Assessment of Clinical Effectiveness and Safety of Adalimumab and High Dose Methotrexate in Routine Clinical Practice (Combo Study; Adalimumab With High Dose MTX)
Conditions: Rheumatoid Arthritis
Sponsor: AbbVie (prior sponsor, Abbott)

HUMIRA® 40mg for S.C. Injection (generic name: adalimumab)
P13-684
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Final Version 7.0 (prepared in 11 Dec.2017) 
1.0                  Title Page  
AbbVie GK 
PMOS PROTOCOL (P13-684)  
Assessment of clinical effectiveness and safety of adalimumab 
and high dose methotrexate in routine clinical practice 
(Combo study; Adalimumab with high dose MTX)
Product Name:
Humira® 40mg for S.C. Injection (generic name: adalimumab)
Type of Study:
Post-Marketing Observational Study (PMOS)
Date:
08-11-2013
CRO(s): 
EPS Corporation
Phone:
Fax:
Biometrics: 
N.N.
Phone
Fax
Sponsor:
AbbVie GK
3-5-27, Mita, Minato-ku, Tokyo 108-
6302, Japan
Phone: +81-3-4577-1125
Fax:
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. 
Version 7.0
NCT01736189

 HUMIRA® 40mg for S.C. Injection (generic name: adalimumab) 
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Final Version 7.0 (prepared in 11 Dec.2017) 
2.0                   Synopsis 
Sponsor; 
AbbVie GK 
3-5-27, Mita, Minato-ku, Tokyo 108-6302, Japan 
Title; 
Assessment of clinical effectiveness and safety of 
adalimumab and high dose methotrexate in routine clinical 
practice  (Combo study; Adalimumab with high dose MTX) 
Short title; 
HAWK study 
Type of study; 
Post-Marketing Observational Study (PMOS) 
Product, dose, and 
administration form; 
Humira® 40mg for S.C. Injection (generic name: adalimumab)  
40 mg subcutaneous (s.c.) every other week 
Project code; 
JPN 12-01 
Indication; 
Rheumatoid arthritis (RA) 
Study objectives; 
The primary objective of the study is to assess the clinical 
effectiveness of adalimumab in combination with high dose 
MTX (≥12 mg/week).  The clinical effectiveness is measured by 
assessing the percentage of patients with the DAS28 score of 
<2.6 at week 52. 
The secondary objective of the study is to assess the clinical 
effectiveness of adalimumab in combination with high dose 
MTX (≥12 mg/week) by the following variables: 
㺃 Clinical Disease Activity Index (CDAI) 
㺃 Simplified Disease Activity Index (SDAI) 
㺃 The severity of functional impairment (HAQ) 

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㺃 The health-related quality of life (EQ-5D) 
㺃 The severity of hand and foot mTSS used for assessment of 
radiographic joint damage.  
Target parameters for safety evaluation of adalimumab + MTX 
are: 
㺃 The evaluation of safety and tolerability by the documentation 
and analysis of serious adverse events (SAEs) and adverse 
events (AEs). 
Study population; 
Adult patients (t16 years) with early (≤2 years), MTX 
(t12mg/week) for at least 3 months before starting on 
adalimumab and DAS28-CRP >3.2, Bio Naive RA patients 
Study design; 
Single-arm, multi-center format, prospective cohort study 
Treatment duration; 
104 weeks 
Methodology; 
Disease Activity Score 28 (DAS28), Clinical Disease Activity 
Index (CDAI), Simplified Disease Activity Index (SDAI), 
Health Assessment Questionnaire (HAQ), EuroQol-5 
Dimensions (EQ-5D), Radiographic joint damage (mTSS)  
Total number of 
patients; 
350 Patients 
Adverse Events; 
As reported by patients and diagnosed at visits 
Data analysis plan; 
The general biometric approach consists of evaluation of 
changes by descriptive statistical methods, as well as of 
regression analysis of parameters influencing the clinical 
effectiveness and additional stratified group analysis.  
Correlation between baseline visit and treatment visits: 
㺃 DAS28, CDAI, SDAI, HAQ, EQ-5D 

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(week 0, 12, 24, 52, 76, 104) 
㺃 Radiographic joint damage (mTSS) 
(week 0, 52, 104) 
Additionally, the strength of the relationship between the 
predictors and the parameters of clinical effectiveness will be 
determined.  The impact of the variables determined by 
regression analysis on the therapeutic success will be illustrated 
by stratified group analysis.  Two interim analyses are planned. 
Planned recruitment 
phase; 
September 2012 - December 2014 
Planned study 
duration; 
September 2012 - March 2017 
Product 
manufacturer; 
AbbVie GK 
 

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3.0  
Abbreviated and Definition 
ADR 
Adverse Dug Reaction 
AE  
Adverse Event 
CDAI 
Clinical Disease Activity Index 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
DAS28 
Disease Activity Score 28 
DMARD 
Disease Modifying Anti-Rheumatic Drug 
EQ-5D 
EuroQol 5 Dimensions 
ESR 
Erythrocyte Sedimentation Rate 
FAS 
Full Analysis Set 
HAQ 
Health Assessment Questionnaire 
IL-6 
Interleukin-6 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labor and Welfare 
MR 
Medical Representative 
mTSS 
modified Total Sharp Score 
MTX 
Methotrexate 
PMDA  
Pharmaceuticals and Medical Devices Agency  
PMOS 
Post-Marketing Observational Study 
QOL 
Quality Of Life 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
S.C. 
Subcutaneus injection 
SDAI 
Simplified Disease Activity Index 
SJ 
Swollen Joint 
SPC 
Summary of Product Characteristics 
TJ 
Tender Joint 
 
TNF-α 
Tumor Necrosis Factor-α 
VAS 
Visual Analog Scale 

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4.0  
Table of Contents 
1.0 
Title Page ................................................................................. 1 
2.0 
Synopsis .................................................................................... 2 
3.0 
Abbreviated and Definition .................................................... 5 
4.0 
Table of Contents .................................................................... 6 
5.0 
Introduction ............................................................................. 8 
6.0 
Rationale .................................................................................. 9 
7.0 
Study Objective (s) .................................................................. 9 
7.1 
Investigational Plan .................................................................................10 
7.2 
Selection of Study Population .................................................................10 
7.2.1 
Inclusion Criteria .....................................................................................10 
7.2.2 
Exclusion Criteria ....................................................................................11 
7.3 
Number of Patients to be Enrolled ..........................................................11 
7.4 
Investigator Selection Criteria .................................................................11 
7.5 
Study Duration .........................................................................................11 
7.6 
Study Conduct .........................................................................................12 
7.6.1 
Schedule of Observations ........................................................................12 
7.6.2 
Description of Activities ..........................................................................13 
7.6.3 
Scales and Scores ....................................................................................16 
7.6.4 
Study Medication .....................................................................................21 
8.0 
Amendments and Updates ................................................... 22 
9.0 
Adverse Events ...................................................................... 22 
9.1.1 
Adverse Event Definition and Serious Adverse Event Categories .........22 
9.2 
Relationship to Pharmaceutical Product ..................................................23 
9.3 
Serious Adverse Event Collection Period ...............................................24 
9.4 
Serious Adverse Event Reporting ...........................................................24 
9.5 
Pregnancy Reporting ...............................................................................25 
10.0 
Product Complaint................................................................ 25 
10.1 
Definition .................................................................................................25 
10.2 
Reporting .................................................................................................26 
11.0 
Ethics and Quality................................................................. 26 

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12.0 
Case Report Forms ............................................................... 27 
13.0 
Data Analysis Plan ................................................................ 27 
13.1 
Sample Size Calculation ..........................................................................27 
13.2 
Analysis Population(s) .............................................................................28 
13.3 
Missing Values ........................................................................................28 
13.4 
Level of Significance ...............................................................................29 
13.5 
Times of Statistical Analyses ..................................................................29 
14.0 
Final Report and Publications ............................................. 29 
15.0 
References .............................................................................. 30 

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5.0  
Introduction  
Treatment of rheumatoid arthritis (RA) has advanced significantly after the 
introduction of biological agents and improved treatment recommendations.  Current 
treatment guidelines for the management of RA advocate the use of an TNF-inhibitor 
in combination with MTX as first line biological therapy.  Multiple studies have shown 
the synergistic effect of TNF-inhibitors and MTX.  In February 2011, dosage regimens 
of methotrexate (MTX) were approved up to until ≤16 mg/week in Japan (2011 
Japanese Guideline for MTX treatment with RA patient). Thus physicians may 
prescribe MTX in a maximum dose of ≤16 mg/week.  Moreover MTX was also 
approved as first-line therapy in adult patients with RA. 
MTX is a low-molecular-weight disease-modifying antirheumatic drug (DMARD) that 
has been demonstrated highly beneficial in inducing clinical remission, preventing the 
progression of bone destruction, improving quality of life (QOL), and ensuring 
durability and safety of treatment.1-6)  On the basis of its usefulness in combination 
with other low-molecular-weight DMARDs and biologics, MTX is positioned as an 
anchor drug in the treatment of RA, and is one of the most commonly used low-
molecular-weight DMARD in RA.7)  The benefits of MTX in combination with 
biological agents have been assessed in retrospective analyses of the data of post-
marketing surveillance of biologics conducted prior to the approval of high-dose MTX 
treatment at ≥10, ≤16 mg/week. Safety evaluation based on the incidence and patterns 
of adverse drug reactions (ADRs) by dose of MTX have revealed that the ADR profile 
does not differ significantly between lower and higher doses of MTX.  Moreover, the 
efficacy of treatment appears better in patients receiving MTX at higher doses, which 
indicates a tendency toward dose-effect relationship.  These results of retrospective 
analyses support the necessity of prospective studies to investigate the usefulness of 
treatment combining biological agents and high-dose MTX. 
In the present prospective post-marketing observational study (PMOS), we will 
investigate the effectiveness and safety of treatment with adalimumab (Humira®) and 
high-dose MTX (≥12 mg/week). 

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6.0                 Rationale 
In Japan, Humira was approved on April 16, 2008 and launched in the market on June 
18, 2008. As a condition of the approval, the Pharmaceuticals and Medical Devices 
Agency (PMDA) requested Abbott Japan to collect data on the safety and efficacy of 
adalimumab in all patients receiving the drug in order to take all necessary measures to 
ensure appropriate use of adalimumab.  According to this requirement, Abbott Japan 
conducted an all-case survey of adalimumab in 7,740 Japanese patients with rheumatoid 
arthritis (RA) receiving the drug during the period between June 2008 and October 2010.  
The results of a recent retrospective data analysis of the all-case survey of Japanese 
patients with RA suggested that the effectiveness of adalimumab in bio-naïve patients 
with RA was more efficacious when they receive adalimumab in combination with MTX 
at a dose of t10 mg/week.  We thus designed a prospective special investigation of ADA 
+ MTX t12 mg/week assessment for DAS28, mTSS and HAQ in bio-naïve and early 
patients with RA and following within the current labeling in Japan. 
 
7.0                  Study Objective (s)  
In daily clinical setting, patients with RA who receive adalimumab (Humira®) and high-
dose MTX (≥12 mg/week) will be observed prospectively and the effectiveness will be 
assessed by  DAS28 and mTTS, In addition the safety of the combination of adalimumab 
and high dose MTX will be assessed in terms of the incidence and pattern of the 
occurrence of adverse events. 
The primary objective of the study is to assess the clinical effectiveness of adalimumab in 
combination with high dose MTX (≥12 mg/week).  This will be measured by assessing 
the percentage of patients with the DAS28 score of <2.6 at week 52. 
The secondary objective of the study is to assess the clinical effectiveness of adalimumab 
in combination with high dose MTX (≥12 mg/week) by assessing the proportion of 
patients with a change in the following variables from baseline to week 104: 
㺃 Clinical Disease Activity Index (CDAI) 

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㺃 Simplified Disease Activity Index (SDAI) 
㺃 The severity of functional impairment (HAQ) 
㺃 The health-related quality of life (EQ-5D) 
㺃 The inhibition of structural progression will be assessed by measuring the modified 
Van der Heijde Total Sharp Score (mTSS).  
The safety profile will be assessed by measuring the following variables:  
㺃 All serious adverse events (SAEs) and adverse events (AEs)

7.1                     Investigational Plan 
7.2                     Selection of Study Population  
The study population will consist of adult patients (≥16 years) with early RA (disease 
duration of RA ≤2years) who have failed other anti-rheumatic drugs (with prior MTX).  
Patients who have been previously treated with biologics (including TNF inhibitors 
others) cannot be included in the PMOS.  The inclusion and exclusion criteria adhere to 
the approved label as stated in the Japan Summary of Product Characteristics (SPC) 
“Interview-form” for adalimumab.  Investigators will fully explain the PMOS and obtain 
informed consent from each patient who is to receive adalimumab for the treatment of 
RA.  Patients to be included will be informed about the PMOS and the use of their 
anonymous data.  
 
7.2.1 
Inclusion Criteria 
The subjects of this study are patients with a diagnosis of RA and to whom adalimumab 
is prescribed as part of their normal treatment of RA.  All subjects should be satisfying 
the following conditions. 
1) Disease duration of RA ≤2 years 
2) MTX administration ≥3 months prior to starting adalimumab 
3) Dose of MTX ≥12mg/week  

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4) DAS28-CRP >3.2  
 
7.2.2 
Exclusion Criteria 
1) Patients who have been previously treated with biologics (including TNF 
inhibitors others) 
 
7.3                      Number of Patients to be Enrolled  
The primary endpoint of this study is the proportion of subjects who achieve DAS28 
(CRP) remission (DAS28 <2.6) after 52 weeks of adalimumab + high dose MTX.  Based 
on data from another trial assessing the effectiveness of adalimumab in daily clinical 
practice, the following power calculation was done 9).  With a significance level of 0.05 
(two-sided) and a power of 0.90 (1-β), 350 subjects are required to detect an expected 
remission rate, i.e., the percentage of patients with the DAS28 score of <2.6 at week 52. 
 
7.4                      Investigator Selection Criteria  
The data for this PMOS will be collected from rheumatology outpatient departments and 
office based rheumatologists that routinely treat patients with RA in Japan. 
Physicians from about 100 sites which are spread across all of Japan will participate in 
this PMOS. 
Principal Investigator: 
Name; Prof. Dr. Yoshiya TANAKA 
Institution; University of Occupational and Environmental Health  
Address; 1-1 Iseigaoka, Yawata Nishi-ku, Kita Kyushu, Fukuoka, Japan  
7.5                      Study Duration 
1) The duration of the whole PMOS is estimated to be about 4 years. 
㺃 Study start: September 2012 

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㺃 Recruiting phase: September 2012 - December 2014 
㺃 Data completion: January 2018 
㺃 End of study: The date on which statistical analysis dataset for Clinical Study Report 
becomes available 
㺃 Data analysis and final report: April 2018 – October 2018 
2) For each individual patient, the PMOS starts with the enrollment at the beginning of 
the treatment with adalimumab.  
㺃 Observation period 
- 104 weeks (or discontinuation of this study) 
㺃 Discontinuation of this study 
- Patients within 52 weeks into this study: When adalimumab treatment is 
discontinued. 
- Patients after 52 weeks into this study: When any biologics other than 
adalimumab is administered. 
7.6                     Study Conduct  
7.6.1 
Schedule of Observations 
This PMOS will be a single-arm, multi-center, prospective cohort study.  
Non-interventional studies are one of several methodical instruments to collect 
information on drugs available on the market.  Their defining characteristic is the lack of 
influence on the relationship between individual physicians and patients in respect to 
determining indication as well as choice and conduct of the treatment, while at the same 
time allowing for the structured and systematic collection of treatment data (see also 
Section 6 “Rationale”).  Adalimumab must not be prescribed for the purpose of including 
a patient in this PMOS.  
Patients will be informed about the type of therapy, alternate therapies, and risks, and 
they have to provide informed consent before the start of adalimumab therapy.  Before 
enrollment in the PMOS, the patients will be made anonymous.  AbbVie GK will only 
receive access to anonymous data.  AbbVie GK can only identify the patients via their 
patient number. 

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The documentation consists of patient self-assessments as well as assessments by the 
physician.  The following table provides an overview of the study visits with 
corresponding study activities (Table 1 “Study Schedule”). 
Table 1. Study Schedule 
Activity 
Visit (Week) 
0 
12 
24 
52 
76 
104* 
Patient Background 
9 
 
 
 
 
 
Inclusion / Exclusion criteria 
9 
 
 
 
 
 
Previous RA therapies 
9 
 
 
 
 
 
Concomitant diseases and therapies  
9 
9 
9 
9 
9 
9 
Current adalimumab therapy  
9 
9 
9 
9 
9 
9 
Current RA therapies  
9 
9 
9 
9 
9 
9 
Effectiveness 
 
 
 
 
 
 
㺃 DAS28 
9 
9 
9 
9 
9 
9 
㺃 CDAI  
9 
9 
9 
9 
9 
9 
㺃 SDAI  
9 
9 
9 
9 
9 
9 
㺃 HAQ  
9 
9 
9 
9 
9 
9 
㺃 EQ-5D  
9 
9 
9 
9 
9 
9 
㺃 mTSS (X-rays of Hands and Feet) 
9 
 
 
9 
 
9 
Adverse Events 
 
9 
9 
9 
9 
9 
* Week 104 or last visit 
 
7.6.2 
Description of Activities 
The following data will be documented (if assessed in routine care): 
Physician: 
Baseline Visit (Week 0) 

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1) Informed consent 
2) Patient Background 
㺃 Patient ID code  
㺃 Demographic Data; Birth date or age, Sex (pregnant/lactation), Race, Weight 
㺃 Patient status (out-patient, in-patient) 
㺃 Duration of illness 
㺃 Indication for the current adalimumab therapy 
㺃 Complications 
㺃 Past illness 
㺃 History; Smoking history, History of allergy 
㺃 Progression of RA; Severity of RA (Stage), Functional class of RA (Class) 
3) Previous treatment of RA; Biologics, DMARDs, Corticosteroids 
4) Inclusion / Exclusion criteria 
㺃 Inclusion criteria; Age ≥16 years old, Duration of RA ≤2 years, MTX dose 
≥12mg/week, MTX administration ≥3 months, DAS28-CRP >3.2 
㺃 Exclusion criteria; Patients who have been previously treated with biologics 
5) Current treatment with adalimumab 
6) Current concomitant drug treatment 
㺃 MTX (From 6 months before adalimumab treatment to current) 
㺃 DMARDs except MTX 

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㺃 Corticosteroids 
㺃 Other concomitant drugs 
7) Current non-drug treatment for RA 
8) Current status 
㺃 Disease activity (Visual Analog Scale by the physician / VAS evaluation) 
㺃 Joint status (28 joints; tender, swollen) 
㺃 Laboratory values (CRP, ESR) 
㺃 X-rays of Hands and Feet 
 
Follow-up Visits (Week 12, 24, 52, 76, 104, last visit) 
1) Current treatment with adalimumab 
2) Current concomitant drug treatment 
㺃 MTX 
㺃 DMARDs except MTX 
㺃 Corticosteroids 
㺃 Other concomitant drugs 
3) Current non-drug treatment for RA 
4) Current status 
㺃 Disease activity (Visual Analog Scale by the physician / VAS evaluation) 
㺃 Joint status (28 joints; tender, swollen) 

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㺃 Laboratory values (CRP, ESR) 
㺃 X-rays of Hands and Feet (Week 52, 104) 
㺃 (S) AE 
㺃 Discontinuation of adalimumab treatment (Reason for discontinuation) 
 
Patient: 
Baseline Visit (week 0) 
1) Informed consent 
2) Disease activity (Visual Analog Scale by the patient / VAS evaluation) 
3) HAQ 
4) EQ-5D 
 
 
Follow-up Visits (Week 12, 24, 52, 76, 104, last visit) 
1) Disease activity (Visual Analog Scale by the patient / VAS evaluation) 
2) HAQ 
3) EQ-5D 
 
7.6.3 
Scales and Scores 
The following scores will be derived from the documented data: 
1) Disease Activity Score (DAS28): 
The DAS28 indicates the severity of the RA. The score varies between 0 and 10, with 10 
indicating the highest degree of severity.  The DAS28 is calculated from the following 

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data documented on the physician form: 
A) Joint status: Number of tender joints (each with a maximum of 28) 
B) Joint status: Number of swollen joints (each with a maximum of 28) 
C) ESR (mm/1. h) or CRP (mg/dL) 
D) Patient’s assessment of current disease activity (from 0 = inactive to 100 = highly 
active) 
The DAS28 is calculated by means of a validated algorithm. 
 
2) Clinical disease activity index (CDAI): 
The CDAI indicates the severity of the RA.  The CDAI is calculated from the following 
data documented on the physician form: 
A) Joint status: Number of tender joints (each with a maximum of 28) 
B) Joint status: Number of swollen joints (each with a maximum of 28) 
C) Patient’s assessment of current disease activity (from 0 = inactive to 10 = highly 
active) 
D) Physician’s assessment of current disease activity (from 0 = inactive to 10 = highly 
active) 
The CDAI is calculated by following formula. 
CDAI = A) + B) + C) + D) 
 
3) Simplified disease activity index (SDAI): 
The SDAI indicates the severity of the RA.  The SDAI is calculated from the following 
data documented on the physician form: 
A) Joint status: Number of tender joints (each with a maximum of 28) 

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B) Joint status: Number of swollen joints (each with a maximum of 28) 
C) Patient’s assessment of current disease activity (from 0 = inactive to 10 = highly 
active) 
D) Physician’s assessment of current disease activity (from 0 = inactive to 10 = highly 
active) 
E) CRP (mg/dL) 
The SDAI is calculated by following formula. 
SDAI = A) + B) + C) + D) + E) 
 
4) Health Assessment Questionnaire (HAQ): 
The HAQ is the internationally most-used instrument for assessing RA-related functional 
impairment.  The patient has to answer 20 questions concerning impairment in daily 
activities within the following 8 areas: 
㺃 Dressing & Grooming 
㺃 Arising 
㺃 Eating 
㺃 Walking 
㺃 Hygiene 
㺃 Reach 
㺃 Grip 
㺃 Activities 
Patients assess their functionality over the past week by means of a 4-level scale ranging 
from 0 (without any difficulty) to 3 (unable to do).  The highest (worst) values will be 

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calculated into a mean value which indicates the degree of functional impairment (HAQ 
Disability Index: 0-3). 
 
5) EuroQol 5 Dimensions (EQ-5D): 
The EQ-5D is a generic (not disease specific) instrument for measuring health-related 
quality of life.  The patient questionnaire includes statements for the following five areas 
(dimensions): 
㺃ᴾAgility & Mobility 
㺃 Self-care 
㺃ᴾUsual activities 
㺃ᴾPain & Bodily discomfort 
㺃ᴾAnxiety & Depression 
For each dimension the patient is asked for a three-level assessment of his health on the 
current day: “no problems” (1), “some problems” (2), “extreme problems” (3).  From the 
possible combinations of the five three-level areas result 241 different health-statuses. 
6) X-ray findings of joint damage: 
According to the guidelines for X-ray examination, investigators will obtain X-ray 
images of the both hands and both feet of each patient at baseline and week 52 of 
treatment.  Members of the TSS Academy will score the X-ray images systemically and 
objectively in terms of bone erosion and joint space narrowing using the mTTS method. 
Criteria for evaluation of joint lesions using the mTTS method: 
The van der Heijde-modified total Sharp score (mTSS) will be used to score the severity 
of bone erosion and join space narrowing shown on the X-ray pictures of the hands and 
feet.  Table 2 shows the scoring criteria8). 
 
Table 2. Scoring for Sharp-van der Heijde method 

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7.6.4 
Study Medication  
This is a non-interventional observational study with adalimumab.  Adalimumabᴾis used 
according to the approved label for rheumatoid arthritis and is prescribed by the attending 
physician.  AbbVie GK 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 adalimumabᴾfor adult patients with RA is 40 mg sc every 
other week. 
 

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8.0                  Amendments and Updates 
Number 
Date 
Section of Study 
Protocol 
Amendment or 
Update 
Reason 
1 
31JUL2012 
 
Create  New 
 
2 
25APR2013 
2.0 Synopsis 
7.0 Study objectives 
Amendment 
1) PMDA 
requirement 
2) Increase the 
number of patients 
3 
27NOV2013 
2.0 Synopsis 
7.0 Study objectives 
Amendment 
Unachieved 
registration 
4 
23FEB2016 
9.0 Adverse events 
10.0 Product 
complaint 
Amendment 
updated 
FDA requirement 
5 
28MAR2017 
7.5 Study Duration 
Amendment 
Add the day of 
data analysis  and 
the end of study 
date due to 
became clear 
6 
23AUG2017 
7.5 Study Duration 
Amendment 
Add the day of 
data analysis  and 
the end of study 
date due to correct 
7 
11DEC2017 
7.5 Study Duration 
Amendment 
Change the day of 
data completion 
and data analysis  
 
9.0                  Adverse Events 
9.1.1 
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 

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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 
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. 
 
9.2                     Relationship to Pharmaceutical Product 
If an adverse event is occurred in the observation period, the physician will assess the 
causality of adalimumab with reference to the latest package inserts of adalimumab and 
concomitant drugs (e.g., methotrexate, corticosteroids).  When the causality of an adverse 
event to the use of a concomitant drug other than adalimumab is suspected, the physician 
will describe the suspected drug. 

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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 
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. 
9.3                     Serious Adverse Event Collection Period 
Serious adverse events will be reported to AbbVie GK 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 PMOS (week 104 or discontinuation of this study). 
9.4                       Serious Adverse Event Reporting 
In the event of a serious adverse event, and additionally, any non-serious events of 
malignancy in patient 30 years of age and younger, whether related to adalimumab or not, 
if applicable - the physician will notify the AbbVie GK contact person (Medical 
Representative in Japan) within 24 hours of the physician becoming aware of the event.  
AbbVie MR will send the AbbVie Pharmacovigilance department identified below. 
AbbVie GK
3-5-27, Mita, Minato-ku, Tokyo 108-6302, Japan
Pharmacovigilance Department 

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9.5                      Pregnancy Reporting 
In the event of a pregnancy, the physician will notify the AbbVie MR within 24 hours of 
the physician becoming aware of the pregnancy.  
AbbVie MR will send the AbbVie Pharmacovigilance department identified in Section 
9.4. 
 
10.0 
Product Complaint 
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). 
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 10.2.) For product complaints, please refer to Section 
10.2. 
 
10.1 
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

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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. 
 
10.2 
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 
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. 
 
 
11.0 
Ethics and Quality 
In accordance to the code of conduct of MHLW/PMDA, the AbbVie GK will forward the 
PMOS protocol to the PMDA for approval.  The PMOS result will also be reported to the 
PMDA. 

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All patient data entered in the patient's CRF will be forwarded to AbbVie GK for 
evaluation - without naming the patient. Each CRF bears a pre-printed patient 
identification number, which replaces the patient's initials.  Accordingly, the patient’s 
identity will not be disclosed to AbbVie GK. 
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 PMOS will be sponsored by AbbVie GK. (Mita 3-5-27, Minato-ku, Tokyo, Japan) 
 
12.0 
Case Report Forms 
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 104 weeks (or 
discontinuation of this study), 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. 
13.0 
Data Analysis Plan 
All statistical analysis procedures will be described in detail in a Statistical Analysis Plan 
(SAP).  This plan will be developed by the responsible biometrician in collaboration with 
the sponsor.  The SAP will be finalized and approved by the responsible biometrician, the 
sponsor, and the principle investigator before the database will be opened for the first 
interim analysis. 
 
13.1 
Sample Size Calculation 
The primary endpoint of this study is the proportion of subjects who achieve DAS28 
(CRP) remission (DAS28 <2.6) after 52 weeks of adalimumab + high dose MTX.  We 
calculated the target sample number for this survey on the basis of an expected remission 

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rate, i.e., the percentage of patients with a DAS28 score of <2.6, at week 52 during the 
treatment with adalimumab 40 mg and MTX at t12 mg/week.   
Table 3 lists the percentages of patients with a DAS28 score of <2.6 at week 52 in a 
study conducted by Takeuchi et al.9) in patients receiving adalimumab and MTX. 
Table 3. Patients with a DAS 28 score of <2.6 at week 52 during the treatment with 
adalimumab and MTX  
adalimumab + MTX dose  
(mg/week) 
Percentage of patients with DAS28 <2.6 
(Week 52) 
8.5 r 2.9  
42.7% (61/143 patients)  
t12  
61.7% (29/47 patients)  
 
As Table 3 shows, 42.7% of patients receiving MTX at 8.5 r 2.9 mg/week at the 
initiation of adalimumab treatment achieved a DAS 28 of <2.6 at week 52, and the 
corresponding percentage of patients receiving DAS at t12 mg/week at baseline was 
61.7%.  When 55% of patients receiving MTX at t12 mg/week at the initiation of 
adalimumab treatment are assumed to achieve a DAS 28 of <2.6 at week 52 (subtracting 
the standard error (7.10%) from the above mentioned percentage; 61.7 – 7.1 = 54.6%), 
the number of patients required to achieve a power (1-E) of 0.90 at an D level of 0.05 
(two-tailed) would be 171 (one-sample test).  
Since 32% of patients enrolled in the all-case survey of adalimumab in patients with 
rheumatoid arthritis dropped out during the 24-week survey period, we assumed that 50% 
of the participants in the survey would drop out during the 52-week survey period, and 
calculated that 342 patients should enroll in the survey.  We thus set the target sample 
size at 350. 
 
13.2 
Analysis Population(s) 
The data of all documented patients will be used in the statistical analysis of tolerability 
and safety. 
 
13.3 
Missing Values 
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 

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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. 
 
13.4 
Level of Significance 
Inferential statistics will be performed at a nominal level of significance of 0.05 (two-
sided). 
 
13.5 
Times of Statistical Analyses 
Interim analyses are planned after 24 and 36 month after the inclusion of the first patients. 
The general analysis will be performed after closure of the follow-up of the last patient (4 
years after starting the study). 
 
14.0 
Final Report and Publications 
After the end of the study, an Integrated Final Report is generated in cooperation with the 
Principal Investigator.  The report includes a description of the objectives of the study, 
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 study may be published 
by AbbVie GK or any of the participating investigators after approval by AbbVie GK. 
 

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15.0 
References 
(1) Aletaha D and Smolen Js: Effectiveness profiles and dose dependent retention of 
traditional disease modifying anti-rheumatic drugs for rheumatoid arthritis; an 
observational study. J Rheumatol, 29: 1631-38, 2002 
(2) Jones G, Halbert J, Crotty M, et al.: The effect of treatment on radiological 
progression in rheumatoid arthritis; a systematic review of randomized placebo-
controlled trials. Rheumatology, 42(1): 6-13, 2003 
(3) Weinblatt ME, Kaplan H, Germain BF, et al.: Methotrexate in rheumatoid arthritis; a 
five-year prospective multicenter study. Arthritis Rheuma, 37: 1492-98, 1994 
(4) Emery P, Breedveld FC, Lemmel EM, et al.: A comparison of the efficacy and safety 
of Leflunomide and Methotrexate for the treatment of rheumatoid arthritis, 
Rheumatology, 39: 655-665, 2000 
(5) Choi HK, Hernan MA, Seeger JD, et al.: Methotrexate and mortality in patients with 
rheumatoid arthritis; a prospective study. Lancet, 359(9313): 1173-77, 2002 
(6) Krishanan E, Lingala VB, Singh G: Declines in mortality from acute myocardial 
infraction in successive incidence and birth cohorts of patients with rheumatoid 
arthritis. Circulation, 110: 1774-79, 2004 
(7) Pincus T, Yazici Y, Sokka T, et al.: Methotrexate as the “anchor drug” for the 
treatment of early rheumatoid arthritis. Clin Exp Rheumatol, 21 (Suppl 31): S179-85, 
2003 
(8) D van der Heijde: How to Read Radiographs According to the Sharp / van der Heijde 
Method. J Rheumatol, 27: 261-3, 2000 
(9) Takeuchi T, Tanaka Y, et al.: Effectiveness and safety of adalimumab in Japanese 
patients with rheumatoid arthritis: retrospective analysis of data collected during the first 
year of Adalimumab treatment in routine clinical practice (HARMONY study). Mod 
Rheumatol, 2011