., minimal 
improvement, unchanged or worsened) at the time of evaluation.  Time of dose escalation 
was justified from the result that the mean percentage change for the baseline in PASI 
score almost reached a steady state by Week 8 in Ps study.
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.


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The investigational product in this trial contains both:
●
Biologic compound(s) and
●
Device component(s) (pre-filled syringe)
Complaints associated with any component of this investigational product must be 
reported to the Sponsor.  For adverse events as medical complaints, please refer to 
Section 6.1, and for product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse events, 
whether in response to a query, observed by site personnel, or reported spontaneously by 
the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.


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Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention (Section 6.2) and/or if the investigator considers them to be adverse 
events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
SAE within 24 hours of the site being made aware of the serious adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.


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


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The CTCAE v4.0 – JCOG (Japanese translation JCOG version on 09 April 2013) can be 
used as a reference as appropriate.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, other cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 70 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events and protocol-related nonserious AEs will be collected from the time the subject 
signed the study-specific informed consent.  Adverse event information will be collected 
and recorded on the appropriate eCRFs.
Subjects will be contacted approximately 70 days following study drug discontinuation 
for an assessment of any new or ongoing AEs.


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All SAEs and AEs of Special Interest, as defined by AbbVie, reported during the 70-day 
follow-up phone call must be captured in the clinical database (Appendix R).  The end of 
trial is the last subject contact, i.e., the 70-day follow-up call.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
SAEs and
Protocol-related 
Nonserious AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study Drug 
Start
Study Drug 
Stopped
70 Days After Study 
Drug Stopped
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any nonserious event of 
malignancy in subjects 30 years of age and younger, whether related to study drug or not, 
the investigator will notify the AbbVie Clinical Pharmacovigilance within 24 hours of the 
site being aware of the event by entering the SAE or nonserious event of malignancy in 
subjects 30 years of age and younger data into the electronic data capture (EDC) system.  
Serious adverse events and nonserious events of malignancy in subjects 30 years of age 
and younger, that occur prior to the site having access to the Rave® EDC system or if 
Rave® is not operable, should be documented on the SAE Non-case report form (CRF) 
forms and send to the AbbVie Clinical Pharmacovigilance within 24 hours of the site 
being made aware of the adverse event.
Email:
FAX to:
For safety concerns, contact Medical Science Group at:


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For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
Secondary Contact (Regional Medical Monitor):


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Should in case of subject safety concerns or medical emergencies the Primary or 
Secondary Study Designated Physician be unavailable, please call the following central 
back-up number:
Phone:
The principal investigators will provide documentation of all serious adverse events to the 
Director of the investigation site and the sponsor.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).  Pregnancies will be collected from the date of the 
first dose through 150 days following the last dose of study drug.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an 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.
6.2
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.


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For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product and/or device must be reported 
to the Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe).  In instances where a return is requested, every effort should be made 
by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
6.3
Toxicity Management
Subjects who develop a new infection while undergoing treatment with adalimumab 
should be monitored closely.  Administration of study injections should be interrupted if a 
subject develops an infection requiring IV anti-infective treatment or if an infection meets 
the definition of "serious" (see Section 6.1.1.2 for definitions).  Study medication may be 


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restarted once the physician determines that the infection has been successfully treated.  
Otherwise prohibited concomitant medications may be given if medically necessary.  
Prior to use, every attempt should be made to contact the AbbVie Study Physician for 
direction on re-introduction of adalimumab therapy after prohibited medication 
administration.
If the subject must undergo elective surgery, the study injections must be interrupted 
2 weeks prior to the surgery.  If the subject must undergo emergency surgery, the study 
injections must be interrupted at the time of the surgery.  The injectable study medication 
can recommence at least 2 weeks after surgery once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.
For the purposes of the protocol, reportable deviations are defined as:
●
Subject entered into the study even though she/he did not satisfy entry criteria
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn
●
Subject who received wrong treatment or incorrect dose
●
Subject who received excluded or prohibited concomitant treatment
If a protocol deviation occurs (or is identified) after a subject has been enrolled, the 
principal investigator is responsible for notifying IEC/Institutional Review Board (IRB), 
regulatory authorities (if appropriate), and 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.
The Investigator will record all protocol deviations in the appropriate medical records at 
site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Complete, specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAPs will be finalized prior to 
the database lock.
8.1.1
Analysis Population
The following populations will be used for analyses in this study:
Full Analysis Set (FAS) population includes all subjects who complied with GCP and 
received at least one dose of study drug and had at least one post-treatment efficacy 


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assessment.  FAS is the primary population for the efficacy analysis.  In general, efficacy 
analysis will be performed for all subjects regardless dose escalation.
The Safety set consists of all subjects who received at least one injection of study drug.
Pharmacokinetic assessments will be conducted on all subjects who were administered at 
least one dose of study drug and have at least one post-dose sample collected for the 
determination of serum adalimumab concentration.
8.1.2
Planned Methods of Statistical Analysis
Descriptive statistics will be provided.  These include the number of observations, mean, 
standard deviation, minimum, median, and maximum for continuous variables; and counts 
and percentages for discrete variables.  The analysis will be performed using SAS® (SAS 
Institute Inc., Cary, NC, USA).
8.1.3
Demographics and Baseline Characteristics
Demographics and Baseline characteristics of the study subjects will be summarized using 
descriptive statistics.
8.1.4
Statistical Analyses of Efficacy
8.1.4.1
Primary Efficacy Variable
The primary efficacy endpoint is the proportion of subjects achieving Clinical Response 
(remission and improvement) at Week 16.
Clinical Response is defined as reduction of 1 (if the subject's Baseline skin score is 3) or 
2 (if the subject's Baseline skin score is 4 or higher) relative to Baseline, according to JDA 
severity index of GPP in GPP Medical Care Guideline 2014 in Japan (Appendix I).
8.1.4.2
Secondary Efficacy Variables
Discrete variables will be summarized by counts and percentages, and continuous 
variables will be summarized by descriptive statistics on the items below at each visit.


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The subjects who have missing data for any reason such as early terminated subjects will 
be included into analysis using NRI for discrete variables or LOCF for continuous 
variables.
For secondary efficacy variables, see Section 5.3.3.2.
8.1.5
Statistical Analyses of Safety
Adverse events (AEs), laboratory data and vital signs are the safety parameters in this 
study.  Treatment-emergent AEs are defined as events that begin or worsen either on or 
after the first dose day of the study medication and within 70 days after the last dose of 
the study medication.  Treatment-emergent AEs will be summarized separately for the 
first half period (Week 0 to Week 24), the second half period (Week 24 to Week 52), and 
entire period (Week 24 to Week 52).
An overview of treatment-emergent AEs, including AEs of special interest, AEs leading 
to death and AEs leading to PD, AEs by MedDRA preferred term and system organ class, 
AEs by maximum relationship to study drug, and AEs by maximum severity will be 
summarized by number and percentage.  Other safety variables like laboratory data will 
be described by descriptive statistics.  In addition, shift tables and listings will be provided 
for abnormal values, whereby the normal range of the analyzing laboratory will be used.
Safety of 40 mg eow and dose escalation may be also summarized separately.
8.1.6
Other Statistical Analyses of Efficacy
The subgroup analysis listed below is planned.  Proportion of subjects achieving Clinical 
Response (remission and improvement) at Weeks 16, 24, and 52.
●
Dose escalation: (without dose escalation, with dose escalation)
●
Previous infliximab experience (infliximab naïve, prior exposure to infliximab)


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8.1.7
Interim Analysis
An interim analysis of the primary endpoint and secondary efficacy variables as well as 
safety data collected from Baseline through Week 24 will be performed after the last 
subject in FAS population completes the 24-week period of the study.  A database lock 
will be performed and any discrepant data will be clarified before the lock.
8.1.8
Pharmacokinetic Analyses
Pharmacokinetic
Adalimumab trough serum concentrations will be reported at each time point using 
descriptive statistics.  The relationship between adalimumab concentrations and Clinical 
Response will be determined as appropriate.
Immunogenicity
AAA will be evaluated for each subject and rates of AAA positive will be calculated.  As 
appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and 
treatment-emergent adverse events may be evaluated.
8.2
Determination of Sample Size
GPP is designated as the specified rare and intractable disease in Japan and patient 
number is quite limited.  Assuming the clinical response rate of adalimumab in GPP is 
similar to that in plaque psoriasis, 50% to 60% as expected response rate in adalimumab 
treatment and 10% as a threshold response rate is hypothesized.
A sample size of 6 to 10 provides over 90% power to detect the difference between 
expected Clinical Response rate (50 to 60%) and threshold response rate (with no 
medication, 10%) in GPP, using a one sample Chi-square test with 2.5% one-sided 
significance level.  Using Fisher's exact test, an exact binomial test with a nominal 0.025 
one-sided significance level will have 82% power to detect the difference between the 
threshold proportion of 10% and the expected proportion of 50%.


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Therefore, the target number of subjects is set 10 subjects, taking the study feasibility into 
consideration.
Threshold Response Rate
Expected Response Rate
Actual Power
No of Subjects
10%
50%
91.2%
10
10%
55%
91.6%
8
10%
60%
90.3%
6
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
GCP requires that the clinical protocol, any protocol amendments, the Investigator's 
Brochure, the informed consent and all other forms of subject information related to the 
study (e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, 
informed consent and subject information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies, as 
required by local regulations.  During the conduct of the study, the investigator should 
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, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject, 
and answer all questions regarding this study.  Prior to any study-related screening 
procedures being performed on the subject, the informed consent statement, including the 
acceptability of photography of skin lesion, will be reviewed and signed and dated by the 
subject, and the person who administered the informed consent.  If the subject is < 20 
years old, a subject's parent or legal guardian must be explained and willing to give 
written informed consent.  A copy of the informed consent form will be given to the 
subject and the original will be placed in the subject's medical record.  An entry must also 
be made in the subject's dated source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
9.3.1
Informed Consent Form and Explanatory Material
The Principal Investigator will prepare the consent form and explanatory material required 
to obtain subject's consent to participate in the study with the cooperation of the sponsor 
and will revise these documents as required.  The prepared or revised consent forms and 
explanatory material will be submitted to the sponsor.  Approval of the IRB will be 
obtained prior to use in the study.


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9.3.2
Revision of the Consent Form and Explanatory Material
When important new information related to the subject's consent becomes available, the 
Principal Investigator will revise without delay the consent form and explanatory material 
based on the information and will obtain the approval of the IRB prior to use in the study.  
The Investigator will provide the information, without delay, to each subject already 
participating in the study, and will confirm the intention of each subject to continue in the 
study or not.  The Investigator will also provide further explanation using the revised 
consent form and explanatory material and will obtain written consent from each subject 
of their own free will to continue participating in the study.  If the subject is < 20 years 
old, a subject's parent or legal guardian must be explained and willing to give written 
informed consent.
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' dosing 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The following assessments that will be completed by subjects on paper will be considered 
source documentation:
●
DLQI
●
SF-36 version 2.0
The following contents recorded in eDRF may also be used as source, and will require an 
Investigator approval on the eCRF as verification of the accuracy of the information:


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●
Route of drug administration
●
Effect of the pre-treatment for GPP
●
Reasons for pre-treatment and concomitant treatment for GPP
●
Diagnostics, time course, severity, frequency and relationship to study drug, 
alternative etiology, medication for recovery, and seriousness for either SAEs 
or Nonserious AEs
●
Investigator's comments
●
Reason for Premature discontinuation for subject
●
Reason why the physician or nurse performed injection of study drug, after 
self-injection started (if applicable)
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case Report Forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  Data entry should be 
completed within 5 days after a subject visit or results are available.  The EDC system and 
the study-specific eCRFs will comply with Title 21 CFR Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, 
while the validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  eCRF data required by this protocol will be 
recorded by investigative site personnel in the EDC system, except for subject-completed 
questionnaires, which will be completed on paper by the subject then transcribed into the 


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EDC system by site personnel.  All data entered into the eCRF will be supported by 
source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or AbbVie's representatives).  AbbVie (or AbbVie's representatives) will also 
be allowed access to all source documents pertinent to the study in order to verify eCRF 
entries.  The principal investigator will review the eCRFs for completeness and accuracy 
and provide his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.  The following assessments will 
be completed by subjects on paper:
●
DLQI
●
SF-36 version 2.0
Site staff will verify completion of these forms.  All questionnaires must be legible and 
completed in indelible ballpoint ink.  Any necessary corrections are to be made by 
drawing a single line through the incorrect entry and writing in the revision, the date of 
the correction, the reason for the correction, and the initials of the study subject who is 
making the correction.  Data are not to be obliterated by blacking out, using correction 
fluid or by erasing the original entry.


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The questionnaire administrator will review the questionnaire for completeness and 
accuracy.  The subject-completed questionnaires will be transcribed into the EDC system 
by study personnel.  The completed paper questionnaire will be considered source 
documentation.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
Investigators and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, eCRF, Subject 
Questionnaires and Subject Dosing Sheet completion, and specimen collection methods.
The AbbVie 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 checks will be run to identify 
items such as inconsistent study dates.  A manual review of selected line listings also will 
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.
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 adalimumab and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.


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The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
adalimumab.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, to the FDA and to other 
governmental agencies.  To allow for the use of the information derived from this clinical 
study and to ensure complete and thorough analysis, the investigator is obligated to 
provide AbbVie with complete test results and all data developed in this study and to 
provide direct access to source data/documents for trial-related monitoring, audits, 
IEC/IRB review, and regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (Screening Log, with subject's name).  This list will be maintained at 
the site.  When a copy is provided to AbbVie, the site should carefully consider that it 
never include any subject identifying information by obscuring subject's name with a 
heavy black marker until the relevant information can no longer be seen.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Director of the Site and 
the sponsor.  Continuation of this study beyond this date must be mutually agreed upon in 
writing by both the Director of the Site and the sponsor.  The investigator will provide a 
final report to the Director of the Site following conclusion of the study, and the Director 
of the Site will inform the summary of the report to IRB and the sponsor.
The Director of the Site must retain any records related to the study according to local 
requirements.  If the Director of the Site is not able to retain the records, he/she must 
notify the sponsor to arrange alternative archiving options.


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AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for adalimumab.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter Open-label Study of Adalimumab in Japanese 
Subjects with Generalized Pustular Psoriasis
Protocol Date:
02 June 2015
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Griffiths CE, Christophers E, Barker JN, et al.  A classification of psoriasis vulgaris 
according to phenotype.  Br J Dermatol.  2007;156(2):258-62.
2.
Sugiura K.  The genetic background of generalized pustular psoriasis:  IL36RN 
mutations and CARD14 gain-of-function variants.  J Dermatol Sci.  
2014;74(3):187-92.
3.
Japan Dermatology Association, Medical Care Guideline for GPP in Japan 2014.
4.
Robinson A, Van Voorhees AS, Hsu S, et al.  Treatment of pustular psoriasis:  
from the Medical Board of the National Psoriasis Foundation.  J Am Acad 
Dermatol.  2012;67(2):279-88.
5.
Smith CH, Anstey AV, Barker JN, et al.  British Association of Dermatologist's 
guidelines for biologic interventions for psoriasis 2009.  Br J Dermatol.  
2009;161(5):987-1019.
6.
Zangrilli A, Papoutsaki M, Talamonti M, et al.  Long-term efficacy of adalimumab 
in generalized pustular psoriasis.  J Dermatol Treat.  2008;19(3):185-7.
7.
Callen JP, Jackson JH.  Adalimumab effectively controlled recalcitrant generalized 
pustular psoriasis in an adolescent.  J Dermatol Treat.  2005;16(5-6):350-2.
8.
Jordan J, Bieber T, Wislmann-Theis D, et al.  Adalimumab:  safe and successful in 
severe pustular psoriasis.  J Eur Acad Dermatol Venereol.  2009; 23(5):592-3.
9.
Antonio CA, Rodriguez-Nevado I, De Argila D, et al.  Recalcitrant pustular 
psoriasis successfully treated with Adalimumab.  Pediatr Dermatol.  
2011;28(2):195-7.
10.
Brenner M, Molin S, Ruebsam K, et al.  Generalized pustular psoriasis induced by 
systemic glucocorticosteroids:  four cases and recommendations for treatment.  Br 
J Dermatol.  2009;161(1):964-6.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Data and Statistical Sciences
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical
Clinical
Clinical, Japan Development
Data and Statistical Sciences, Japan Statistics
Clinical, Japan Development


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Appendix C.
Clinical Expense and Compensation
Expenditure of the Clinical Expense
The sponsor will pay the expenses related to this study to the investigative site in 
accordance with "Special Healthcare Expenditure."  The expenses of screening test, etc. 
will be paid based on the contract concluded with each investigative site.  To lighten the 
burden imposed on the subject with participation to the study, transportation expenses, etc. 
will be paid to the subjects via participating investigative site in accordance with the rules
of the investigative site.
Compensation for Health Impairment and Insurance
1.
If a subject suffers some sort of health impairment due to this study, the 
investigative site will provide treatment and take other necessary measures.  
Among the expenses required for the treatment, the amount not covered by health 
insurance that the patient must pay directly will be borne by the sponsor only when 
the event is associated with the use of the study drug.
2.
When a subject suffers health impairment during this study and a dispute occurs or 
might occur between the investigative site and the subject, the investigative site 
will immediately report this to the sponsor and resolve it.  The sponsor will 
cooperate with the investigative site in resolving any issues or problems.
3.
When the investigative site must compensate subject for any health impairment 
caused by this study, the compensation paid by the investigative site and the 
expenses related to any dispute will be borne in full by the sponsor, except in cases 
where the responsibility for the problem is attributed to the investigative site.  This 
shall not apply to cases where the health impairment occurred because the 
investigative site performed the study with marked deviation from the GCP or the 
protocol or because of a deliberate action or a major error by the investigative site.
4.
When a subject suffers health impairment during this study and liability for 
compensation arises, the sponsor will compensate in accordance with the SOP 
regarding the compensation prepared in advance.


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5.
The sponsor will obtain clinical study insurance and will take other necessary 
measures to cover the claims and compensation required in such cases.


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Appendix D.
Screening Log – Sample
Name of the Investigation Site
#
Subject ID 
Number
Subject's Name
Sex
Age
Date of Informed 
Consent
Sending info to the 
Sponsor's CRA
Date of the 
First Administration
Comments
Last
First
1
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
2
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
3
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
4
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
5
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
6
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
7
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
8
M  /  F
20__  _mon_  _day_
□
20__  _mon_  _day_
20___  _mon__  _day__         Principal Investigator's Signature  __________________________


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Appendix E.
Eligibility Assessment Form for Enrollment
FAX Number
Reporter
AbbVie GK
03-4577-1017
Study Institution
Department
Dermatology
Investigator's name
Subject ID Number
Date of Informed Consent
Date of Eligibility Assessment
_________________
20__   mon   day
20__   mon   day
Sex
Age
Total Skin score
Score of Erythema with Pustule
M   /   F
Inclusion Criteria
Yes
No
Not Applicable
□
□
1
Subject must be able and willing to provide written informed 
consent and comply with the requirements of this study 
protocol. If the subject is < 20 years old, a subject's parent or 
legal guardian must be willing to give written informed consent.
□
□
2
Male or female ≥ 15 and ≤ 75 years of age at the Baseline visit.
□
□
3
Subject must have a diagnosis of Generalized Pustular Psoriasis 
(GPP) for at least 60 days prior to Screening and determined by 
the Investigator through subject interview and review of medical 
history during the Screening Period.
□
□
4
Subject must have had an inadequate response to, or 
demonstrated intolerance to, or have a contraindication to the 
currently approved treatment for their GPP (excluding 
infliximab).
□
□
5
Subject must have total skin score of at least 3 and erythema 
with pustules (skin score of at least 1) in JDA severity index of 
GPP in GPP Medical Care Guideline 2014 in Japan at Baseline.
□
□
6
Subject may be included if they have previously experienced a 
benefit for their GPP from infliximab and discontinued its use 
due to a subsequent loss of response or intolerance.  Confirmed 
documentation indicating loss of response or lack of tolerability 
will be required.


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Yes
No
Not Applicable
□
□
□
The subject is 
male, or female 
without 
childbearing 
potential
7
If female, subject is either not of childbearing potential, defined 
as postmenopausal for at least 1 year or surgically sterile 
(bilateral tubal ligation, bilateral oophorectomy and/or 
hysterectomy) or is of childbearing potential who must have 
negative result of pregnancy test performed at the Screening and 
at the Baseline.  Female subject of childbearing potential is 
practicing an approved method of birth control throughout the 
study and for 150 days after last dose of study drug.  
□
□
□
The subject is male
8
If female, subject is not breast-feeding throughout the study and 
for 150 days after last dose.
□
□
9
Subject has a negative TB Screening Assessment (including a 
PPD test and/or Quantiferon TB Gold test, or equivalent) and 
negative chest x-ray (CXR) (posterior anterior [PA] and lateral 
view). If the subject has evidence of a latent TB infection, the
subject must initiate and complete a minimum of 2 weeks of an 
ongoing TB prophylaxis or have documented completion of a 
full course of TB prophylaxis prior to Baseline.
□
□
10
Subject is judged to be in good general health, as determined by 
the Principal Investigator based upon the results of a medical 
history, physical examination, laboratory profile, chest x-ray, 
and a 12 lead electrocardiogram (ECG) performed during the 
Screening.
Exclusion Criteria
Yes
No
Not Applicable
□
□
1
Subject has erythrodermic psoriasis, guttate psoriasis, or 
subcorneal pustular dermatosis at Screening.
□
□
2
Subject diagnosed drug-induced GPP.
□
□
3
Total score of 14 or more in JDA severity index of GPP in GPP 
Medical Care Guideline 2014 in Japan.
□
□
4
Subject has other active skin disease (e.g., urticarial, atopic 
dermatitis) or skin infections (bacterial, fungal, or viral) that 
may interfere with evaluation of GPP, with the exception of 
footpad trichophytosis (athlete's foot).
□
□
5
Subject who cannot taper off cyclosporine until Week 8 after 
the Baseline and during the study. Subject who cannot taper 
etretinate to 20 mg/day at the maximum dose prior to the 
Baseline.


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Yes
No
Not Applicable
□
□
6
Subjects who is receiving oral corticosteroid more than 10 
mg/day at the Baseline, and cannot taper off until Week 4 after 
the Baseline and during study.
□
□
7
Subject who received GMA (granulocyte and monocyte 
adsorption apheresis) therapy for at least 28 days prior to the 
Baseline and cannot avoid this therapy during the study.
□
□
8
Subjects who received any investigational agents of chemical or 
biologic nature (including anti-IL17 agents), which would be 
efficacious to GPP or psoriasis-related skin disease for at least 
28 days or 5 half-lives of the drug prior to the Baseline,
whichever is longer, and during the study.
□
□
9
Subjects who received ustekimumab for at least 84 days prior to 
the Baseline and during the study.
□
□
10
Subject who cannot avoid PUVA or narrow-band UVB 
phototherapy for at least 14 days prior to the Baseline and 
during the study.
□
□
11
Subject who cannot avoid "strongest" corticosteroid in Japanese 
classification of topical therapy for at least 14 days prior to the 
Baseline and during the study.
□
□
12
Subject who cannot avoid anti-tumor necrosis factor (TNF) 
agent other than infliximab and adalimumab (including but not 
limited to etanercept [Enbrel], golimumab [Simponi] or 
certolizumab pegol [Cimzia]) for at least 28 days prior to the 
Baseline and during the study.
□
□
13
Prior exposure to adalimumab.
□
□
14
Subject who has previous used infliximab:
! and has not clinically responded at any time ("primary non-
responder") unless subject experienced a treatment limiting 
reaction,
or
! who used infliximab ("secondary treatment failure") within 
42 days prior to the Baseline.
□
□
15
Prior exposure to medications that have a potential or known 
association with progressive multifocal leukoencephalitis 
(PML) (i.e., natalizumab [Tysabri], rituximab [Rituxan], 
efalizumab [Raptive]).
□
□
16
Subject with any active viral infection that makes the subject an 
unsuitable candidate for the study based on the investigator's 
clinical assessment.


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Yes
No
Not Applicable
□
□
17
Hepatitis B: HBs Ag positive (+) or detected sensitivity on the 
HBV-DNA PCR qualitative test for HBc Ab/HBs Ab positive 
subjects.
18
Subject with known hypersensitivity to the excipients of 
adalimumab.
□
□
□
The subject is 
male, or female 
without 
childbearing 
potential
19
Positive pregnancy test at the Screening (serum) or the Baseline 
(urine).
□
□
□
The subject is male
20
Female who is breast-feeding or considering becoming pregnant 
during the study.
□
□
21
History of clinically significant drug or alcohol abuse in the last 
12 months.
□
□
22
History of demyelinating disease (including myelitis) or 
neurologic symptoms suggestive of demyelinating disease.
□
□
23
History of moderate to severe congestive heart failure (NYHA 
class III or IV), recent cerebrovascular accident and/or any other 
condition which, in the opinion of the investigator, would put 
the subject at risk by participation in the study.
□
□
24
Current evidence of dysplasia or history of malignancy 
(including lymphoma and leukemia) other than a successfully 
treated non-metastatic cutaneous squamous cell carcinoma, 
basal cell carcinoma or localized carcinoma in situ of the cervix.
□
□
25
Chronic recurring infections or active TB.
□
□
26
Infection(s) requiring treatment with intravenous (IV) 
anti-infectives (antibiotics, antivirals, antifungals) within 
28 days prior to Baseline or oral anti-infectives (antibiotics, 
antivirals, antifungals) within 14 days prior to Baseline
□
□
27
History of invasive infection (listeriosis, histoplasmosis), human 
immunodeficiency virus (HIV).


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Yes
No
Not Applicable
□
□
28
Screening laboratory and other analysis show any of the 
following abnormal results:
!
AST, ALT > 1.75 × upper limit of the reference range;
!
WBC count < 3.0 × 109/L;
!
Electrocardiogram (ECG) – with clinically significant 
abnormalities;
!
Total bilirubin ≥ 3 mg/dL; except for subjects with 
isolated elevation of indirect bilirubin relating to Gilbert 
syndrome. 
!
Serum creatinine > 1.6 mg/dL.
□
□
29
Subject is considered by the Investigator, for any reason, to be 
an unsuitable candidate for the study.


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Appendix F.
Injection Instructions – Sample Pre-Filled Syringe
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M14-193
Tables of Contents
●
Dosing Schedule
●
General Information
●
Injection Procedures


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Study Drug Dosing Schedule
Subject Number:  _____________________________________
You will require subcutaneous injections throughout the study.
You will receive the following number of injections during this study:
●
Baseline visit (the first visit to receive study medication for this study), you 
will receive 2 injections at the investigation site subcutaneously.
●
On or after Week 2 until Week 50, you will receive 1 injection (1 syringe from 
1 package) subcutaneously.
●
If the Investigator considers dose escalation is appropriate on or after Week 8, 
you will receive 2 injections (1 package).
●
If you prefer to self-injection at home (or any place outside the investigation 
site), you will be allowed to do it after the site staff qualifies your skill of the 
administration procedures.
For all doses, packages of study medication must be used in the order dispensed.
Please return all used and unused syringes and empty boxes to the clinic on your next visit.  
Used syringes should be placed in the special sharps container provided.  All unused 
syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
contact your study center immediately for further instructions. 
Remember to complete your dosing sheet after each injection and to call the doctor's 
office if you are having problems administering your study medication.


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


Adalimumab 
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Injection Procedures 
1. Setting up for an injection
●
Find a clean flat surface.
●
Do not use if the seals on the carton are broken or missing.  Contact your study 
doctor's office if the seals are broken.
●
Take one package with the prefilled syringe(s) of adalimumab from the 
refrigerator.  Do not use a prefilled syringe that has been frozen or if it has 
been left in direct sunlight.
●
Return any unused syringe(s) to the refrigerator.
You will need the following items for each dose:
●
study medication in pre-filled syringe(s)
●
alcohol prep(s)
●
cotton ball or gauze pad(s)
If you do not have all of the items you need to give yourself an injection, call your study 
physician.  Use only the items provided in the box your adalimumab comes in.
●
Make sure the liquid in the prefilled syringe is clear and colorless.  Do not use 
a prefilled syringe if the liquid is cloudy or discolored or has flakes or particles 
in it.
●
Have a special sharps (puncture proof) container nearby for disposing of used 
needles and syringes.


Adalimumab 
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For your protection, it is important that you follow these instructions.
2. Choosing and preparing an injection site
●
Wash your hands well.
●
Choose a site on the front of your thighs or your stomach area (abdomen). If 
you choose your abdomen, you should avoid the area 2 inches around your 
belly button (navel).
●
Choose a different site each time you give yourself an injection.  Each new 
injection should be given at least one inch from a site you used before.  Never 
inject into areas where the skin is tender, bruised, red or hard or where you 
have scars or stretch marks.
●
If you have psoriasis, you should try not to inject directly into any raised, thick, 
red or scaly skin patches or lesions.
●
You may find it helpful to keep notes on the location of your injection sites.
●
Wipe the site where adalimumab is to be injected with an alcohol prep (swab), 
using a circular motion.  Do not touch this area again until you are ready to 
inject.


Adalimumab 
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3. How to prepare your adalimumab dose for injection with a Prefilled Syringe
●
Hold the syringe upright with the needle facing down.  Check to make sure 
that the amount of liquid in the syringe is the same or close to the 0.8 mL line 
for the 40 mg prefilled syringe.  The top of the liquid may be curved.  If the 
syringe does not have the correct amount of liquid, do not use that syringe.  
Call your study doctor.
●
Remove the needle cover taking care not to touch the needle with your fingers 
or allow it to touch any surface.
●
Turn the syringe so the needle is facing up and slowly push the plunger in to 
push the air in the syringe out through the needle.  If a small drop of liquid 
comes out of the needle that is okay.
●
Do not shake the syringe.
4. Injecting Adalimumab
●
With your other hand, gently squeeze an area of the cleaned area of skin and 
hold it firmly.
●
You will inject into this raised area of skin.  Hold the syringe like a pencil at 
about a 45° angle (see picture) to the skin.
●
With a quick, short, "dart-like" motion, push the needle into the skin.
●
After the needle is in, let go of the skin.  Pull back slightly on the plunger.  If 
blood appears in the syringe it means that you have entered a blood vessel.  Do 
not inject adalimumab.  Pull the needle out of the skin and repeat the steps to 
choose and clean a new injection site.  Do not use the same syringe.  Dispose 
of it in your special sharps container.  If no blood appears, slowly push the 
plunger all the way in until all of the adalimumab is injected.
●
When the syringe is empty, remove the needle from the skin keeping it at the 
same angle it was when it was pushed into the skin.
●
Press a cotton ball or gauze pad over the injection site and hold it for 
10 seconds.  Do not rub the injection site.  You may have slight bleeding.  This 
is normal.
●
Dispose of the syringe right away into your special sharps container.


Adalimumab 
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5. Training of "Dosing at home" for Japanese subjects
Training will include:
a.
Guidebook and DVD
●
How to transport and storage the study drug
●
How to perform self-injection
●
How to treat and collect the used syringe
●
How to do when the subject's physical condition is changed suddenly
●
How to fill in self-injection dosing sheet
b. Practice of the SC injection under supervision by a physician or nurse
Following cases may expect to occur;
1.
The same training course is necessary when a family member will perform 
subcutaneous injection.
2.
If a subject gives up "dosing at home" or investigator decides a subject can no 
longer perform the self-injection appropriately, study drug should be administered 
by an investigator or nurse.
3.
If the subject wants to terminate "dosing at home" or continuation of "dosing at 
home" becomes difficult, investigator should record the circumstances on the 
medical record and the study should continue with treatment by an investigator or
nurse.  In this case, record of Subject Dosing Sheet is not necessary afterward.


Adalimumab 
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4.
Even after the subject initiated "dosing at home," it is acceptable that an 
investigator or nurse performs the SC injection at the site, depending on the 
situation (e.g., time of dose escalation, this is not a protocol deviation).  The reason 
why an investigator or nurse performed the injection should be recorded in the 
subject's medical record.
5.
If the self-injection was once terminated and the subject wants to re-start it, 
investigator should confirm the subject can perform the self-injection appropriately.  
If it occurs after a long period (ca. 3 months or longer), investigator must confirm 
again the subject or his/her family member can perform the SC injection 
appropriately.


Adalimumab 
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Appendix G.
Subject Dosing Sheet for Self-Injection – Sample
M14-193      Subject ID:  
#
Date
Wk
Number of 
Syringes
Time of 
Administration
Was the Entire 
Volume 
Injected?
Person Who 
Administer
Place
Injection Site 
(1st Syringe)
Comments  
(Injection Site Of 
2nd Syringe etc.)
1
2015/xx/xx
0
2
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
no problem
2
2
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
3
4
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
4
6
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
5
8
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
6
10
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
7
12
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
8
14
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
9
16
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
10
18
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
11
20
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
12
22
:
Y/N
Patient / Family
Home / Hospital
R/L, Abdomen/Thigh
13
:
14
:
15
:


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Appendix H.
Severity Assessment Criteria from the Medical Care Guideline for 
Pustular Psoriasis (Generalized)
Total GPP Score and JDA Severity Index of GPP
Total GPP score = skin score + systemic/laboratory test score
JDA severity index of GPP:  Mild (0 – 6), Moderate (7 – 10), Severe (11 – 17)
(1) Evaluation of Skin Score (0 – 9)
Severe
Moderate
Mild
None
Erythema area (overall)*1
3
2
1
0
Erythema area with pustules*2
3
2
1
0
Edema area*2
3
2
1
0
*1
% of body surface area (severe, ≥ 75%; moderate, ≥ 25% and < 75%; mild, < 25%).
*2
% of body surface area (severe, ≥ 50%; moderate, ≥ 10% and < 50%; mild, < 10%).
(2) Evaluation of Systemic/Laboratory Test Score (0 - 8)
Score
2
1
0
Pyrexia (°C)
≥ 38.5
38.5 > ≥ 37
37 >
White blood cell count (/μL)
≥ 15,000
15,000 > ≥ 10,000
10,000 >
CRP (mg/dL)
≥ 7.0
7.0 > ≥ 0.3
0.3 >
Serum albumin (g/dL)
3.0 >
3.8 > ≥ 3.0
≥ 3.8




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Appendix J.
Observation of Skin Lesions – Example
Assessor Requirements
●
The assessor must be a dermatologist or experienced physician.
●
The same assessor must determine all skin lesion assessment for any 
individual subject throughout the trial.  A backup assessor is only allowed in 
case of emergency or special situation when the designated assessor is unable 
to perform the evaluation.  The backup assessor must be a dermatologist or an 
experienced physician.
Assessment of Skin Lesion and Record
Skin lesion should be an erythema, erythema with pustule, or edema, which is typical for 
GPP.
The Area (size) of erythema, erythema with pustule, or edema of each part of body will be 
assessed and recorded.  Skin score of each skin lesion and total skin score will be 
calculated automatically, according to the scoring criteria by severity scores of 0 – 3 
where higher scores denote worse conditions.
The site should make every attempt to have the same investigator conduct these 
assessments throughout the study for each subject.
Assignments for the following body regions are as follows:
●
Neck:  include with the head
●
Buttocks:  include with the lower extremities
●
Axillae:  include with the trunk
●
Genitals:  include with the trunk
●
The inguinal canal separates the trunk and legs anteriorly


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Appendix K.
Skin Lesion Evaluation Form (GPP) and Scoring Form for 
Systemic Symptoms – Example
Area of Skin Lesion (Body Surface Area)
Erythema (E)
Erythema with 
Pustule (P)
Edema (D)
Head
(max. 10%)
%
%
%
Upper extremity 
(max. 20%)
%
%
%
Body Trunk
(max. 30%)
%
%
%
Lower extremity
(max. 40%)
%
%
%
Total 
(max. 100%)
%
%
%
Scoring Criteria
3:   ≥75%,
3:  ≥ 50%,
3:  ≥ 50%,
2:  75% > ≥ 25%,
2:  50% > ≥ 10%,
2:  50% > ≥ 10%,
1:  25% >
1:  10% >
1:  10% >
Skin score (0 – 3)
Total Skin score (0 – 9)
BSA below 1% should be round up to integer number.
Scoring Form for Systemic Symptoms (GPP) – Example
Pyrexia
(Body temp., °C)
WBC (/μL)
CRP (mg/dL)
Serum albumin 
(g/dL)
Measurement
.
.
.
Scoring Criteria
2:  ≥ 38.5
2:  ≥ 15,000
2:  ≥7.0
2:  < 3.0
1:  38.5 > ≥ 37
1:  15,000 > ≥ 10,000
1:  7.0 > ≥ 0.3
1:  3.8 > ≥ 3.0
0:  37 >
0:  10,000 >
0:  0.3 >
0:  ≥ 3.8
Systemic score
(0 – 2)
Total Systemic score  
(0 – 8)
JDA severity index in GPP:           (Total Skin score 
+ Total Systemic score 
)


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Appendix L.
PGA Scale for Generalized Pustular Psoriasis
The Physician's Global Assessment of Generalized Pustular Psoriasis (PGA-GPP) 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 severity will be evaluated 
using the following categories:  erythema, pustulation, and edema.
Scoring Instructions:
If a subject has signs of erythema, pustulation, or edema intermediate between two grades, 
then the subject's erythema, postulation, or edema grade should be assigned the higher of 
the two grades.  For example, if a subject's erythema is considered to be worse than 'mild' 
but less than 'moderate,' the subject's erythema grade should be considered 'moderate.'
The subject's score is an arithmetic average (mean) of the grades for erythema, pustulation, 
and edema, rounded to the nearest whole integer.  For example, if a subject's erythema is 
moderate (3), pustulation is mild (2), and edema is moderate (3), the average grade is 
2.67, which is rounded to the nearest whole integer of 3, giving the subject a score of 
'moderate.'
Grade
Erythema
Pustulation
Edema
Score
0
No evidence of 
erythema
No evidence of postulation
No evidence of 
edema
Cleared, except 
for residual 
discoloration
1
Faint erythema
Scattered isolated pustules
Minimal edema
Minimal
2
Light red 
coloration
A cluster of non-confluent 
pustules involving 1 skin location
Mild edema
Mild
3
Moderate red 
coloration
Clusters of non-confluent 
pustules involving more than 
1 skin location
Moderate edema
Moderate
4
Bright-red 
coloration
A confluent 'lake of pus' in 1 skin 
location
Marked edema
Severe
5
Dusky to deep-
red coloration
Confluent 'lakes of pus' in more 
than 1 skin location
Severe edema
Very severe
'Treatment Success' is defined by at least 2 grade improvement relative to baseline:


Adalimumab 
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●
Very severe  Moderate or better
●
Severe  Mild or better
●
Moderate  Minimal or better
●
Mild  Cleared


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Appendix M.
Psoriasis Area and Severity Index (PASI)
Assessor Requirements
●
The assessor must be a dermatologist or experienced physician.
●
The same assessor must determine all PASIs for any individual subject 
throughout the trial.  A backup assessor is only allowed in case of emergency 
or special situation when the designated assessor is unable to perform the 
evaluation.  The backup assessor must be a dermatologist or an experienced 
physician and have attended the PASI training session of the investigator 
meeting or have been trained by a physician who attended the investigator 
meeting.
PASI Scoring
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:
●
0 = No symptoms
●
1 = Slight
●
2 = Moderate
●
3 = Marked
●
4 = Very marked
The below table outlines the characteristics seen with each category:


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Erythemaa
Desquamation
Induration
0 = none
No redness
No scaling
No elevation over normal skin
1 = slight
Faint redness
Fine scale partially covering 
lesions
Slight but definite elevation, 
typically edges indistinct or 
sloped
2 = moderate
Red coloration
Fine to coarse scale covering 
most of all of the lesions
Moderate elevation with rough 
or sloped edges
3 = marked
Very or bright red 
coloration
Coarse, non-tenacious scale 
predominates covering most 
or all of the lesions
Marked elevation typically 
with hard or sharp edges
4 = very 
marked
Extreme red 
coloration; dusky to 
deep red coloration
Coarse, thick, tenacious 
scale over most or all 
lesions; rough surface
Very marked elevation 
typically with hard sharp edges
a.
Do not include residual hyperpigmentation or, hypopigmentation as erythema.
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:
●
0 = no involvement
●
1 = < 10%
●
2 = 10% to < 30%
●
3 = 30% to < 50%
●
4 = 50% to < 70%
●
5 = 70% to < 90%
●
6 = 90% to 100%
Assignments for the following body regions are as follows:
●
Neck:  include with the head
●
Buttocks:  include with the lower extremities
●
Axillae:  include with the trunk
●
Genitals:  include with the trunk
●
The inguinal canal separates the trunk and legs anteriorly


Adalimumab 
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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 body surface area, 
respectively, the PASI score is calculated using the formula.
PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + Iu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il + Dl)Al
Where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, 
and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, respectively.  
PASI ranges from 0.0 to 72.0 with the highest score representing complete erythroderma 
of the severest degree.
References for PASI
1.
Fredriksson T, Pettersson U.  Severe psoriasis--oral therapy with a new retinoid.  
Dermatologica.  1978;157(4):238-44.
2.
Marks R, Barton SP, Shuttleworth D, et al.  Assessment of disease progress in 
psoriasis.  Arch Dermatol.  1989;125(2):235-40.




Adalimumab 
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Appendix O.
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
□
Not relevant
□
A lot
□
A little
□
Not at all
□
4.
Over the last week, how much has your skin influenced 
the clothes you wear?
Very much
□
Not relevant
□
A lot
□
A little
□
Not at all
□
5.
Over the last week, how much has your skin affected any 
social or leisure activities?
Very much
□
A lot
□
Not relevant
□
A little
□
Not at all
□
6.
Over the last week, how much has your skin made it 
difficult for you to do any sport?
Very much
□
A lot
□
Not relevant
□
A little
□
Not at all
□


Adalimumab 
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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?
Very much
□
A lot
□
Not relevant
□
A little
□
Not at all
□
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
□
Not relevant
□
A little
□
Not at all
□
9.
Over the last week, how much has your skin caused any 
sexual difficulties?
Very much
□
A lot
□
Not relevant
□
A little
□
Not at all
□
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
□
Not relevant
□
A little
□
Not at all
□
Please check you have answered EVERY question.  Thank you.


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


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3. The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much?
Yes, limited 
a lot
Yes, limited 
a little
No, not 
limited at all
a.
Vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports
1
2
3
b.
Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing golf
1
2
3
c.
Lifting or carrying groceries
1
2
3
d.
Climbing several flights of stairs
1
2
3
e.
Climbing one flight of stairs
1
2
3
f.
Bending, kneeling, or stooping
1
2
3
g.
Walking more than a mile
1
2
3
h.
Walking several hundred yards
1
2
3
i.
Walking one hundred yards
1
2
3
j.
Bathing or dressing yourself
1
2
3
4. During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your 
physical health?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
a.
Cut down on the amount of time you
spent on work or other activities
1
2
3
4
5
b.
Accomplished less than you would 
like
1
2
3
4
5
c.
Were limited in the kind of work or 
other activities
1
2
3
4
5
d.
Had difficulty performing the work 
or other activities (for example, it 
took extra effort)
1
2
3
4
5


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


Adalimumab 
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9. These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time during the 
past 4 weeks:
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
a.
Did you feel full of life?
1
2
3
4
5
b.
Have you been very nervous?
1
2
3
4
5
c.
Have you felt so down in the dumps 
that nothing could cheer you up?
1
2
3
4
5
d.
Have you felt calm and peaceful?
1
2
3
4
5
e.
Did you have a lot of energy?
1
2
3
4
5
f.
Have you felt downhearted and 
depressed?
1
2
3
4
5
g.
Did you feel worn out?
1
2
3
4
5
h.
Have you been happy?
1
2
3
4
5
i.
Did you feel tired?
1
2
3
4
5
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
1
2
3
4
5


Adalimumab 
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11. How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don't 
know
Mostly 
false
Definitely 
false
a.
I seem to get sick a little easier than 
other people
1
2
3
4
5
b.
I am as healthy as  anybody I know
1
2
3
4
5
c.
I expect my health to get worse
1
2
3
4
5
d.
My health is excellent
1
2
3
4
5
THANK YOU FOR COMPLETING THESE QUESTIONS
SF-36v2™ Health Survey© 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.
SF-36® is a registered trademark of Medical Outcomes Trust
(SF-36v2 Standard, US Version 2.0)


Adalimumab 
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121
Appendix Q.
Guidelines to Evaluate Loss of Response and Intolerance to 
Infliximab
To enroll in this study, subjects who have previously been exposed to infliximab must 
meet one of the two conditions defined below.
Loss of Response
A subject to have responded to infliximab in the past and subsequently experienced an 
overall lack of improvement or worsening of symptoms after a full and adequate course of 
infliximab based on the investigator's assessment.
Intolerance to Infliximab
A subject is defined as intolerant when, in the opinion of the investigator, therapy was 
discontinued as a result of a significant acute or delayed infusion/administration reaction 
to the medication.


Adalimumab 
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Appendix R.
70-Day Follow-Up Phone Call – Sample
Site Name/Number:  ____________________________
Subject Number:  __________________
Please contact subjects who discontinue adalimumab 70 days following study drug 
discontinuation.
Date of Call:  _____________________
Lost to Follow-up (Please check this box if subject was not willing to provide 
any follow-up information or you were unable to speak to the subject 
following at least one attempt.)
No Events Reported
N/A subject started adalimumab therapy after the end of study participation
List any Adverse Events (AE) and/or Serious Adverse Events (SAE) that occurred since the 
subject was last seen in clinic for this study.  If needed, provide AE/SAE details on the AE 
worksheet attached.  (Please report all SAEs to AbbVie within 24 hours of being made aware of 
the event.)
If events are listed above, your monitor will review and retrieve the appropriate eCRF pages 
during their next visit.
Please fax all completed forms to:
[Name] at XXX-XXX-XXXX



SAP_000.pdf: 
Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
1 
1.0
Title Page
Statistical Analysis Plan
Study M14-193
A Multicenter, Open-Label Study of Adalimumab in 
Japanese Subjects with Generalized Pustular 
Psoriasis
Incorporating Administrative Change 1,2,3 and 4
Date: 25 Apr 2017 
/$5


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
2
2.0
Table of Contents
1.0 
Title Page..................................................................................1 
2.0 
Table of Contents.....................................................................2 
3.0 
Introduction .............................................................................7 
4.0 
Study Objectives, Design and Procedures.............................7 
4.1 
Objectives ..................................................................................................7 
4.2 
Design Diagram .........................................................................................7 
4.3 
Sample Size..............................................................................................13 
4.4 
Interim Analysis.......................................................................................13 
5.0 
Analysis Populations .............................................................13 
5.1 
Definition for Analysis Populations.........................................................13 
5.2 
Variables Used for Stratification of Randomization................................14 
6.0 
Analysis Conventions ............................................................14 
6.1 
Definition of Baseline..............................................................................14 
6.2 
Definition of Final Observation Value ....................................................15 
6.3 
Definition of Rx Days (Days Relative to the First Dose of Study 
Drug)........................................................................................................15 
6.4 
Definition of Analysis Windows .............................................................15 
6.5 
Definition of Missing Data Imputation....................................................19 
7.0 
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............21 
7.1 
Demographic and Baseline Characteristics .............................................21 
7.2 
Medical History .......................................................................................23 
7.3 
Prior and Concomitant Therapy...............................................................25 
8.0 
Patient Disposition.................................................................25 
9.0 
Study Drug Exposure and Compliance...............................26 
9.1 
Study Drug Exposure...............................................................................26 
9.2 
Compliance ..............................................................................................27 
9.3 
Study Drug Dose......................................................................................27 
10.0 
Efficacy Analysis....................................................................27 
10.1 
General Considerations............................................................................27 
10.2 
Efficacy Analysis.....................................................................................28 


Adalimumab
M14-193 – Statistical Analysis Plan
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3
10.3 
Secondary Efficacy Analyses...................................................................29 
10.4 
Handling of Multiplicity ..........................................................................30 
10.5 
Efficacy Subgroup Analysis ....................................................................30 
11.0 
Safety Analysis.......................................................................30 
11.1 
General Considerations............................................................................30 
11.2 
Analysis of Adverse Events.....................................................................31 
11.2.1 
Treatment-Emergent Adverse Events ......................................................31 
11.2.2 
Listing of Adverse Events........................................................................36 
11.3 
Analysis of Laboratory Data....................................................................36 
11.3.1 
Variables and Criteria Defining Abnormality..........................................37 
11.3.2 
Statistical Methods...................................................................................41 
11.4 
Analysis of Vital Signs and Weight.........................................................41 
11.4.1 
Statistical Methods...................................................................................42 
12.0 
Summary of Changes ............................................................42 
12.1 
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP .......................................................................................42 
12.2 
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .....................................................................42 
13.0 
Appendix.................................................................................42 
14.0 
Reference................................................................................42 
List of Tables
Table 1. 
Study Activities:.........................................................................................9 
Table 2. 
Visit Windows for Analysis of Efficacy Variables, General 
Laboratory Parameters (Blood Chemistry and Hematology) ..................17 
Table 3. 
Visit Windows for Analysis of DLQI, SF-36, Laboratory 
Parameters (Urinalysis)............................................................................17 
Table 4. 
Visit Windows for Analysis of Vital Signs..............................................18 
Table 5. 
Visit Windows for GPP skin score relative to dose escalation................19 
Table 6. 
The clinical response categories were defined according to the 
total skin score at Baseline.......................................................................28 
Table 7. 
Clinical Laboratory Tests.........................................................................37 
Table 8. 
Potentially Clinically Significant Laboratory Findings ...........................39 


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
4
Table 8. 
Potentially Clinically Significant Laboratory Findings 
(Continued) ..............................................................................................40 
List of Figures
Figure 1. 
Study Schematic.........................................................................................8 


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
5
List of Abbreviations
AAA
Anti-adalimumab Antibody
ADA
Adalimumab
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine Transaminase
ANA
Antinuclear Antibody
AST
Aspartate Transaminase
BCG
Bacillus Calmette-Guérin
BUN
Blood Urea Nitrogen
CDC
Centers for Disease Control and Prevention
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
dsDNA
Double-stranded Deoxyribonucleic Acid
ECG
Electrocardiogram
EU
European Union
eCRF
Electronic Case Report Form 
eow
every other week
ew
every week
FDA
Food and Drug Administration
FAS
Full Analysis Set
GCP
Good Clinical Practice
GMA 
Granulocyte and Monocyte absorbent Apheresis
GPP
Generalized Pustular Psoriasis
hs-CRP
high-sensitivity C-Reactive Protein
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IRB
Institutional Review Board
JDA
Japanese Dermatological Association
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Activities


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
6
MTX
Methotrexate
NRI
Non-Responder Imputation
PA
Posterior-anterior
PASI
Psoriasis Area and Severity Index
PD
Premature Discontinuation
PGA
Physician's Global Assessment
PK
Pharmacokinetics
POR
Proof of Receipt
PML
Progressive Multifocal Leukoencephalopathy
PPD
Purified Protein Derivative
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SDP
Study Designated Physician
TB
Tuberculosis
TNF
Tumor Necrosis Factor


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
7
3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Global Statistics Department for adalimumab study Protocol M14-193 dated 
06 April 2017, that incorporates administrative changes 1,2,3, and 4. (original protocol:
08 June 2015).  It provides details to further elaborate statistical methods as outlined in 
the protocol and describes analysis conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS version 9.3 (SAS 
Institute Inc.) under the UNIX operating system or in the PC environment.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective is to investigate efficacy, safety and pharmacokinetics of 
adalimumab in Japanese subjects with Generalized Pustular Psoriasis (GPP).
4.2
Design Diagram
This study is a 52-week trial.  The study will include a 30-day screening period, 52-week 
open-label active treatment period, and a subsequent 70-day follow-up period after the last 
dose.
Subjects will be Japanese patients diagnosed as GPP with total skin score of at least 3 and 
erythema with pustule (skin score of at least 1) in Japan Dermatology Association (JDA) 
severity index of GPP in GPP Medical Care Guideline 2014.
Subjects who meet all the inclusion criteria and none of the exclusion criteria will be 
enrolled and treated subcutaneously with adalimumab 80 mg at the Baseline for initial 
dose and then 40 mg eow on and after Week 2 until Week 50.  Dose-escalation to 80 mg 
eow is allowed if subjects have inadequate response (i.e., minimal improvement, 
unchanged or worsened) on or after Week 8.  Dose reduction is not allowed throughout 
the study period for the dose-escalated subjects.


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
8
The primary efficacy variable is the proportion of subjects achieving Clinical Response 
(CR) at Week 16.  CR is defined as the reduction of skin score of at least 1 (if the subject's 
Baseline skin score is 3) or at least 2 (if the subject's Baseline skin score is 4 or higher) 
relative to Baseline, according to JDA severity index of GPP in GPP Medical Care 
Guideline 2014.
Study visits will occur at Baseline (Week 0), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48 and 52, and at the Premature Discontinuation visit if the subject discontinues prior 
to Week 52.  No open label extension (OLE) study is planned after this 52-week study.
Adverse events will be collected throughout the study.  Subjects who complete this study 
or who decide to withdraw the study participation will have a Day 70 follow-up phone 
call following their last dose of study drug to determine the status of any ongoing adverse 
events (AEs) or serious adverse events (SAEs), or the occurrence of any new AEs or 
SAEs.
Figure 1.
Study Schematic


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
9
Table 1.
Study Activities:
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Informed Consent
X
Assign Subject ID 
Number
X
Subject Background
X
Inclusion/Exclusion 
Criteria
X
Xb
Medical/Surgical History
X
Xb
Prior and Concomitant 
Therapy Assessment
X
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol Use
X
Tobacco Use
X
Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-Rayd/12-Lead 
ECGe
X
Xf
Xg
TB Screeningh
X
Vital Signs
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Tests
Xj
Xk
Xk
General Labsl:  Blood 
Chemistry and 
Hematology
X
Xm
X
X
X
X
X
X
X
X
Xs


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
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Table 1.
Study Activities: (Continued)
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Urinalysisn
X
X
X
X
X
X
X
HIV Screeno
X
Hepatitis B Screenp
X
Hepatitis C Screen
X
Antinuclear Antibody 
(ANA)/Anti-Double-
Stranded DNA (dsDNA)q
X
Photographyr
X
X
X
X
X
X
X
X
X
GPP Skin Score and 
BSA,
Systemic/Laboratory 
Score
X
X
X
X
X
X
X
X
X
X
Xs
PGA
X
X
X
X
X
X
X
X
X
X
Xs
PASI Score
X
X
X
X
X
X
X
X
X
X
Xs
DLQI
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
Administer Study Drugt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
PK Measurementsu
X
X
X
X
X
X
X
X
X
Xs
AAA Measurementsu
X
X
X
X
X
X
Xs


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
11
Table 1.
Study Activities: (Continued)
Activity
Screening 
(Day –30 
to Day –1)
Baselinea
(Day 1)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 52 or 
Premature 
Discontinuation 
Visit
Unscheduled 
Study Visit
70-
Day 
Call
Monitor Adverse Eventsv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Follow-Up Phone Call
Xw
Footnote for Table 1;
a.
The Baseline visit date will serve as the reference for all subsequent visits.  A ± 7-days window is permitted around scheduled study visits.
b.
Update inclusion/exclusion, medical/surgical history, and prior and concomitant therapy information to assure subject eligibility.
c.
Physical examinations performed at Screening, Week 24 and Week 52/PD Visits will be full physical examinations.  Physical exams performed at all other visits will be 
symptom-based.
d.
Chest x-ray (CXR) includes posterior-anterior [PA] and lateral views.  Subjects with normal chest x-ray within 90 days of Screening will not require a repeat chest x-ray, if 
documentation is available.
e.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.
f.
Subjects will have a repeat CXR or ECG at Week 52 or the appropriate Premature Discontinuation visit, only if in the opinion of the investigator, clinically significant AEs 
develop during the study that warrant a repeat.
g.
Subjects can have a repeat CXR/ECG at any time during the study as warranted based on the opinion of the Investigator.
h.
Subjects with negative latent TB test(s) (In case a subject received both a PPD test and IGRA, both must be negative) within 90 days of Screening will not require a repeat 
latent TB test, if documentation is available.  PPD skin test is to be read 48 to 72 hours after placement.
i.
Height will be measured at the Screening only.
j.
All females of childbearing potential will have a serum pregnancy test at the Screening that is performed at the central laboratory.


Adalimumab
M14-193 – Statistical Analysis Plan
Version 2.0 – 25Apr2017
12
Table 1.
Study Activities: (Continued)
k.
All females of childbearing potential will have a urine pregnancy test at the Baseline and Week 52 or Premature Discontinuation visits at the central laboratory.  Any subject 
with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior to start of the treatment in the study.  Urine pregnancy test at the 
Baseline will be performed also at site to confirm negative result on site.  If the result at site is positive, treatment with study drug should not be started until the serum 
pregnancy test at the central laboratory is confirmed negative.
l.
Subject should be fasting.  Please refer to the laboratory manual for further instructions.
m.
Laboratory assessments will only need to be repeated at the Baseline if the time between blood sampling for Screening and Baseline is greater than 14 days, or if the subject's 
health status has changed to warrant a repeat test.
n.
Dipstick urinalysis will be conducted by the central laboratory at all required study visits.  A microscopic analysis will be performed in the event the dipstick results show 
protein, ketones or blood greater than negative or glucose greater than normal.
o.
Subjects will be tested for HIV and documented that the test has been performed.  This testing is to be done at the central laboratory.  A subject will not be eligible for study 
participation if test results indicate a positive HIV infection.  AbbVie will not receive results from the testing and not be made aware of any positive result.
p.
Subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core antibodies (HBc Ab Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc 
Ab Total (+) require PCR qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds detection sensitivity will be exclusionary.
q.
Anti-dsDNA will be measured if ANA is positive.
r.
Photographs of skin lesion will be taken at the time points above in subjects who agree to do in the pre-selected sites.
s.
When dose escalation is decided on unscheduled visit or on any visit when the data collection is not planned, the investigator must assess skin lesion (GPP skin score, BSA, 
PGA and PASI score), and perform blood sampling for laboratory test and PK/AAA prior to dose escalation.  Body temperature will come from Vital Signs.  Additional study 
drug dispense may be necessary, if appropriate.
t.
Administration of study drug will be performed after all assessments and examinations scheduled for that day have been completed.  Study drug will be administered every 
other week in the investigator's office or at subject's home after training of self-injection to ensure proper technique.
u.
Blood samples for the measurement of adalimumab and AAA concentrations will be collected prior to dosing.
v.
All AEs reported from the time of study drug administration until 70 days following discontinuation of study drug administration will be collected.  SAEs and protocol-related 
nonserious AE will be collected from the time the subject signed the study-specific informed consent until 70 days following discontinuation of study drug administration.
w.
Site personnel will contact all subjects by phone 70 days after the last dose of study drug to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
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4.3
Sample Size
GPP is designated as the specified rare and intractable disease in Japan and patient 
number is quite limited. Assuming the Clinical Response rate of adalimumab in GPP is 
similar to PASI 75 response in plaque psoriasis, 50% to 60%  as expected response rate in 
adlimumab treatment and 10% as a threshold response rate is hypothesized.
A sample size of 6 to 10 provides over 90% power to detect the difference between 
expected Clinical Response rate (50 to 60%) and threshold response rate (with no 
medication, 10%) in GPP, using a one sample Chi-square test with 2.5% one-sided 
significance level.  In case of using Fisher's exact test, an exact binomial test with a 
nominal 0.025 one-sided significance level will have 82% power to detect the difference 
between the threshold proportion of 10% and the expected proportion of 50%.
Therefore, the target number of subjects is set 10 subjects, taking the study feasibility into 
consideration.
4.4
Interim Analysis
An interim analysis of the primary endpoint and secondary efficacy variables as well as 
safety data collected from Baseline through Week 24 will be performed after the last 
subject in FAS population completes the 24-week period of the study.  A database lock 
will be performed and any discrepant data will be clarified before the lock.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Full Analysis Set:
Full Analysis Set (FAS) population includes all subjects who complied with GCP and 
received at least one dose of study drug and had at least one post-treatment efficacy 
assessment. FAS is the primary population for the efficacy analysis.  In general, efficacy 
analysis will be performed for all subjects regardless dose escalation.


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Safety Dataset:
The Safety set consists of all subjects who received at least one injection of study drug.
Dose Escalation Dataset:
This set consists of all subjects who escalated the study dose from 40 mg eow to 80 mg 
eow on or after Week 8. In order to evaluate the effect of dose escalation, these subjects 
will be analyzed for the efficacy and safety (AEs only) using the data prior- and post-
dose escalation date, separately.
Pharmacokinetic assessments will be conducted on all subjects who were administered at 
least one dose of study drug and have at least one post-dose sample collected for the 
determination of serum adalimumab concentration.
5.2
Variables Used for Stratification of Randomization
Not applicable.
6.0
Analysis Conventions
Unless otherwise specified, the efficacy and safety continuous variables will be 
summarized using the descriptive statistics (including mean, standard deviation, median, 
minimum and maximum), and for qualitative variables, the number (n) and percentage 
(%) of subjects with non-missing data per category will be the default summary 
presentation.
All statistical analyses will be conducted at a two-sided significance level of 0.050 or a 
one-sided significance level of 0.025 (when rounded to 3 decimal places).
6.1
Definition of Baseline
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referred to as Day 1. The baseline value for a variable is defined as the last non-missing 
value on or before the date of the first dose of study drug.
6.2
Definition of Final Observation Value
For subjects who did not discontinue the study before Week 24, final observation is the 
last non-missing observation collected after the first dose of study drug and on the dose of 
study drug at Week 24. Final observation for the interim analysis at Week 24 is defined as 
the last non-missing observation collected after the first dose of study drug and within 70 
days after the last dose of study drug for subjects who discontinued the study before Week 
24.
Final observation for the final analysis at Week 52 is defined as the last non-missing
observation collected after the first dose of study drug and within 70 days after the last 
dose of study drug.
6.3
Definition of Rx Days (Days Relative to the First Dose of 
Study Drug)
Rx Days are calculated for each time point of interest and it provides a quantitative 
measure of days between the event and the first dose date. That is, the Rx Day is 
calculated as the event date minus the date of first dose of study drug plus 1. The Rx Day 
will be a negative value when the time point of interest is prior to the date of first dose of 
study drug, and the Rx Day will be a positive value when the time point of interest is after 
the first dose date. By this calculation algorithm the first dose day is Rx Day 1, while the 
day prior to the date of first dose is defined as Rx Day –1 (there is no Rx Day 0). Rx days 
are used to map actual study visits to the protocol specified study visits.
6.4
Definition of Analysis Windows
Since subjects do not always adhere to the study visit schedule, the following rules will be
applied to assign actual visits to protocol-specified visits including early termination visits.


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For each study visit mentioned in the protocol, a nominal or target day will be selected to
represent the corresponding visit along with a window around the target day. Windows
will be selected in a non-overlapping fashion so that a date collected on the CRF does not
correspond to multiple visit windows. Moreover, windows will not discard any post
baseline measurement recorded on the CRF. If a subject had two or more actual visits in
one visit window, the visit closest to the target will be used as the study visit for that
window. If two visits are equal distance from the target, then the later visit will be used
for reporting. 
The protocol specified visits and corresponding time windows used in the analyses are
presented in Table 2, Table 3, Table 4 and Table 5.
The following visit windows will be used for the analysis of assessment of each efficacy
variables which are collected at baseline visit and Week 52 Visit or early termination (ET).


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Table 2.
Visit Windows for Analysis of Efficacy Variables, General 
Laboratory Parameters (Blood Chemistry and Hematology)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Day 1
1

Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71
Week 12
85
72 – 99
Week 16
113
100 – 141
Week 24
169
142 – 211
Week 36
253
212 – 309
Week 52
365
310 – 421
Table 3.
Visit Windows for Analysis of DLQI, SF-36, Laboratory 
Parameters (Urinalysis)
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Day 1
1

Week 8
57
2 – 85
Week 16
113
86 – 141
Week 24
169
142 – 211
Week 36
253
212 – 309
Week 52
365
310 – 421


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Table 4.
Visit Windows for Analysis of Vital Signs
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Day 1
1

Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71
Week 12
85
72 – 99
Week 16
113
100 – 127
Week 20
141
128 – 155
Week 24
169
156 – 183
Week 28
197
184 – 211
Week 32
225
212 – 239
Week 36
253
240 – 267
Week 40
281
268 – 295
Week 44
309
296 – 323
Week 48
337
324 – 351
Week 52
365
352 – 379
Visit Windows for Dose Escalation Analysis Set
The study days for the analysis of dose escalation effect will be calculated with reference 
to the dose escalation date.
Study Day = Date of evaluation – date of dose escalation + 1.


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Table 5.
Visit Windows for GPP skin score relative to dose escalation
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Day 1 (= date of dose escalation)
1

Week 2
15
2 – 22
Week 4
29
23 – 36
Week 6
43
37 – 50
Week 8
57
51 – 64
Week 10
71
65 – 78
Week 12
85
79 – 92
Week 14
99
93 – 106
Week 16
113
107 – 120
Week 18
127
121 – 134
Week 20
141
135 – 148
Week 22
155
149 – 162
Week 24
169
163 – 176
Week 26
183
177 – 190
Week 28
197
191 – 204
Week 30
211
205 – 218
Week 32
225
219 – 232
Week 34
239
233 – 246
Week 36
253
247 – 260
Week 38
267
261 – 274
Week 40
281
275 – 288
Week 42
295
289 – 302
Week 44
309
303 – 316
6.5
Definition of Missing Data Imputation
The following  methods will be used to impute missing values in the efficacy analyses. In 
general, missing Baseline and safety data will not be imputed. In addition, an observed 
case analysis will be performed.


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Baseline Value is Missing
Subjects will be excluded from analysis of change from baseline if baseline evaluation is 
missing.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy variables. These variables can take values of 
'Achieved' or 'Not Achieved' or may be missing for any reason including discontinuation 
from study. According to the NRI imputation approach, all missing value will be 
considered as 'Not Achieved.'
Last Observation Carried Forward (LOCF)
For continuous variables, the following rules will be used for the LOCF approach:
1. Baseline and pre-baseline values will not be used to impute the missing post-baseline 
values.
2. Missing values after Study Day 1 will be imputed using the latest non-missing values 
after Day 1 and prior to the missing value. If there are no non-missing values after 
baseline, then the LOCF value will be missing.
Observed Cases (OC)
Observed case analysis will be performed such that missing values will not be imputed.
Imputation of Missing Dates
For baseline, efficacy, and safety parameters, if the day and/or month are missing, the 
following conventions will be used to impute the missing dates:
ە 01 for missing start day
ە
End of month for missing end day


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ە January 1st for missing start month
ە December 31st for missing end month
In case of missing or partially missing dosing dates, the dates will not be imputed.
In case of missing or partially missing adverse event start and stop dates, the dates will be
imputed by comparing to the first dosing date so that the corresponding adverse events
will be made treatment-emergent, whenever possible.
Rounding
Rounding will be performed only for presentation of results. No rounding will be
performed before or during computations. The ROUND function of SAS will be
used to round results for presentation.
The mean and median will be rounded for presentation to one decimal more than the
data were entered into the database. For example, mean systolic blood pressure will be
presented to one decimal place (125.2 mmHg) when it is recorded to integer level in
the database (110 mmHg). The standard deviation will be rounded to two decimal 
places more than the data were entered into the database (e.g., 25.31 mmHg for 
systolic blood pressure). The minimum and maximum values will be presented as 
entered into the database.
Percentages will be rounded for presentation to one decimal place; e.g., the proportion
0.1244 will be reported in percent as 12.4.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in FAS, demographic information and baseline values will be 
summarized by descriptive statistics. Categorical data will be summarized by number and 


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percent; and quantitative data will be presented by the number of subjects, mean, standard 
deviation, minimum value, median, and maximum value.
The following demographic and baseline values will be summarized.
Continuous variables:
ە Age (years)
ە Body Weight (kg)
ە Body Height (cm)
ە Body mass Index (kg/m2)
ە Blood Pressure (systolic/diastolic) (mmHg)
ە Pulse (bpm)
ە Respiratory Rate (rpm)
ە Body Temperature (°C)
ە Duration of Generalized Pustular Psoriasis (GPP) [years:  [Date of first dose of 
study drug – Date of first diagnosis of GPP]/365.25]
ە Body Surface Area (BSA; percent [%])
ە Psoriasis Area and Severity Index (PASI) score [0.0-72.0]
ە Dermatology Life Quality Index (DLQI) [0-30]
ە Short Form 36 Health Survey (SF-36)
Categorical variables:
ە Sex [male/female]
ە Race 
ە Ethnicity
ە Age categories [< 65,Ӎ 65]
ە Age categories [< 30, 30 - < 50, Ӎ50]
ە Body Weight categories [Median]


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ە Medical History (using MedDRA, Version 19.1)
ە Tobacco [Current, Former, Never, Unknown]
ە Alcohol use [Current, Former, Never, Unknown]
ە PASI [< 10, 10 - < 30, Ӎ30 ]
ە BSA [< 10%, 10 - < 25%, 25 - < 50%, 50 - < 75%, 75 - < 100%]
ە Tuberculin PPD skin test result
ە Chest x-ray finding [finding, calcified granulomas, pleural scarring,
ە pleural thickening, sign of active TB, previous TB infection]Antinuclear antibody 
(ANA)  [positive/negative]
ە Anti-double stranded DNA (dsDNA) [positive/negative]
ە Physician's Global Assessment (PGA) [clear (score=0), minimal (score=1),
mild (score=2), moderate (score=3), severe (score=4), very severe (score=5)]
7.2
Medical History
For the FAS population, the medical history data will be summarized and presented using 
body systems and conditions/diagnoses 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.
In addition, the medical history data for each subject will be provided in the listing.
Chest X-Ray Results
All subjects undergo a standard chest x-ray of chest (including a posterior-anterior [PA] 
and lateral views) at the screening visit. Finding status (Normal, Abnormal), findings on 
calcified granulomas (Absent, Present), pleural scarring/thickening (Absent, Present),
signs of active TB (Yes, No), and findings indicative of previous TB infection (Yes, No) 
will be summarized by number and percentage of subjects with these findings.


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TB Test Results
Results of Tuberculin PPD skin test or Interferon-Gamma Release Assay (IGRA;
QuantiFERON-TB Gold In-Tube test or T-SPOT TB test) at screening visit will be
summarized by results.
ە Tuberculin PPD skin test (Negative [Induration < 5 mm], Positive [Induration
PP@
ە IGRA (Negative, Positive, Indeterminate)
ECG Results
ECG results at screening will be presented as frequency distribution showing results as
Normal, Abnormal (Not clinically significant), Abnormal (Clinically significant) and 
Unable to evaluate/missing.
Pregnancy Tests
Pregnancy information collected at screening (serum test), baseline and Week 
52/premature discontinuation (urine test) visits will be listed.
Pharmacokinetic
Adalimumab trough serum concentrations will be reported at each time point using 
descriptive statistics.  The relationship between adalimumab concentrations and Clinical 
Response will be determined as appropriate.
Immunogenicity
AAA will be evaluated for each subject and rates of AAA positive will be calculated.  As 
appropriate, the effect of AAA on adalimumab pharmacokinetics, efficacy variable(s), and 
treatment-emergent adverse events may be evaluated.


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7.3
Prior and Concomitant Therapy
Prior and concomitant therapy using drug generic name coded using WHO Drug 
dictionary (version 2016Q1) will be summarized by the generic name with counts and
percentages. 
8.0
Patient Disposition
Subject disposition will be presented for subjects in the safety analysis set using the 
following information
ە Number and percent of subjects in various analysis sets by investigator and site
number
ە For the interim analysis at Week 24, number and percent of subjects completing 
Week 24 and discontinuing on or before Week 24 visit
ە For the interim analysis at Week 24, subject disposition including the number
and percent of subjects who prematurely discontinued the study (on or before
Week 24) by primary reason and by any reason
ە For the final analysis at Week 52, number and percent of subjects completing
Week 52 and discontinuing before Week 52 visit
ە For the final analysis at Week 52, subject disposition including the number and
percent of subjects who prematurely discontinued the study (before Week 52) by 
primary reason and by any reason
ە Number and percent of subjects by visit
Summary of protocol deviations will be provided.
The number and percentage of screened subjects who screen failed and the reasons for 
screen failure (inclusion/exclusion criteria, withdrew consent, lost to follow-up, and/or 
other) will be summarized. A CSR listing of reason for screen failure will be provided for 
all subjects who screen failed.


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9.0
Study Drug Exposure and Compliance 
For the Safety Analysis Set population, study drug exposure will be summarized through
the study as follows:
9.1
Study Drug Exposure
The duration (days) of exposure to study drug will be summarized using the number of 
subjects treated, mean, standard deviation, minimum, median, and maximum.  Duration of 
exposure is defined the number of days since first dose of study drug through the last dose 
date plus 14 days.  For interim analysis at Week 24, the Week 24 dosing date will be used 
instead of last dose plus 14 days only for ongoing subjects.  In addition, the number and 
percentage of subjects exposed to study drug will be summarized for the following 
duration intervals.
1 – 15 days
16 – 29 days
30 – 57 days
58 – 85 days
86 – 113 days
114 – 141 days
142 – 169 days
170 – 197 days
198 – 225 days
226 – 253 days
254 – 281 days
282 – 309 days
310 – 337 days
338 – 365 days
> 365 days
Exposure to study drug (total patient years) will be summarized.


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Cumulative Dose (mg)
Cumulative dose is derived as dose per administration times the number of injections 
given during the study.  Cumulative dose will be summarized using the number of 
subjects treated, mean, standard deviation, minimum, median, and maximum.
The Number of Study Drug Injections
The number of injections received at each scheduled time point by subject will be 
summarized with numbers.
9.2
Compliance
Compliance (%) is defined as the number of adalimumab injections received divided by 
the number of adalimumab injections planned (rounded to 0.1) during the subject's 
participation in the study. For subjects who discontinued the study, planned study drug 
injections counted until the last dose date or the date of last efficacy or vital sign 
measurement.
9.3
Study Drug Dose
80 mg starting at Baseline (Week 0) and 40 mg eow on and after Week 2 until Week 50. 
Dose escalation to 80 mg eow is allowed for subjects who do not have appropriate 
response and meeting dose escalation criteria on or after Week 8.  Dose reduction is not 
allowed after dose escalation until the study end. Treatment of study drug will not occur at 
Week 52.
The number of adalimumab injections received by subjects will be summarized.
10.0
Efficacy Analysis
10.1
General Considerations
This study is an open-label study without any comparator. The significant level is not 
defined, and descriptive statistics will be provided. These include the number of 




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10.3
Secondary Efficacy Analyses
Discrete variables will be summarized by counts and percentages, and continuous 
variables will be summarized by descriptive statistics on the items below at each visit.
The subjects who have missing data for any reason such as early terminated subjects will 
be included into analysis using NRI for discrete variables or LOCF for continuous 
variables.
ە Proportion of subjects achieving Clinical Response (expect Week 16, which is the 
primary endpoint).
ە Proportion of subjects achieving remission.
ە Change from the Baseline in total GPP score (skin and systemic/laboratory test).
ە Change from the Baseline in JDA severity index of GPP.
ە Change and Percent change from the Baseline in total skin score.
ە Change from the Baseline in total systemic/laboratory test score.
ە Change from the Baseline in score of erythema area (overall) and BSA (BSA of GPP).
ە Change from the Baseline in score of erythema area with pustule and BSA.
ە Change from the Baseline in score of edema area and BSA.
ە Change from the Baseline in Body temperature.
ە Change from the Baseline in WBC.
ە Change from the Baseline in hs-CRP.
ە Change from the Baseline in serum Albumin.
ە Proportion of subjects achieving "Mild" in JDA severity index of GPP for patients 
with "Moderate" or "Severe" at the Baseline.
ە Proportion of subjects achieving Treatment Success in PGA (reduction of
2 grades).
ە Change from the Baseline in PGA grade.
ە Proportion of subjects achieving PGA 0/1 for patients with PGA grade at least 2 at 
Baseline.
ە Proportion of subjects achieving PASI 90.


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ە Proportion of subjects achieving PASI 75.
ە Proportion of subjects achieving PASI 50.
ە Change and Percent change from the Baseline in PASI score.
ە Proportion of subjects achieving DLQI = 0.
ە Change from the Baseline in DLQI score.
ە Change from the Baseline in SF-36 score.
ە Proportion of subjects taking systemic co-medication for GPP (etretinate, MTX, oral 
steroids, cyclosporine).
ە Proportion of subjects taking topical co-medication for GPP (corticosteroid,
vitamin D3, tacrolimus).
10.4
Handling of Multiplicity
No adjustment for multiplicity will be done.
10.5
Efficacy Subgroup Analysis
The subgroup analysis listed below is planned for the subgroups shown. Proportion of 
subjects achieving Clinical Response (remission and improvement) at Weeks 16, 24, and 
52.
ە Dose escalation: (without dose escalation, with dose escalation)
ە Previous infliximab experience (infliximab naïve, prior exposure to infliximab)
For all subject in Dose Escalation Set will be summarized as:
z
Proportion of subject achieving Clinical Response by dose escalation.
11.0
Safety Analysis
11.1
General Considerations
Unless otherwise specified, all safety analysis will be performed on the Safety dataset. 


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11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as events that begin or worsen 
either on or after the first dose day of the study medication and within 70 days after the 
last dose of the study medication.  Treatment-emergent AEs will be summarized 
separately for the first half period (Week 0 to Week 24), the second half period (Week 24 
to Week 52), and entire period (Week 0 to Week 52).
For the interim analysis at Week 24, treatment-emergent adverse events are defined as any 
event with an onset or worsening on or after the first dose of study drug and on or prior to 
the Week 24 dosing date for subjects who continued in the study after Week 24, and up to 
70 days after the last dose of study drug for subjects who discontinued prior to Week 24 
visit.
Treatment-emergent adverse events will be summarized and presented using primary 
Medical Dictionary for Regulatory Activities (MedDRA) system organ classes (SOCs) 
and preferred terms (PTs) according to the version of the MedDRA coding dictionary 
used for the study at the time of database lock. The actual version of the MedDRA coding 
dictionary used will be noted in the clinical study report. The system organ classes will be 
presented in alphabetical order and the preferred terms will be presented in alphabetical 
order within each system organ class.
For the Dose Escalation set, TEAEs will be reported before the date of dose escalation 
and also on or after the date of dose escalation, separately. 
Adverse Event Overview
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event categories.
ە Any treatment-emergent adverse event


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ە Any treatment-emergent adverse event that was rated as possibly related to study 
drug by the investigator (Reasonable Possibility)
ە Any treatment-emergent severe adverse event
ە Any treatment-emergent serious adverse event
ە Any treatment-emergent adverse event leading to discontinuation of study drug
ە Any treatment-emergent serious adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility)
ە Any treatment-emergent adverse event leading to death
ە Any treatment-emergent adverse event of special interest
ە Any Deaths
Adverse Events by SOC and PT
The number and percentage of subjects experiencing adverse events will be tabulated 
according to the primary MedDRA system organ class (SOC) and preferred term (PT).  
Subjects reporting more than one adverse event for a given MedDRA PT will be counted 
only once for that term (most severe incident for the severity tables and most related 
incident for the relationship tables).  Subjects reporting more than one type of adverse 
event within a MedDRA SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
The following AEs will be summarized using the conventions described above:
ە Any treatment-emergent adverse event
ە Any treatment-emergent adverse event that was rated as possibly related to study 
drug by the investigator (Reasonable Possibility)
ە Any treatment-emergent adverse event by maximum severity
ە Any treatment-emergent adverse event by maximum relationship to study
ە Any treatment-emergent serious adverse event
ە Any treatment-emergent adverse event leading to discontinuation of study drug


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ە Any treatment-emergent serious adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility)
ە Any treatment-emergent adverse event leading to death
ە Any treatment-emergent adverse event of special interest
Adverse Events by Maximum Severity
Adverse events will also be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 
category of "unknown," even if the subject has another occurrence of the same adverse 
event with a severity present.  The only exception is if the subject has another occurrence 
of the same adverse event with the most extreme severity – "Severe."  In this case, the 
subject will be counted under the "Severe" category.
Adverse Events by Maximum Relationship
Adverse events will also be summarized by maximum relationship to study, as assessed 
by the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same adverse event with a relationship present.  The only 
exception is if the subject has another occurrence of the same adverse event with a 
relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category, respectively.
Adverse Event Rates per 100 Patient Years of Study Drug Exposure
Incidence rates per 100 patient years of exposure to study drug will be presented for 
adverse event overviews and for adverse events by SOC and PT.
The treatment-emergent adverse event rate per 100 patient years of exposure will be 
calculated overall, for each primary SOC, and each PT.  For this calculation, 1 year will 
be considered to be 365.25 days.  The numerator of the overall rate, the SOC rate, or the 
PT rate, will be the total number of treatment-emergent adverse events reported overall, 


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for the SOC, or for the PT, respectively; i.e., a subject can be counted more than 
once overall, for a SOC, and for a PT.  The denominator of the rates will be the total 
number of days exposed to study drug summed across all treated subjects divided by 
365.25, and rounded to one decimal place.  The adverse event rate per 100 subject-years 
of exposure will be calculated as [(numerator/denominator)]*100.  The number of adverse 
events reported (numerator), the total number of years of study drug exposure 
(denominator), and the adverse event rate per 100 subject-years will be presented overall, 
for each SOC, and for each PT.
Adverse Events of Special Interest (AESI)
The analysis of treatment-emergent adverse events of special interest based on
Standardized MedDRA Queries (SMQs) or Company MedDRA Queries (CMQs) will be
presented for the adverse event overviews and for adverse events by SOC and PT.
The final analyses will follow the latest version of Product Safety Statistical Analysis Plan 
(PSSAP). 
The current list of AEs of special interest in PSSAP (version 5.0, dated 20Jan2016) for 
treatment with adalimumab is:
ە Any Infections AE
ە Any Serious Infection AE
ە Any Legionella Infection AE
ە Any Diverticulitis AE
ە Any Opportunistic Infection AE (Excluding Oral Candidiasis and TB)
ە Any Oral Candidiasis AE
ە Any Tuberculosis AE
ە Any Active Tuberculosis AE
ە Any Latent Tuberculosis AE
ە Any Parasitic Infection AE
ە Any Reactivation of Hepatitis B AE
ە Any Progressive Multifocal Leukoencephalopathy (PML) AE
ە Any Malignancy AE


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ە Any Lymphoma AE
ە Any Hepatosplenic T-Cell Lymphoma AE (HSTCL)
ە Any Non-Melanoma Skin Cancer (NMSC) AE
ە Any Melanoma AE
ە Any Leukaemia AE
ە Any Other Malignant AE (Excluding NMSC, Melanoma, Lymphoma, HSTCL, 
and Leukemia)
ە Any Allergic Reaction AE (Including Angioedema/Anaphylaxis)
ە Any Lupus-Like Reactions and Systemic Lupus Erythematosus AE
ە Any Vasculitis AE
ە Any Cutaneous Vasculitis AE
ە Any Non-Cutaneous Vasculitis AE
ە Any Sarcoidosis AE
ە Any Autoimmune Hepatitis AE
ە Any Myocardial Infarction Related AE
ە Any Cerebrovascular Accident Related AE
ە Any Congestive Heart Failure Related (CHF) AE
ە Any Pulmonary Embolism Related AE
ە Any Interstitial Lung Disease AE
ە Any Intestinal Perforation AE
ە Any Pancreatitis AE
ە Any Stevens-Johnson Syndrome AE
ە Any Erythema Multiforme Related AE
ە Any Worsening/New Onset of Psoriasis AE
ە Any Demyelinating Disorder AE (Including Multiple Sclerosis, Guillain-Barré 
Syndrome, and Optic Neuritis and Others)
ە Any Amyotrophic Lateral Sclerosis AE
ە Any Reversible Posterior Leukoencephalopathy Syndrome (RPLS) AE
ە Any Hematologic Disorders AE (Including Pancytopenia)


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ە Any Liver Failure and Other Liver Event AE (Except Gall Bladder Related Events)
ە Any Humira Administration Related Medication Errors AE
ە Any Injection Site Reaction AE
ە Any AE Leading to Death
ە Any AE Leading to Discontinuation of Study Drug
ە Any Deaths
Additional AEs may be considered for tabulation/summary based on recommendations
from Clinical and Safety as deemed appropriate.
11.2.2
Listing of Adverse Events
The following additional summaries of adverse events will be prepared.
ە Listing of treatment-emergent adverse events
ە Listing of subject numbers associated with each PT for treatment-emergent
adverse events
ە Listing of treatment-emergent serious adverse events
ە Listing of pre-treatment serious adverse events
ە Listing of treatment-emergent adverse events that led to discontinuation of study drug
ە Listing of treatment-emergent fatal adverse events.
ە Listing of deaths
ە Listing of treatment-emergent adverse events of special interest
11.3
Analysis of Laboratory Data
Laboratory test variables are specified in Table 7.  Laboratory test variables will use 
standard units.


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Table 7.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysisa
Hematocrit
Hemoglobin
Red Blood Cell count
White Blood Cell count
Neutrophils (Stab, Seg)
Bands (Stab)
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase/alanine 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase/aspartate 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
hs-CRP
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Additional Blood Samples Collected
ȕ-hCG (serum pregnancy test)
QuantiFERON-TB Gold or T-SPOT TB (IGRA)
HIV 
HBV
HCV
ANA
anti-dsDNA – if ANA positive
Pharmacokinetic, Anti-adalimumab antibody
a.
A microscopic analysis will be performed by the central laboratory, in the event the dipstick results show protein, 
ketones or blood greater than negative or glucose greater than normal.
11.3.1
Variables and Criteria Defining Abnormality
The liver specific laboratory tests include the serum glutamic-pyruvic transaminase
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline


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phosphatase and total bilirubin. Each of these laboratory values will be categorized as
follows:
1. < 1.5 ULN,
î8/172î8/1
î8/1728/1
5 × ULN TO < 8 ULN, and
î8/1
where ULN is the upper normal limit. 
Shift tables showing shift from Baseline to maximum and final values 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 4 criteria:
$/7î8/1RU
$67î8/1RU
$ONDOLQH3KRVSKDWDVHî8/1RU
7RWDO%LOLUXELQî8/1
For selected laboratory parameters (Hematology:  Hemoglobin, Platelet count, WBC, 
1HXWURSKLOV/\PSKRF\WHV&OLQLFDO&KHPLVWU\$/7$67$ONDOLQH3KRVSKDWDVHȖ-GTP, 
Total Bilirubin, Albumin, CPK, Creatinine, Uric Acid, Calcium, Sodium, Potassium, 
Inorganic Phosphorus, Magnesium, Glucose, Cholesterol, Triglycerides) with Common 
Toxicity Criteria (CTC), Potentially Clinically Significant (PCS) Laboratory Findings 
(Common Toxicity Criteria CTC [Version 4.0] Grades 3 and 4) will be assessed.
The following table describes the Criteria for Potentially Clinically Significant Laboratory 
Findings:


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Table 8.
Potentially Clinically Significant Laboratory Findings
Laboratory Parameter
CTC Grade 1
CTC Grade 2
CTC Grade 3
CTC Grade 4
Hemoglobin – Low (G/L)
< LLN – 100
< 100 – 80
< 80
–
Hemoglobin – High (G/L)
CH > 0.0 – 20
CH > 20 – 40
CH > 40
–
Platelet count (× 109/L)
< LLN – 75
< 75 – 50
< 50 – 25
< 25
WBC (× 109/L)
< LLN – 3.0
< 3.0 – 2.0
< 2.0 – 1.0
< 1.0
Neutrophils (× 109/L)
< LLN – 1.5
< 1.5 – 1.0
< 1.0 – 0.5
< 0.5
Lymphocytes (× 109/L)
< LLN – 0.8
< 0.8 – 0.5
< 0.5 – 0.2
< 0.2
ALT
> ULN - 3.0 × ULN
> 3.0 - 5.0 × ULN
> 5.0 - 20.0 × ULN
> 20.0 × ULN
AST
> ULN - 3.0 × ULN
> 3.0 - 5.0 × ULN
> 5.0 - 20.0 × ULN
> 20.0 × ULN
Alkaline phosphatase
> ULN - 2.5 x ULN
> 2.5 - 5.0 x ULN
> 5.0 - 20.0 x ULN
> 20.0 x ULN
Ȗ-GTP
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
Total bilirubin
> ULN - 1.5 × ULN
> 1.5 - 3.0 × ULN
> 3.0 - 10.0 × ULN
> 10.0 × ULN
Albumin (G/L)
< LLN – 30
< 30 – 20
< 20
–
CPK
> ULN – 2.5 × ULN
> 2.5 × ULN – 5.0 × ULN
> 5.0 × ULN – 10.0 × ULN
> 10.0 × ULN
Creatinine*
> ULN – 1.5 × ULN;
or > 1 - 1.5 × BL
> 1.5 – 3.0 × ULN
or > 1.5 – 3.0 × BL
> 3.0 – 6.0 × ULN
or > 3.0 × BL
> 6.0 × ULN
Uric Acid (MCMOL/L)
> ULN – 590
–
–
> 590
Calcium – Low (MMOL/L)
< LLN – 2.0
< 2.0 – 1.75
< 1.75 – 1.5
< 1.5
Calcium – High (MMOL/L)
> ULN – 2.9
> 2.9 – 3.1
> 3.1 – 3.4
> 3.4
Sodium – Low (MMOL/L)
< LLN – 130
–
< 130 – 120
< 120


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Table 8.
Potentially Clinically Significant Laboratory Findings (Continued)
Laboratory Parameter
CTC Grade 1
CTC Grade 2
CTC Grade 3
CTC Grade 4
Sodium – High (MMOL/L)
> ULN – 150
> 150 – 155
> 155 – 160
> 160
Potassium – Low (MMOL/L)
< LLN – 3.0
–
< 3.0 – 2.5
< 2.5
Potassium – High (MMOL/L)
> ULN – 5.5
> 5.5 – 6.0
> 6.0 – 7.0
> 7.0
Inorganic Phosphorus 
(MMOL/L)
< LLN – 0.8
< 0.8 – 0.6
< 0.6 – 0.3
< 0.3
Magnesium - Low (MMOL/L)
< LLN – 0.5
< 0.5 – 0.4
< 0.4 – 0.3
< 0.3
Magnesium - High (MMOL/L)
> ULN – 1.23
–
> 1.23 – 3.30
> 3.30
Glucose – Low (MMOL/L)
< LLN – 3.0
< 3.0 – 2.2
< 2.2 – 1.7
< 1.7
Glucose – High (MMOL/L)
> ULN – 8.9
> 8.9 – 13.9
> 13.9 – 27.8
> 27.8
Cholesterol (MMOL/L)
> ULN – 7.75
> 7.75 – 10.34
> 10.34 – 12.92
> 12.92
Triglycerides (MMOL/L)
1.71 – 3.42
> 3.42 – 5.7
> 5.7 – 11.4
> 11.4
CH = change in ULN or change in baseline, if baseline > ULN; ULN = upper limit of normal range; LLN = lower limit of normal range; BL = baseline;
* = identify by ULN if baseline is normal else use BL if baseline is abnormal;


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11.3.2
Statistical Methods
Mean changes from baseline to each post-baseline visits (as defined in Table 1) and 
final value in continuous laboratory parameters will be summarized with the baseline 
mean, visit mean, change from baseline mean, standard deviation, minimum value, 
median, and maximum value.
Laboratory data values will be categorized as low, normal, or high based on normal 
ranges of the laboratory used in this study.  Cross (shift) tables from baseline to the 
minimum/maximum/final values according to the normal range will be provided for each 
hematology, clinical chemistry parameter and urinalysis parameters. The shift tables will 
cross tabulate the frequency and percentage of subjects with baseline values 
below/within/above the normal range versus minimum/maximum/final values 
below/within/above the normal range.
Incidence of abnormal laboratory values for hematology, clinical chemistry parameter and 
urinalysis parameters will be provided.
Scatter plot of Baseline values versus the final values in laboratory parameters will be
provided.
11.4
Analysis of Vital Signs and Weight
The following vital signs are measured at the designated study visits in Table1.
ە Blood Pressure (Systolic/Diastolic) (mmHg)
ە Pulse (bpm)
ە Respiratory rate (rpm)
ە Body temperature (°C)
ە Body Weight (kg)


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11.4.1
Statistical Methods
For each vital sign and weight variable, analyses of the mean change from baseline to 
each post-baseline value will be presented for the Safety Dataset using the descriptive 
statistics including 95% confidence interval based on standard normal distribution.
12.0
Summary of Changes
No major changes were made to the analysis plan. Minor correction are as follows.
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
12.2
Summary of Changes Between the Previous Version and the
Current Version of the SAP
z
Corrected the information of protocol version and updated the SAP version in section
3.0.
z
The sentence, This is the first version of SAP for Protocol M14-193., was removed.
z
Add Efficacy Assessment Criteria table for clinical response in section 10.2 based on 
Administrative change 4.
13.0
Appendix
14.0
Reference