Humira® 40mg Syringe 0.8mL Subcutaneous Injection Special Investigation in Patients With Intestinal Behcet's Disease
Conditions: Behcet's Disease
Sponsor: AbbVie

HUMIRA® 40mg for S.C. Injection (generic name: adalimumab)
P14-152
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Title Page 
AbbVie GK 
PMOS PROTOCOL (P14-152)
Humira® 40mg Syringe 0.8mL for Subcutaneous Injection 
Special Investigation in patients 
with Intestinal Behcet’s disease
Title
Humira® 40mg Syringe 0.8mL subcutaneous injection
Special investigation in patients with intestinal Behcet’s disease
Protocol Version Identifier
P14-152
Date of Last Version of 
Protocol
14 Jun 2013
EU PAS Register Number
Not applicable
Active Substance
Not applicable
Medicinal Product
Not applicable
Product Reference
Not applicable
Product Number
Not applicable
Marketing 
Authorization 
Holder(s)
Joint PASS
Not applicable
Research 
Question 
and 
Objectives
A specified use-results survey of HUMIRA® is to be performed for 
the purpose of obtaining the safety and effectiveness data in the 
patients with Intestinal Behcet’s disease.
Country of Study
Japan
Author
This study will be conducted in compliance with this protocol. 
Confidential Information 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
NCT01960790

 
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1.0 
Table of Contents 
1.0 
Table of Contents .................................................................... 2 
2.0 
Abbreviations .......................................................................... 3 
3.0 
Responsible Parties ................................................................. 5 
4.0 
Abstract .................................................................................... 5 
5.0 
Amendments and Updates ..................................................... 7 
6.0 
Milestones ................................................................................ 7 
7.0 
Rationale and Background .................................................... 8 
7.1 
Background ................................................................................................8 
7.2 
Rationale ....................................................................................................8 
8.0 
Research Question and Objectives ...................................... 10 
9.0 
Research Methods ................................................................. 10 
9.1 
Study design ............................................................................................10 
9.2 
Setting ......................................................................................................12 
9.3 
Variables ..................................................................................................16 
9.4 
Data sources .............................................................................................19 
9.5 
Study Size ................................................................................................19 
9.6 
Data Management ....................................................................................19 
9.7 
Data Analysis ...........................................................................................20 
9.8 
Quality Control ........................................................................................20 
9.9 
Limitation of the research Methods .........................................................21 
9.10 
Other aspects ...........................................................................................21 
10.0 
Protection of Human Subjects ............................................. 22 
11.0 
Management Reporting of Adverse Events/Adverse 
Reactions/Complaints ........................................................... 22 
11.1 
Adverse Event Definition and Serious Adverse Event Categories .........22 
11.2 
Severity ....................................................................................................23 
11.3 
Relationship to Pharmaceutical Product ..................................................23 

 
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11.4 
Serious Adverse Event Collection Period ...............................................24 
11.5 
Serious Adverse Event Reporting ...........................................................24 
11.6 
Pregnancy Reporting ...............................................................................24 
11.7 
Management and Reporting of Complaints .............................................25 
11.7.1 
Definition .................................................................................................25 
11.7.2 
Reporting .................................................................................................25 
12.0 
Final Report and Publications ............................................. 27 
 
2.0 
Abbreviations 
ADR 
Adverse Dug Reaction 
AE  
Adverse Event 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
DNA 
Deoxyribonucleic acid 
FAS 
Full Analysis Set 
HBc 
Hepatitis B core 
HBs 
Hepatitis B surface 
HBV 
Hepatitis B virus 
MR 
Medical Represantatives 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labor and Welfare 
NIS   
Non-Interventional Study 
PMDA 
Pharmaceuticals and Medical Devices Agency 
QOL 
Quality Of Life 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
S.C. 
Subcutaneous injection 
SPC 
Summary of Product Characteristics 
PMS 
Post marketing surveyllance 
TNF-α 
Tumor Necrosis Factor-α 

 
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WBC 
White blood cell 
 

 
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3.0 
Responsible Parties 
1) Eisai Co., Ltd. 
 
Zip code : 112-8088 
 
Address : 4-6-10, Koishikawa, Bunkyo-ku, Tokyo, Japan 
 
Phone : +81-3-3817-3700 
 
2) A2 Healthcare Corporation 
 
Zip code : 112-0002 
 
Address : 1-4-1, Koishikawa, Bunkyo-ku, Tokyo, Japan 
 
Phone : +81-3-3830-1122 
 
4.0 
Abstract 
Title : Humira® 40mg Syringe 0.8mL Subcutaneous Injection 
Special Investigation in patients with Intestinal Behcet’s disease 
Rationale and Background :  
See 7.1 and 7.2 
Research Question and Objectives :  
A specified use-results survey of HUMIRA® 40 mg Syringe 0.8 mL for Subcutaneous 
Injection (Nonproprietary name: Adalimumab (recombinant)” is to be performed for the 
purpose of obtaining the following information in the Japanese patients with intestinal 
Behcet’s disease. 
Study Design : 
See 9.1 
Population :  
Setting : 
<inclusion Criteria> 
Patients receiving Humira® for the treatment of Behcet’s disease on proper use after 
the approval of the indication are to be all enrolled. 
The survey is to be performed in the patients with intestinal Behcet's disease (not 
sufficiently responsive to existing therapies, e.g. steroids, immunomodulator), who are 
treatable with Humira® (Also refer to “Precautions relating to the indications”).  
When using this drug, please pay adequate attention to the latest package insert.  
 
<Exclusion Criteria> 
Patients included in “Contraindication” in the package insert 
1. 
Patients with serious infection (sepsis etc.) [Symptomatic worsening may 
occur.] 

 
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2. 
Patients with active tuberculosis [Symptomatic worsening may occur.] 
3. 
Patients with a history of hypersensitivity to any of the ingredients of HUMIRA 
4. 
Patients with a current or past history of demyelinating disorder (multiple 
sclerosis, etc.) [Symptomatic relapse or worsening may occur.] 
5. 
Patients with congestive heart failure [Symptomatic worsening may occur.] 
Variables : 
See 9.3 
Data Sources : 
Not appplicable 
Study Size :  
Number of sample size : No decided 
㸺Rationale for setting㸼 
It is impossible to determine the number of survey centers and the number of survey 
centers is not decided because the survey is to be performed in all treated subjects and 
the drug is used only in the institutions qualified for the facility-related and doctor-
related requirements. 
Data Analysis : 
All statistical analysis procedures will be described in detail in the Statistical Analysis 
Plan (SAP). This plan will be developed by the responsible protocol author in 
collaboration with CRO. The SAP shall be finalized and approved by the responsible 
protocol author and study-designed physician before the database is used for the final 
analysis. 
Milestones : 
Start of Data Collection :  
 
01 July 2013 
End of Data Collection :  
 
15 May 2017 
Study Progress Report :  
 
Not Applicable 
Interim Report :  
 
 
Not Applicable 
Registration in the EU PAS register : Not Applicable 
Final Report of Study results :  
15 Aug 2017 (Submit to PMDA) 
 
 
 
 
 
 
 
 
 
 

 
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5.0 
Amendments and Updates 
 
 
No. 
Date 
Section of study 
Protocol 
Amendment  
or Update 
Reason 
1 
26 Feb 2016 
11.5 Serious 
Adverse Event 
Reporting  
11.7
Management 
and Reporting 
of Complaints  
Amendment 
FDA requirement  
 
 
6.0 
Milestones 
 
Start of Data Collection :  
 
01 July 2013 
 
End of Data Collection :  
 
15 May 2017 
 
Study Progress Report :  
 
Not Applicable 
 
Interim Report :  
 
 
Not Applicable 
 
Registration in the EU PAS register : Not Applicable 
 
Final Report of Study results :  
15 Aug 2017 (Submit to PMDA) 

 
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7.0 
Rationale and Background 
7.1 
Background 
Although there are not so many clinical reports of anti-TNF agents for intestinal Behcet’s 
disease, infliximab is reported effective. Naganuma et al. performed a drip infusion of 
infliximab at the dosage of 5 mg/kg in Weeks 0, 2, 6, and at the interval of 8 weeks 
subsequently to six Japanese patients with intestinal Behcet’s disease and assessed 
efficacy based on gastrointestinal symptoms and endoscopic findings. As a result, 
infliximab was assessed effective in four of the six patients and the effectiveness was 
maintained under continued therapy in the patients who were responsive to infliximab. 
Iwata et al. also performed a drip infusion of infliximab at the dosage of 3 mg/kg in 
Weeks 0, 2, 6, and at the interval of 8 weeks subsequently to ten Japanese patients with 
intestinal Behcet’s disease. As a result, all the patients had alleviation of gastrointestinal 
symptoms and ulcer disappearance was confirmed in the endoscopy performed six month 
later in five patients and twelve months later in nine patients.Apart from these reports, 
some case reports suggest that infliximab is effective but they do not include any clinical 
study report. Meanwhile, it is also suggested based on a retrospective study performed in 
patients with intestinal Behcet’s disease treated with infliximab in 38 Japanese 
institutions that infliximab was effective in 42 (61%) of the 69 patients. These findings 
suggest that TNFD plays important roles in the pathological condition of intestinal 
Behcet’s disease. Meanwhile, adalimumab, as well as infliximab, is expected effective 
for the treatment of intestinal Behcet’s disease judged from the report that patients 
maintained endoscopic and histological remission under adalimumab monotherapy even 
in 22 months after switch from concomitant therapy with infliximab and 
immuneregulator which alleviated intestinal Behcet’s disease㸬 
 
7.2 
Rationale 
This survey is to be performed as a total survey in Japanese patients with intestinal 
Behcet’s disease for the purpose of verifying the safety and efficacy of the Product used 
for the patients in usual clinical practice.  
 
The Japanese clinical study (Study M11-509) is to be performed in patients with 
intestinal Behcet’s disease for the first time in the world for verifying the safety and 
efficacy of adalimumab in the patients with intestinal Behcet’s disease (including 
“complete type of Behcet’s disease”, “incomplete type of Behcet’s disease”, and 
“suspected Behcet’s disease”) who are not adequately responsive to existing therapy 
(adrenocorticosteroid or immunoregulator also used for the treatment of Crohn’s disease 

 
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or ulcerative colitis). Complete type of Behcet’s disease and incomplete type of Behcet’s 
disease based on the diagnostic criteria for Behcet’s disease are certified as designated 
diseases and patients having typical ileocecal ulcer are diagnosed as having intestinal 
Behcet’s disease. Meanwhile, there is no difference in the intestinal lesion (ileocecal 
ulcer, gastrointestinal symptoms) between “complete type or incomplete type” of 
Behcet’s disease and “suspected” Behcet’s disease and they are treated in the same way 
in usual clinical practice. The number of patients with “suspected” Behcet’s disease is 
considered almost the same as the number of patients with “complete type” or 
“incomplete type” of Behcet’s disease in combination. Since medical needs are 
considered high and adalimumab, anti-TNFD agent, is equivalently expected effective, 
trial subjects include those with “suspected” Behcet’s disease. It is estimated that there 
are 2000 to 3000 patients with intestinal Behcet’s disease (“complete type or incomplete 
type” of Behcet’s disease) in Japan and when patients with “suspected” Behcet’s disease 
are included, the number is about twice larger. Of the patients, 10 to 20% were not 
considered adequately responsive to existing therapies and the number of patients who 
would fulfill the inclusion/exclusion criteria for the clinical study and give consent was 
considered limited. Actually, 20 patients participated in the clinical study. 
In the Japanese clinical study performed in the above described 20 patients with intestinal 
Behcet’s disease (Study M11-509), the percentage of marked response was 45.0% (9/20) 
after 24 weeks of treatment and 60.0% (12/20) after 52 weeks.  
During 52 weeks of treatment, adverse events were seen in 100% of the patients (20 
patients, 102 cases), and adverse events were assessed “definitely” or “probably” causally 
related with the study drug in 25.0% (5 patients, 9 cases) of the patients, were assessed 
serious in 5.0% (1 patient, 1 case) of the patients, and needed study discontinuation in 
10.0% (2 patients, 2 cases) of the patients. None of the adverse events was severe or 
resulted in death. None of the trial subjects died in the study. Infectious diseases were 
reported from 70.0% (14 patients, 30 cases) of the patients, non-dermal angitis and 
hepatic dysfunction were reported from 15.0% each of the patients (non-dermal angitis 3 
patients, 3 cases, hepatic dysfunction 3 patients, 4 cases), injection site reaction and 
allergic reaction were reported from 10.0% each of the patients (2 patients, 2 cases), and 
tuberculosis-related adverse event, intestinal stenosis, and ALT increase were reported 
from 5.0% each of the patients (1 patient, 1 case). The patient with tuberculosis-related 
adverse event was tested positive for tubercle bacillus (QuantiFERON-TB2G) but was 
assessed less likely to have active tuberculosis.  
The sponsor was instructed to perform a total survey for the purpose of verifying the 
safety and efficacy of adalimumab in the patients with intestinal Behcet’s disease in 
actual clinical use since the clinical study substantiated the safety and efficacy but was 
performed in a limited number of patients. 
 

 
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8.0 
Research Question and Objectives 
A specified use-results survey of HUMIRA® 40 mg Syringe 0.8 mL for 
Subcutaneous Injection (Nonproprietary name: Adalimumab (recombinant)” is to be 
performed for the purpose of obtaining the following information in the Japanese 
patients with intestinal Behcet’s disease. 
(Primary Endpoints) 
1. Unknown adverse reactions (in particular, clinically significant) 
2. Incidence and conditions of occurrence of adverse reactions in clinical 
practice 
3. Factors likely to affect the safety 
< Key survey items in safety> 
Infection, tuberculosis, malignant tumor, administration site reaction, autoimmune 
disease, pancytopenia, demyelinating disorders, congestive cardiac failure, and 
interstitial pneumonia 
 
(Secondary Endpoints) 
4. Efficacy measured by overall evaluation of gastrointestinal symptoms, 
evaluation of gastrointestinal symptoms of Behcet’s disease, evaluation of 
main symptoms of Behcet’s disease, evaluation of secondary symptoms of 
Behcet’s disease, degree of improvement of endoscopic findings, and CRP 
5. Factors likely to affect the efficacy 
 
 
9.0 
Research Methods 
9.1 
Study design 
The observation period of the survey is 156 weeks at the longest and is segmented to 52 
weeks, 104 weeks, and 156 weeks depending on the treatment stage. The observation 
period differs from patient to patient because of the need to recover CRFs from all 
patients registered during the re-examination period (4 years) and submit the report to 
PMDA㸬 

 
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Primary Endpoints 
Safety 
z 
List of adverse reactions and infections 
Stratified analyses of safety 
z 
Factors likely to affect the safety  
 
Incidence of adverse reactions stratified by patient background (sex, age, 
morbidity period, smoking history, presence or absence of concomitant 
symptom, presence or absence of past medical history, presence or absence 
of past history of allergic disease, presence or absence of foregoing 
medication, presence or absence of concomitant medication) 
 
Incidence of adverse reactions stratified by non-intestinal symptom of 
Behcet’s disease 
 
Incidence of adverse reactions stratified by the changes in the 
corticosteroid dose in the patients treated with corticosteroids 
 
Adverse events which were developed during or after administration 
 
List of serious adverse events 
 
Onset of self-injection malpractice 
 
Relation with the safety when anti-adalimumab antibody is measured 
 
Secondary Endpoint 
Efficacy 
z 
Overall evaluation of gastrointestinal symptoms, evaluation of gastrointestinal 
symptoms of Behcet’s disease , evaluation of main symptoms of Behcet’s disease , 
evaluation of secondary symptoms of Behcet’s disease, degree of improvement of 
endoscopic findings, and CRP 
Stratified analyses of efficacy 
z 
Factors considered to have efficacy influence  
 
Factors stratified by patient background (sex, age, morbidity period, 
smoking history, presence or absence of concomitant symptom, presence or 
absence of past medical history, presence or absence of past history of 
allergic disease, presence or absence of foregoing medication, presence or 
absence of concomitant medication) 
 
Factors stratified by the diagnosis type of intestinal Behcet’s disease 
 
Factors stratified by the changes in the corticosteroid dose in the patients 
treated with corticosteroids 
 
Relation with the efficacy when anti-adalimumab antibody is measured 

 
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9.2 
Setting 
Inclusion Criteria 
Patients receiving Humira® for the treatment of Behcet’s disease on proper use after the 
approval of the indication are to be all enrolled. 
The survey is to be performed in the patients with intestinal Behcet's disease (not 
sufficiently responsive to existing therapies, e.g. steroids, immunomodulator), who are 
treatable with Humira® (Also refer to “Precautions relating to the indications”).  
When using this drug, please pay adequate attention to the latest package insert.  
 
Exclusion Criteria 
Patients included in “Contraindication” in the package insert  
1. 
Patients with serious infection (sepsis etc.) [Symptomatic worsening may occur.] 
2. 
Patients with active tuberculosis [Symptomatic worsening may occur.] 
3. 
Patients with a history of hypersensitivity to any of the ingredients of HUMIRA 
4. 
Patients with a current or past history of demyelinating disorder (multiple 
sclerosis, etc.) [Symptomatic relapse or worsening may occur.] 
5. 
Patients with congestive heart failure [Symptomatic worsening may occur.] 
 
Dosage and Administration 
The product should be administered to the adults by subcutaneous injection at the 
adalimumab (recombinant) dose of 160 mg in the initial administration and 80 mg in 2 
weeks after the initial administration. Subsequently after 4 weeks after the initial 
administration, the product should be administered once in two weeks by subcutaneous 
injection at the dosage of 40 mg.  
When using this drug, please take sufficient cautions to the latest package insert.  
 
Investigator site selection 
The survey is to be performed in all institutions/departments where the drug is used for 
the indication. Use of the drug for the treatment of intestinal Behcet’s disease is limited in 
the institutions and doctors that fulfill the following facility-related and doctor-related 
requirements and having concluded the agreement between medical centers and the 
company.  
 
㸦1㸧Institutes criteria 
The survey is to be performed in the institutions fulfilling all the following 
requirements. 
1㸧 Institution specializing in medical care for intestinal Behcet’s disease 
2㸧 Institution capable of making a diagnosis of/providing treatment for 
tuberculosis in collaboration with internal or external specialists of 
respiratory diseases and radiology  

 
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3㸧 Institution capable of making a diagnosis of/providing treatment for severe 
infections in collaboration with internal or external specialists of infections 
 
㸦2㸧Doctor criteria 
Doctors who are qualified as any of the following specialists and have received 
the set of materials of information on safety measures for HUMIRA® from 
Medical Representatives (MR) and have adequate knowledge about the properties 
of the drug 
1㸧 Specialist accredited by the Japanese Society of Gastroenterology 
2㸧 Specialist accredited by the Japan Gastroenterological Endoscopy Society 
3㸧 Specialist accredited by the Japan Society of Coloproctology  
4㸧 Specialist accredited by the Japanese Gastroenterological Association 
5㸧 Specialist accredited by the Japanese Society of Gastroenterological Surgery 
6㸧 Doctor who have participated in a clinical trial of adalimumab for intestinal 
Behcet’s disease 
7㸧 Specialist accredited by the Japan College of Rheumatology or the doctor 
registered to the Japan Rheumatism Foundation Information Center 
8㸧 Doctor who have experienced joining to investigation of all cases PMOS for 
any biologics in Japan 
 
Study Conduct 
㸦1㸧Surveillance system 
The survey is to be performed in all treated patients according to the central 
registration system in the institutions which fulfill facility-related and doctor-
related requirements and have concluded the agreement. 
(2) Request and contract of post-marketing surveillance 
1㸧 Medical representatives (MR) provides a full set of materials of information 
on safety measures for HUMIRA® to doctors in charge of survey, and 
explains the character of this drug, the objective of surveillance, patients to be 
surveyed, and survey methods. 
2㸧 The doctor in charge of the survey will check that he/she has received 
explanations about the set of materials of information on safety measures for 
HUMIRA® and that the doctor and the institution fulfill facility-related and 
doctor-related requirements and sign “Statement of Acceptance of Proper Use 
Information”. MR will obtain and review “Statement of Acceptance of Proper 
Use Information” signed by the doctor in charge of the survey, commission 
the post-marketing survey to the institution, and conclude the written 
agreement.  
㸦3㸧Survey methods 

 
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1㸧 Paper-based CRF (case report form) is used to collect the survey data. 
2㸧 Patients are observed for a period of 52, 104, or 156 weeks after 
administration of this drug was initiated. 
3㸧 A physician in charge of surveillance explains proper use information on this 
drug to participating patients, to obtain their written informed consent to 
participate in the surveillance. 
4㸧 A physician in charge completes the enrollment form as soon as this drug was 
decided to be administered to the patients who consented to participation, and 
sends it to the enrollment center. 
5㸧 A physician in charge completes CRF with the observation results at weeks 
52, 104, and 156 after commencement of administration, and submits the 
CRF to MR. In cases of the observation period uncompleted, CRF is 
completed promptly when the surveillance is discontinued, and submitted to 
Medical representatives (MR). 
6㸧 The sponsor will review the enrollment form and the CRF and recheck them 
where necessary. 
 
Case Report Form 
All data specified in Section 8.5 “Study Conduct” will be collected on paper forms (CRF). 
For each visit, the CRF includes forms to be completed by the physician as well as forms 
to be completed by the patient. Each center receives a folder with all documents and 
forms necessary for the baseline and follow-up documentation of contract number of 
cases. 
Any observation of an adverse event in the time period up to 52, 104, and 156 weeks, 
beginning with the initiation of adalimumab therapy, is to be documented on the CRF. If 
the event fulfills the serious criterion (Serious Adverse Event), the "Serious Adverse 
Event Report” form is to be completed additionally. 
 
 
The following table provides an overview of the required visits and corresponding 
activities for the study. 

 
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Table 1. Study Schedule 
 
Assessment time 
At week 0 
 
 
At Week 156 or 
discontinuation 
Baseline patient characteristics 
{ 
 
 
 
Condition of administration of the product 
{ 
 
 
History of administration of biological 
preparations for intestinal Behcet's disease 
{ 
 
 
 
Foregoing medication/treatment for 
intestinal Behcet's disease 
{ 
 
 
 
Condition of use of antitubercular agent 
{ 
 
 
Condition of use of Concomitant Drugs 
{ 
 
 
Presence or absence of treatment other than 
drug therapy for intestinal Behcet's 
disease/concomitant therapy for intestinal 
Behcet's disease 
{ 
 
 
Presence or absence of onset of 
tuberculosis and serious respiratory 
diseases 
Before start of 
administration 
 
 
 
Total evaluation of digestive symptoms 
(determined by the attending physician)  
Evaluation of digestive symptoms of 
Behcet's disease 
{ 
Week 4, 8, 12, 24, 52, 76, 104 
and 128 
{ 
Evaluation of predominant symptoms of 
Behcet's disease 
Evaluation of accessory symptoms of 
Behcet's disease 
{ 
Week 24, 52, 104 and 156 
{ 
Improvement in endoscopic findings 
{ 
1㸧 Endoscopic findings implemented to Week 24 
2㸧 Endoscopic findings implemented from Week 
24 to 52  
3㸧 Endoscopic findings implemented from Week 
52 to 76 
4㸧 Endoscopic findings implemented from Week 
76 to 104 
5㸧  Endoscopic findings implemented from Week 
104 to 128 
6㸧 Endoscopic findings implemented from Week 
128 to 156 
CRP value 
{ 
Week 24, 52, 76,104 and 128 
{ 
Global improvement rate 
 
 
{ 
Therapeutic drugs after discontinuation of 
administration of this drug 
 
 
{ 
(After 
discontinuation) 
Adverse Event 
 
 
 
 
 

 
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9.3 
Variables 
The following data are to be obtained using the Registration Sheet and CRF㸬 
 
(1) 
Information to provide in the Registration Sheet 
Institution name 
Date of preparation of the Registration Sheet 
Treatment department 
Name of the attending investigator 
Patient identification number  
Patient consent 
Birth date or age 
Sex and pregnancy/breast feeding (for female patients) 
Ethnicity 
Reasons for use (intestinal Behcet's disease, complete, abortive, suspected) 
Date (or) anticipated date of commencement of the product 
Contraindications 
Careful administration 
Tuberculosis test and infection test (tuberculosis reaction test, QuantiFERON test, T-spot, chest X-ray, CT) 
HBV test (HBs antigen, HBs antibody, HBc antibody, HBV-DNA quantitative assay) 
Pre-treatment laboratory tests (D-glucan in blood, peripheral leukocyte count, peripheral lymphocyte count) 
 

 
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(2) 
Information to provide in CRF 
Survey items 
1) Patient Information 
(Items other than those covered 
in the Registration Sheet) 
[1] History of smoking (presence or absence, years) 
[2] Treatment category 
[3] Body height 
[4] Body weight 
[5] Disease duration 
[6] Concomitant symptoms (presence or absence, disease name) 
[7]Past history (presence or absence, disease name) 
[8] Allergic history (presence or absence, cause) 
2) Previous medication/therapy 
for intestinal Behcet's disease 
[1] Previous medication/therapy 
[2] Previous medication (other than biological products) 
[3] Previous medication (biological products) 
[4] History of administration (period of administration, dosage) 
[5] Reason for discontinuation 
[6] Previous therapy 
3) Status of Administration of 
This Drug 
Initial administration 
[1] Classification of administration method 
[2] Starting dose 
[3] Date of initial administration 
Second administration 
[1] Classification of administration method 
[2] 2nd dose 
[3] Date of 2nd dose 
3rd and subsequent administration: 
[1] Classification of administration method 
[2] One-time dose 
[3] Number of administration 
[4] Treatment period (Date of commencement, date of completion) 
[5] Reason for change 
Other 
[1] Obtainment of consent on shift to self-administration 
[2] Preparation of record on shift to self-administration 
[3] Presence or absence of error associated with self-injection, 
description/reason 
4) Discontinuation of the Survey 
Reason for discontinuation (onset of adverse event, inadequate efficacy, 
patient request, no show, other) 
 
Provide the information when the administration of the product is 
discontinued or the patient is not followable during the survey (not earlier 
than 156 weeks after the commencement of administration).  
5) Status of Administration of 
Antituberculous Drugs 
Presence or absence of use of the antitubercular agent, name of the drug, 
dose, period of administration 
6) Status of Administration of 
Concomitant Drugs 
[Concomitant drugs for intestinal Behcet's disease and other concomitant 
drugs] 
[1] Name of drug 
[2] Reason for use 
[3] Route of administration 
[4] Dose 
[5] Duration of administration 
7) Presence or absence of 
treatment other than drug 
therapy for intestinal Behcet's 
[1] Presence or absence of treatment other than drug therapy for intestinal 
Behcet's disease/concomitant therapy for intestinal Behcet's disease 
[2] Name of treatment/therapy other than drugs 

 
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disease/concomitant therapy for 
intestinal Behcet's disease 
[3] Treatment period 
8) Presence/Absence of 
Occurrence of Tuberculosis and 
Serious Respiratory Diseases 
[1] Date of test/exam 
[2] Diagnostic imaging 
[3] Abnormal finding 
[4] Name of abnormal finding 
9) Total evaluation of digestive 
symptoms 
(determined by the attending 
physician) 
At commencement of administration, 4, 8, 12, 24, 52, 76, 104, 128 and 156 
weeks after commencement of administration, discontinuation of 
administration 
10) Evaluation of digestive 
symptoms of Behcet's disease 
At commencement of administration, 4, 8, 12, 24, 52, 76, 104, 128 and 156 
weeks after commencement of administration, discontinuation of 
administration 
11) Evaluation of predominant 
symptoms of Behcet's disease 
At commencement of administration, 24, 52, 104 and 156 weeks after 
commencement of administration, discontinuation of administration 
12) Evaluation of accessory 
symptoms of Behcet's disease 
At commencement of administration, 24, 52, 104 and 156 weeks after 
commencement of administration, discontinuation of administration 
13) Improvement in endoscopic 
findings 
[1] Endscopic findings to Week 0 (before administration of Humira) 
[2] Endoscopic findings implemented to Week 24 
[3] Endoscopic findings implemented from Week 24 to 52  
[4] Endoscopic findings implemented from Week 52 to 76 
[5] Endoscopic findings implemented from Week 76 to 104 
[6] Endoscopic findings implemented from Week 104 to 128 
[7] Endoscopic findings implemented from Week 128 to 156 
14) CRP value 
At commencement of administration, 24, 52, 76, 104, 128 and 156 weeks 
after commencement of administration, discontinuation of administration 
15) Therapeutic drugs after 
discontinuation of 
administration 
Therapeutic drugs used after discontinuation of administration of this drug 
16) Global improvement rate 
(determined by the attending 
physician) 
[1] Date of assessment of efficacy (at commencement of administration, 
52, 104, 156weeks after commencement, discontinuation) 
[2] Overall improvement (markedly effective, effective, not effective, 
unassessable) 
*1) 
For endoscopic findings, determine overall improvement by diameter of the maximum ulcer at 
implementation of the test. 
 

 
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9.4 
Data sources 
 
Not applicable 
 
 
9.5 
Study Size 
Number of sample size : No decided 
 
㸺Rationale for setting㸼 
It is impossible to determine the number of survey centers and the number of survey 
centers is not decided because the survey is to be performed in all treated subjects and the 
drug is used only in the institutions qualified for the facility-related and doctor-related 
requirements. 
 
9.6 
Data Management 
CRO will prepare the database of information obtained using the Registration Sheet and 
CRF and perform the tabulation and statistical analysis in the survey. SAS is used for the 
tabulation and statistical analysis 
In the survey, data will be collected using the paper form of CRF, and EDC will not be 
used. MRs will collect the CRFs. Data clarification for missing data will be performed 
through the requested doctors by mediation of MRs and MRs will recover the CRFs for 
data clarification.   
 
 
 
 
 
 

 
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9.7 
Data Analysis 
All statistical analysis procedures will be described in detail in the Statistical Analysis 
Plan (SAP). This plan will be developed by the responsible protocol author in 
collaboration with CRO. The SAP shall be finalized and approved by the responsible 
protocol author and study-designed physician before the database is used for the final 
analysis. 
 
1) Sample size calculation 
Number of patients to be included: All patients 
Patients receiving the drug for the treatment of Behcet’s disease after the approval of the 
indication are to be all enrolled.  
 
㸺Rationale for setting㸼 
 The survey is to be performed in all treated patients since Japan is the first country, in 
the world, where the drug is to be used for the treatment of intestinal Behcet’s disease 
and data from only 20 patients were obtained in the clinical study performed as an open 
study. Since each subject is to be followed for at least 52 weeks for the purpose of the 
post-re-examination report, enrollments are to be performed for 3 years after the date of 
approval of the additional indication. In the subsequent years after 3 years, subjects 
continuously using the drug will remain enrolled. 
 
2) Analysis population 
Data from all the document patients will be used in the statistical analysis. 
 
3) Missing observations will be documented as missing values. Instructions for the 
minimum documentation required for a patient to be evaluable will be established in the 
SAP. 
All data will be analyzed on the basis of “observed cases”. For the statistical analysis of 
data concerning the course of disease (if related to changes from baseline values), an 
additional approach will be followed considering only patients with complete data at all 
visits. 
 
4) Level of Significance 
Inferential statistics will be performed at a nominal significance level of 0.05 (two-sided) 
 
 
9.8 
Quality Control 
Doctors will be requested to complete the Registration Sheet promptly after 
administration of the Product to the patient and complete the CRF promptly after 

 
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completion of the observation period. MRs will recover all the Registration Sheet and 
CRF. 
The inspection of the Registration Sheet and CRF will be performed for missing or 
erroneous entries and theoretical contradictions using DM Checklist. 
The sponsor will inspect the Registration Sheet and CRF after data recovery for missing 
or erroneous entries and CRO will also inspect the Registration Sheet and CRF  for 
missing or erroneous entries during data entry. Data clarification for missing data will be 
performed for doctors by mediation of MRs and doctors will be requested to provide 
missing essential information.  
In-house monitoring of incoming CRF pages with respect to completeness and 
plausibility will be done by the CRO responsible for data management and statistics. 
Queries to the study centers will be handled by the sponsor. 
This NIS will be sponsored by AbbVie GK. (Mita 3-5-27, Minato-ku, Tokyo, Japan) 
 
 
9.9 
Limitation of the research Methods 
The survey is to be performed as a non-interventional survey for assessing the safety and 
efficacy of the Product in patients with intestinal Behcet’s disease in actual clinical use. 
Unlike clinical studies, obtainable data are limited and there is a possibility of missing 
data.㸪 
 
 
9.10 
Other aspects 
Study Medication 
 
This is a non-interventional observational study with adalimumab. Adalimumabis used 
according to the approved label for intestinal Behcet’s disease and is prescribed by the 
attending physician. AbbVie does not provide any study medication. HUMIRA®-
injection is available as ready-to-use syringes (injector, pre-filled) and includes 40 mg 
adalimumab. The recommended dose of adalimumabfor adult patients with intestinal 
Behcet’s disease is 160mg of first dose, 80mg at Week 2 after first dose and 40 mg every 
other week after 80mg.. 
 

 
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10.0 
Protection of Human Subjects 
In accordance with the code of conduct of the Ministry of Health, Labour and Welfare 
(MHLW)/PMDA, AbbVie will forward the study protocol to the PMDA for approval. 
The study results will be reported to the PMDA. 
 
Doctors will obtain consent from patients for use of the Product for the treatment of 
intestinal Behcet’s disease before use of the Product. Doctors will explain appropriately 
that patients will incur no disbenefit even if they choose other therapies. 㸬 
 
All patients data entered in the patient’s CRFs will be forwarded to AbbVie for 
evaluation, without naming the patients. Each CRF shall bear a pre-print patients 
identification number in place of the patient’s initials. Accordingly, the patients’s identify 
will not be disclosed to AbbVie. 
 
 
11.0 
Management Reporting of Adverse Events/Adverse 
Reactions/Complaints 
 
11.1 
Adverse Event Definition and Serious Adverse Event 
Categories 
An adverse event (AE) is defined as any untoward medical occurrence in a patient which 
does not necessarily have a causal relationship with their 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 product, 
whether or not the event is considered causally related to the use of the product. Such an 
event can result from use of the drug as stipulated in the 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. If an adverse event meets 
any of the following criteria, it is considered a serious adverse even (SAE): 
 
 
Hospitalization or prolongation of hospitalization: An event that results in the 
admission to the hospital for any length of time. This does not include an emergency 
room visit or admission to an outpatient facility. Or An event that occurs while the study 
subject is hospitalized and prolongs the subject’s hospital stay. 
Disability: An event that results in a condition that substantially interferes with the 

 
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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). 
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  
Death: An event that results in the death of a subject. 
Congenital anomaly in the fetus/offspring: An anomaly detected at or after birth that 
results in fetal loss. 
Other medically important conditions: 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). 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 of drug abuse. 
 
 
11.2 
Severity 
In Japan, 3 kinds of definitions, “Mild”, “Moderate”, and “Severe”, aren’t used to rate the 
severity for any adverse event being collected as an endpoint/data point in the study and 
for all SAEs. 
 
 
11.3 
Relationship to Pharmaceutical Product 
The physician will use the following definitions for any adverse event being collected as 
an endpoint/data point the study and for all serious adverse events, to assess the 
relationship of the adverse event to the use of the pharmaceutical product: 
Probable: An adverse event has a strong temporal relationship to the study drug or recurs 
on re-challenge, and another etiology is unlikely or significantly less likely. 
Possible: An adverse event has a strong temporal relationship to the study drug, and an 
alternative etiology is equally or less likely compared to the potential relationship to 
study drug. 
Not related: An adverse event is due to an underlying or concurrent illness or effect of 

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another drug is not related to the study drug (e.g., has no temporal relationship to study 
drug or has a much more likely alternative etiology). 
Impossible to judge: 
If an investigator’s opinion of “not related” to pharmaceutical product is given, an 
alternate etiology must be provided by the investigator. 
11.4 
Serious Adverse Event Collection Period 
Serious adverse events will be reported to AbbVie from the time the physician obtains the
patient’s authorization to use and disclose information (or the patient’s informed consent) 
until the end of the NIS (week 52, 104, and 156 or discontinuation of adalimumab 
therapy). 
11.5 
Serious Adverse Event Reporting 
In the event of a serious adverse event, and additionally, any non-serious events of 
malignancy in patients 30 years of age and younger, whether related to adalimumab or 
not, if applicable - the physician will notify the AbbVie contact person (MR:Medical 
Representative in Japan) within 24 hours of the physician becoming aware of the event. 
Serious adverse events will be reported to AbbVie from the time the physician obtains the 
patient’s authorization to use and disclose information (or the patient’s informed consent) 
until 70 days following the intake of the last dose of adalimumab taken during the study. 
AbbVie MR will send the AbbVie Pharmacovigilance department identified below. 
AbbVie GK
3-5-27, Mita, Minato-ku, Tokyo 108-6302, Japan
Pharmacovigilance Department 
11.6 
Pregnancy Reporting 
Pregnancies in patients and their partners will be collected from the date of the first dose 
through 150 days following the last dose of adalimumab taken during the study. In the 
event of a pregnancy occurrence in the patient, the physician will notify AbbVie contact 
person (MR in Japan) within 24 hours of the physician becoming aware of the pregnancy. 

 
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11.7 
Management and Reporting of Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution. 
The investigational product in this trial contains both:  
x Biologic compound(s) and 
x Device component(s) (pre-filled syringe, pen). 
 
11.7.1 
Definition  
A Product Complaint is any Complaint related to the biologic or drug component of the 
product or to the medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues. 
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors. 
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured. 
 
11.7.2 
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 
local Product Complaint reporting practices.  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 involving a non-Sponsor investigational product and/or device should 

 
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be reported to the identified contact or manufacturer, as necessary per local regulations. 
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort 
should be made by the investigator to return the product within 30 days.  If returns cannot 
be 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. 
 

 
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12.0 
Final Report and Publications 
The report of the survey will be submitted to PMDA within 3 months after completion of 
the re-examination period (4 years)㸬 
After the end of the NIS, an Integrated Final Report is generated in cooperation with the 
Principal Investigator. The report includes a description of the objectives of the NIS, the 
employed methods, the results, as well as the conclusions. As the property of AbbVie GK, 
the completed CRFs and the report are to be treated as confidential and may not be made 
accessible to unauthorized persons in any form (publication or presentation) without the 
explicit approval of AbbVie GK.  The results of this NIS may be published by AbbVie 
GK or any of the participating investigators after approval by AbbVie GK. 
 

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AbbVie GK 
PMOS PROTOCOL (P14-152) 
Humira® 40mg Syringe 0.8mL for Subcutaneous Injection 
Special Investigation in patients 
with Intestinal Behcet’s disease 
Approved by: 
Protocol Author/
Date
Study-Designated Physician/
Date
Statistics Representative/
Date
Project Director/
Date
GMA Therapeutic Area Lead  /
Date