Humira® for Subcutaneous Injection Special Investigation ( All-case Survey ) in Patients With Juvenile Idiopathic Arthritis Study
Conditions: Arthritis, Juvenile Rheumatoid
Sponsor: AbbVie

Protocol # P12-769 
 
Version Date: 6APR2018 
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Humira® for Subcutaneous Injection 
Special Investigation (All-case survey) 
in Patients with Juvenile idiopathic arthritis 
Study Protocol  
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AbbVie GK 
NCT01412021

Protocol # P12-769 
 
Version Date: 6APR2018 
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1. 
Purpose of the surveillance 
This postmarketing surveillance of Humira® for Subcutaneous Injection (generic name: adalimumab 
(recombinant)) will be conducted to clarify the following with regard to the treatment of juvenile idiopathic 
arthritis (JIA) affecting multiple joints with this drug:    
c Unknown adverse drug reactions (ADRs) (especially important ADRs) 
d Incidence and conditions of occurrence of adverse reactions in the clinical setting 
e Factors that may affect the safety and efficacy of Humira 
 
< Items of investigation of particular interest> 
Development of infections, tuberculosis, malignant tumor, administration site reactions, autoimmune 
diseases, pancytopenia, demyelinating disease, congestive heart failure, and interstitial pneumonia 
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2. 
Target number of patients 
Target sample size: 100 patients 
Immediately after the approval of JIA as an indication for treatment with Humira, all patients who receive 
Humira for the treatment of JIA affecting multiple joints will be registered, and the data for the first 100 
patients will be tabulated and analyzed, and the results reported to the regulatory authority.  Registration of 
patients will be continued until the authority concludes its final evaluation. 
 
<Rationale> 
Considering the number of patients for whom registration is considered feasible, we will analyze data for 100 
patients to detect ADRs with an incidence of 3% at a probability of 95%.  
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3. 
Patients to be investigated 
All patients with JIA affecting multiple joints who have not responded well to conventional therapy and 
receive Humira will be enrolled in the survey. 
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4. 
Number of participating institutions by department 
Not yet determined 
 
<Rationale> 
Since this is an all-case survey to be conducted only in institutions that satisfy the criteria for institutions and 
physicians, it is impossible to accurately determine the number of applicable institutions. The number of 
participating institutions is thus not yet determined. 
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5. 
Participating institutions 
The surveillance will be conducted in all medical institutions/departments in which Humira is used for the 
treatment of JIA. Treatment with Humira for patients with JIA will be limited to those institutions that satisfy 
the following criteria for institutions and physicians and have concluded agreements with AbbVie GK Japan 
for implementation of the all-case survey. 
(1) 
Institutions participating in the survey  
Institutions that meet the following criteria will participate in the survey: 
1) 
Institutions that can cooperate with and conclude a contract for the all-case survey 
2) 
Institutions that can provide treatment of JIA by specialists.  

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(Such as hospitals certified by the Pediatric Rheumatology Association of Japan (PRAJ) as 
institutions providing specialist education in JIA, hospitals in which PRAJ-certified JIA 
specialists are working, hospitals in which biological therapy has been performed etc).   
3) 
Institutions that can diagnose and treat tuberculosis in cooperation with in-house pneumologists 
or radiologists or in cooperation with other institutions.  
4) 
Institutions that can diagnose and treat severe infections in cooperation with in-house infectious 
disease specialists or in cooperation with other institutions. 
 
(2) 
Investigators participating in the survey 
Investigators with at least one of the following qualifications will participate in the survey after they 
receive a complete set of informational materials on safety measures from medical representatives to 
ensure full understanding of the characteristics of Humira and its use in the treatment of JIA.  
 
Physicians who have treated patients with JIA and satisfy any of the following criteria will be allowed 
to participate.  
M Physicians who are board-certified specialists of the Japan Pediatric Society and board-specified 
specialists of the JCR 
N Physicians who are members of the PRAJ and board-specified specialists of the JCA   
O Physicians who have participated in all-case survey(s) of biologic agents including Humira in 
patients with RA and JIA.  
P Physicians who have participated in clinical studies of Humira in patients with JIA. 
Q Physicians who have been educated by physicians with expertise in the treatment of JIA by 
Humira. 
R Physicians who can prescribe Humira or treat patients with JIA under the instruction of physicians 
who satisfy any of the above criteria M~P.  
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6. 
Methods of surveillance 
(1) 
Methods of registration and agreement 
This surveillance involves all-patient enrollment using a central registration method. All patients 
receiving Humira for the treatment JIA affecting multiple joints in institutions which meet the criteria 
for physicians and institutions and have concluded agreements with AbbVie GK Japan for enrollment 
in the all-case survey will be investigated. 
(2) 
Procedures for requesting cooperation and obtaining agreement 
1) 
Medical representatives will provide investigators and other healthcare professionals with a 
complete set of informational materials on safety measures, and will inform them about the 
characteristics of Humira, treatment of JIA, the purpose of the surveillance, patients to be 
investigated, and methods of investigation. 
2) Investigators and other healthcare professionals receiving the materials will confirm that 
they have received an explanation of Humira and the surveillance using the complete set 
of materials, that they will cooperate with the surveillance, and that they and their 
institutions meet the criteria for institutions and physicians in the survey, and then sign a 
"Confirmation of Distribution of Proper Use Information" form.  Medical representatives 
will obtain the signed Form and confirm its contents, and then formally request that the 
institutions participate in the surveillance and conclude written agreements between these 

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institutions and AbbVie GK Japan regarding surveillance. 
(3) 
Methods of investigation 
1) 
A paper-based case report form (CRF) will be used to collect survey data. 
2) 
All patients who use Humira during the period between approval of JIA as an indication for 
Humira and the conclusion of evaluation of the results of the all-case survey by the regulatory 
authority will be registered. 
3) 
Each patient will be observed for 24 weeks. 
4) 
Investigators will fully explain the proper use information on Humira and obtain informed 
consent for the treatment with Humira from each patient and his/her legal guardian (if the patient 
is less than 20 years of age). 
5) 
When treatment with Humira is selected for a patient who has provided informed consent, the 
investigator will fill out a registration form and submit it to the registration center to register the 
patient. 
6) 
Investigators will fill out the case report form for each patient following the 24-week observation 
period without delay, and provide it to a medical representative. When a patient discontinues 
treatment during the observation period, the investigator will follow up the patient until the end of 
the 24-week observation period, fill out the case report form for him/her at the end of the 
observation period, and provide it to a medical representative. 
7) 
The sponsor will confirm the contents of the registration and case report forms, and perform 
reinvestigation whenever necessary. 
8) 
Medical representatives will also visit investigators once every week or every other week, in 
principle, to monitor for the occurrence of adverse events, provide proper use information, and 
determine the progress of patient registration. 
9) 
Following the 24-week observation period, the investigator will evaluate each patient for 
malignancy annually for 2 years after the initiation of Humira treatment using a separate 
follow-up investigation form. When the occurrence of malignancy is found in a patient, the 
investigator will perform detailed investigation of him/her.  Investigators will be instructed to 
report the occurrence of malignancy to the sponsor without delay when they are found, regardless 
of the timing of follow-up investigation.  
10) 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 (Medical Representative in Japan) within 24 
hours of the physician becoming aware of the event. 
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7. 
Duration of surveillance 
Duration of surveillance:  1st JUL2011~26thFEB2018 
Duration of registration:  1st JUL2011~26thFEB2016 
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<Milestones> 
Major study milestones and their planned dates are as follows: 
Start of Data Collection: 
 
1 JUL 2011  
Registration in the EU PAS register: 
Not Applicable 
End of Study: 
 
 
The date on which statistical analysis dataset for 

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Clinical Study Report becomes available 
Final Report of Study Result: 
 
2 Oct 2018 
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8. 
Items to be investigated 
(1) 
Duration of observation 
Each patient will be observed for 24 weeks.  
(2) 
Registration form 
Date of completion of the registration form, name of institution, department, name of investigator, 
obtaining of informed consent of the patient or his/her legal guardian, history of Humira treatment, sex, 
age, patient ID, reasons for use of Humira and type of JIA, day (or planned day) of initiation of Humira 
treatment, contraindications to use of Humira, conditions requiring special care in administration, 
presence/absence and efficacy of previous treatment of JIA, presence/absence of tuberculosis or other 
infection (tuberculin skin test, Quantiferon test, chest X-ray, and chest CT), preventive 
anti-tuberculosis treatment, hepatitis B virus test, and baseline laboratory data (blood E-D glucan level, 
peripheral blood WBC, peripheral blood lymphocyte count, serum creatinine). 
(3) 
Case Report Form 
1) Patient background 
 
History of Humira treatment, in/out-patient status, duration of illness, Steinbrocker classification, 
Steinbrocker functional classification, complications, past illness, history of allergy, history of 
vaccines 
2)  Treatment with Humira 
 
In/outpatient treatment, dosage, interval of administration, duration of administration, reasons for 
change in dose or interval of administration 
Patients performing self-injection: presence/absence of written consent for transition to 
self-injection, and presence/absence of self-injection transition record. 
Errors in administration during self-injection: presence/absence, date of onset, description, and 
reasons for. 
3)  History of biological treatment of JIA 
Presence/absence of history of biological therapy, name of drug, dose, duration (start date and end 
date), and reason for discontinuation. 
4)  Previous treatment of JIA affecting multiple lesions (treatment during the 3-month period 
preceding Humira treatment) 
Presence/absence of previous treatment of JIA, names of drugs [methotrexate and other DMARDs, 
NSAIDs, corticosteroids]. 
* For patients who have received methotrexate and/or corticosteroids, the routes, doses and 
durations, as well as the use of NSAIDs and other DMARDs will be investigated. 
5)  Status of administration of concomitant drugs 
ձ Use of drugs for JIA  
Presence/absence of concomitant drug use for JIA, names of drugs, routes, doses, and 
durations 
ղ Use of other drugs 
Presence/absence of concomitant drug use for conditions other than JIA, names of drugs, 
routes, doses, and durations 
If an adverse event occurs: Names of drugs, reasons for use, routes, doses, and durations 

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6) Non-drug concomitant therapy 
Non-drug concomitant therapy for JIA 
7) Presence/absence of tuberculosis or serious respiratory diseases 
 
Date of confirmation, method of diagnostic imaging, and presence/absence and type of abnormal 
findings 
8) Clinical evaluation 
Patients will be evaluated for the following at the time points described below:  
ձ DAS28 (number of tender joints and number of swollen joints), global assessment by patient 
(VAS), global health by physician (VAS), erythrocyte sedimentation rate (ESR, 1 hr value), 
and CRP. (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment) 
ղ Serum MMP-3 level. (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment) 
ճ Anti-CCP antibody (Baseline and 24 weeks of treatment) 
մ Height and body weight. (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment) 
9) Discontinuation of Humira treatment 
Reasons for discontinuation of Humira treatment 
Treatment after discontinuation of Humira treatment 
10) Adverse events (including abnormal laboratory findings) 
Presence/absence of adverse events, nature of adverse events, dates of onset, seriousness, causal 
relationship with Humira treatment, suspected drugs, clinical course of adverse events, measures 
taken (measures related to Humira treatment and symptomatic treatment), outcomes, and 
laboratory findings (indicate laboratory values when abnormal laboratory findings are observed). 
11) Items of investigation of particular interest 
Occurrence of infections, tuberculosis, malignant tumor, administration site reactions, 
autoimmune diseases, pancytopenia, demyelinating disease, congestive heart failure, and 
interstitial pneumonia. 
(4) Preparation of written consent form for transition to self-injection and self-injection transition record 
It will be confirmed whether written consent for transition to self-injection has been obtained and a 
self-injection transition record has been prepared. 
(5) Presence/absence of malignant tumor during the long-term follow-up period.  
Patients will be evaluated for the occurrence of malignancy during the first and second years of 
treatment. 
(6) Product Quality Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device after it is released for distribution. 
The investigational product in this trial contains both:  
-Biologic compound(s) and 
-Device component(s) (pre-filled syringe, pen). 
 
࣭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 

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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. 
 
࣭ 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 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. 
 
9. 
Items to be analyzed and methods of analysis 
(1)  Items to be analyzed 
1) Information on characteristics of evaluable patients 
ձ Number of registered patients 
ղ Number of patients for whom case report forms have been retrieved 
ճ Number of patients who are evaluable for safety 
մ Number of patients who are evaluable for efficacy 
2) Information on the safety of Humira 
ձ List of adverse drug reactions (ADRs)/infections 
ղ Factors which may affect the safety of Humira 
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Incidence of ADRs by patient background factor 
z 
Incidence of ADRs before and after increase in Humira dose 
ճ Adverse events occurring during or after the treatment period 
z 
List of occurrences of serious adverse events 
մ Errors in administration during self-injection 
3) Information on the efficacy of Humira 
ձ Clinical course 
z 
DAS28 (number of tender joints and number of swollen joints), global assessment by 

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patient (VAS), global health by physician (VAS), erythrocyte sedimentation rate (ESR, 1 
hr value), and CRP. (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment)
z
Serum MMP-3 level (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment)
z
Anti-CCP antibody (Baseline and 24 weeks of treatment)
z
Height and body weight (Baseline, and Weeks 4, 8, 16, and 24 weeks of treatment)
ղ Factors that may affect the efficacy of Humira
z
Summarized efficacy data by patient background factor
4) Matters related to special populations
List of occurrences of ADRs/infections in special populations such as pregnant/lactating women, 
patients with renal function disorder, and patients with hepatic function disorder
(2) Methods of analysis
Appropriate methods of analysis such as the chi-square test will be used according to the scale and 
nature of the data analyzed.
10. Measures to be taken when the use of Humira in pregnant women is observed
When the use of Humira in pregnant women is noted during the surveillance, follow-up investigation will be 
performed whenever necessary to examine its effects on labor and/or neonates.
11. Organizations conducting the surveillance
The organizations conducting the surveillance are described in the basic plan of the postmarketing 
surveillance. Parties who will be entrusted activities related to the surveillance are described in Section 12 
"Names and addresses of parties entrusted activities related to the surveillance and the ranges of their 
activities".
12. Names and addresses of parties entrusted activities related to the surveillance and the 
ranges of their activities
(1) Contractor #1
1) Address: 4-6-10, Koishi-gawa, Bunkyo-ku, Tokyo.
Name: Eisai Co., Ltd.
GPSP Controller: 
 
2) Duties
Implementation of the special surveillance (e.g., requests, contracts, retrieval and reinvestigation of 
registration forms, retrieval and reinvestigation of CRFs, report on progress of surveillance, and 
collection of information on adverse events including abnormal laboratory findings)
(2) Contractor #2
1) Address: 20th Floor (Reception), Sumitomo Fudosan Korakuen Bldg., 1-4-1, Koishikawa, 
Bunkyo-ku, Tokyo 
Name:,A2 Healthcare Corporation 
 
2) Duties
Implementation of the special surveillance (e.g., patient registration, report on progress of surveillance, 
data management, and data analysis)

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13. Other requirements 
(1) Amendment of the protocol 
The protocol for the surveillance will be amended as appropriate according to the results of evaluation 
of the need for such amendment, considering the findings obtained during the surveillance.  For 
example, when applications for partial modification of dosage & administration or indications are 
approved during the period of reexamination (this will not apply to cases in which the period of 
reexamination is newly designated), the sponsor will consider whether the protocol should be amended 
or not, and will revise the protocol whenever necessary. 
(2) Responses to problems/questions 
When a serious unknown ADR appears to have occurred, when the incidence of an ADR is significantly 
increased, when any problems related to the efficacy or safety of Humira are found, or when the 
occurrence of ADRs that differ significantly from those observed during premarketing clinical studies is 
reported, among other conditions, the sponsor will consider whether special surveillance or 
postmarketing clinical studies should be conducted to detect or confirm the causes of such conditions, or 
to verify conclusions reached on the basis of the results of the present surveillance. 
 
14. Amendments and Updates 

Protocol # P12-769 
 
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Number 
Date 
Section of Study 
Protocol 
Amendment or 
Update 
Reason 
1 
28 JAN 2011 
 
Create New 
 
2 
26 ARP 2011 
8. Items to be 
investigated 
9. Items to be 
analyzed and methods 
of analysis 
Amendment 
Advice of KOL 
3 
8 JUL 2011 
6. Methods of 
surveillance 
8. Items to be 
investigated 
Amendment 
insufficient 
description 
4 
4 ARP 2013 
Front cover 
Amendment 
Change  to 
Avvibe 
5 
23 Feb 2016 
6. Methods of 
surveillance 
8. Items to be 
investigated 
Amendment 
FDA requirement 
6 
05 APR 2016 
7. Duration of 
surveillance 
Amendment 
Released of 
all-case 
surveillance  
7  
20 DEC 2016 
Dosage form 
Amendment 
Delete dosage 
name 
8 
20 DEC 2016 
12. Names and 
addresses of parties 
entrusted activities 
related to the 
surveillance and the 
ranges of their 
activities 
Amendment 
Change due to 
merger of CRO  
9 
6 APR 2018 
7. Duration of 
surveillance 
12. Names and 
addresses of parties 
entrusted activities 
related to the 
surveillance and the 
ranges of their 
activities 
Amendment 
Add the end of 
study date due to 
this date became 
clear and change 
address of the 
CRO 
 
 
Attachments 
a.  Contract document (draft) 
b.  Guidance of implementation of the special surveillance (draft) 
c.  Registration form and case report form for the special surveillance (draft) 
d.  Written confirmation of successful transmission of proper use information (draft) 
e.  Explanatory materials for informed consent and informed consent form (draft) 

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e.  Written consent for transition to self-injection (draft) 
g.  Self-injection transition record (draft)