Long Term Documentation of the Safety and Efficacy as Well as the Effects on Quality of Life and Work Productivity in Patients With Rheumatoid Arthritis Under HUMIRA® (Adalimumab) in Routine Clinical Practice (AGIL)
Conditions: Rheumatoid Arthritis
Sponsor: AbbVie (prior sponsor, Abbott)

NCT01076205

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
3 
Target parameters for safety evaluation of adalimumab are: 
x
The evaluation of safety and tolerability by the documentation 
and analysis of serious adverse events (SAEs) and adverse 
events (AEs) 
x
Evaluation of safety and tolerability for subgroups of patients 
with common frequent concomitant diseases, especially 
diabetes type II, cardiovascular, liver, and renal insufficiencies, 
and related concomitant medications. 
Study population 
Adult patients ( 18 years) with moderate to severe active RA 
and/or severe, active and progressive RA 
Study design 
Single-arm, multi-center format, prospective cohort study 
Treatment duration 
5 years 
Methodology 
Disease Activity Score (DAS28), Health Assessment Questionnaire 
(HAQ), Health Questionnaire Short Form (EQ-5D), WPAI 
Total number of patients  
2500 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 therapeutic success and additional 
subgroup analysis. By forward and backward stepwise regression, 
those patient and disease characteristics (baseline values of all 
target 
parameters, 
disease 
duration, 
previous 
therapies, 
demographic and anthropometric data, health-related quality of life 
etc.) will be selected which show a statistically significant partial 
correlation with the parameters of therapeutic success at month 3 
(improvements in the number of affected joints [DAS28], HAQ, 
number of missed working days, and WPAI). Due to the clear 
temporal relation between the baseline values and the treatment 
effects at month 3, the selected predictors can be interpreted both as 
causal explanation and as prognosing factors concerning therapy-
modifying influencing variables (since an reactive influence of the 
3-month values on the baseline values can be ruled out). 
Additionally, the strength of the relationship between the predictors 
and the parameters of therapeutic success will be determined. The 
impact of the variables determined by regression analysis on the 
therapeutic success will be illustrated by subgroup analysis. The 
impact of adalimumab therapy on health-related quality of life (EQ-
5D), the number of physician visits and hospitalization, the days of 
impairment in non-occupational activities, and the subjective 
symptoms (morning stiffness, pain, exhaustion/fatigue) will be 
descriptively evaluated and additionally analyzed by between-group 
comparison. Two interim analyses are planned. 
Planned recruitment phase 
March 2009 - March 2012 
Planned study duration 
March 2009 – March 2018 
Product manufacturer 
Abbott 
142

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
4 
3 Abkürzungen und Definitionen 
AE 
Adverse event
AMG 
Arzneimittelgesetz 
BMI
Body Mass Index 
CCP
Cyclic citrullinated peptide 
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 Questionnaire 5 Dimensions 
ESR 
Erythrocyte sedimentation rate
FAS
Full analysis set 
HAQ
Health Assessment Questionnaire  
Hb 
Hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIS 
Non-interventional study
RF 
Rheumatoid factor
SAE
Serious adverse event 
SAP
Statistical analysis plan 
SDV
Source Data Verification 
WPAI-GH 
Work Productivity and Activity Impairment-General Health 
version
143

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
5 
4 Table of Contents 
1
Title Page .................................................................................1
2
Synopsis....................................................................................2
3
Abkürzungen und Definitionen.............................................4
4
Table of Contents....................................................................5
5
Introduction.............................................................................7
6
Rationale ..................................................................................9
7
Study Objectives....................................................................10
8
Investigational Plan ..............................................................12
8.1 
Selection of Study Population .................................................................12
8.2 
Number of Patients to be Enrolled ..........................................................12
8.3 
Investigator Selection Criteria.................................................................12
8.4 
Study Duration.........................................................................................13
8.5 
Study Conduct .........................................................................................13
8.5.1 
Schedule of Observations........................................................................13
8.5.2 
Description of Activities..........................................................................16
8.5.3 
Scales and Scores ....................................................................................18
8.5.4 
Study Medication.....................................................................................20
9
Adverse Events......................................................................21
9.1 
Adverse Event Definition and Serious Adverse Event 
Categories................................................................................................21
9.2 
Severity....................................................................................................22
9.3 
Relationship to Pharmaceutical Product..................................................22
9.4 
Serious Adverse Event Collection Period ...............................................23
9.5 
Serious Adverse Event Reporting ...........................................................24
9.6 
Pregnancy Reporting ...............................................................................25
10
Ethics and Quality.................................................................26
11
Case Report Form.................................................................28
12
Data Analysis Plan................................................................29
12.1 
Sample Size Calculation..........................................................................29
144

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
6 
12.2 
Analysis Population(s).............................................................................29
12.3 
Missing Values ........................................................................................29
12.4 
Level of Significance...............................................................................30
12.5 
Biometric Concept...................................................................................30
12.6 
Times of Statistical Analyses ..................................................................31
13
Final Report and Publications.............................................32
14
Literature...............................................................................33
145

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
7 
5 Introduction 
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints that often 
results in progressing joint destruction and lead to substantial functional losses, 
impairment, and reduced quality of life. On the social level, disease-related costs (due 
to lack of functionality) to be paid by social security systems are increasingly gaining 
priority (1), (2).
An important cytokine that activates and intensifies inflammation in RA is the tumor 
necrosis factor Į (TNF-Į). Introduction of TNF-Į inhibitors 10 years ago 
revolutionized RA treatment options and led to the development of further 
recombinant antibodies and fusion products, respectively, which are called biologics. 
Adalimumab is one of these biologics, a human monoclonal antibody against TNF-Į,
which has been approved in Germany for RA treatment under the trade name 
HUMIRA® since 2003. Adalimumab inhibits the interaction of TNF-Į with its 
receptors and thus suppresses the biological effect of this proinflammatory cytokine. 
HUMIRA® is administered as a subcutaneous (sc) injection at a recommended dose of 
40 mg every other week.  
Several clinical trials have shown that adalimumab both reduces the clinical 
symptoms of RA and decelerates the structural destruction of the joints, thus 
significantly improving health-related quality of life. 
Patients who had been included in a non-interventional long term study and had been 
treated with adalimumab under conditions of routine rheumatology practice had been 
suffering from RA for many years (mean disease duration 12 years) and showed a 
high disease activity (DAS28 = 5.8). These patients experienced a significant 
reduction in clinical signs and symptoms of RA after 24 months of adalimumab 
therapy (interim analysis July 2007). 20 % of patients were in clinical remission and 
over 40 %had improved in their physical functionality. 
Unlike the previous RA documentation, this NIS will put added emphasis on data 
concerning work productivity and work ability as well as data concerning health-
related quality of life. This will result in an according large-scale patient 
documentation form.  
146

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
8 
In order to improve quality, all filled questionnaires will be checked for completeness 
and missing data will be added by written query. A defined percentage of 
participating physicians will be audited. An independent CRO will perform double 
data entry, perform plausibility checks and statistically evaluate the data according to 
criteria determined in the protocol. The results will be published after finalization of 
the evaluation.
The planned documentation is a non-interventional study (NIS) according to & 4 
section 23, point 3, Arzneimittelgesetz (AMG) and will be conducted in compliance 
with the recommendations of the Verband der forschenden Arzneimittelhersteller 
(Association of Research-based Pharmaceutical Companies). 
147

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
9 
6 Rationale 
This NIS is designed to provide additional data on treatment effects of adalimumab in 
the long term treatment in patients with moderate to severe active RA under 
conditions of routine rheumatology care. In contrast to clinical trials, all patients 
treated in clinical routine will be included in the NIS, independent of comorbidities, 
concomitant medication, severity of their illness, or features such as age and gender.  
Course of work productivity and work ability, the course of health-related quality of 
life, and changes in functionality under long term treatment with adalimumab will be 
documented. The numbers of patients included in the NIS allow identifying and 
quantifying the impact of disease and patient characteristics on the therapeutic 
success.
148

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
10 
7 Study Objectives 
In this NIS, a long term documentation of treatment with adalimumab in RA patients 
over 60 months with 8 data collection points (visits) is planned. The documentation 
will be performed by the physician as well as by patient’s self-assessment.  
The primary objective is to explore the therapeutic success by interim analyses after 
12 and 24 months of treatment as well as by the final analysis after 60 months of 
treatment. Improvements concerning the following target variables will be evaluated 
(with regard to the respective baseline value):  
x
the number of missed working days 
x
the self-assessed work ability (WPAI) 
x
the severity of clinical symptoms (number of tender and swollen joints, CRP and 
ESR, respectively; total score DAS28) 
x
Severity of functional impairment (HAQ) 
x
The health-related quality of life (EQ-5D) 
At month 3, patient and disease characteristics will we evaluated with regard to their 
additional impact on changes in the number of affected joints (DAS28), in the HAQ, 
and in the WPAI. The impact on the number of missed working days will be 
evaluated at month 6.
The secondary objective is to document the therapeutic success by interim analyses 
at month 12 and 24 months as well as by the final analysis after 60 months. The 
therapeutic success will be evaluated by the following variables:  
x
The number of physician visits 
x
The number and duration of hospitalizations 
x
The number of days of impairment in non-occupational activities
x
The duration of morning stiffness, pain, exhaustion/fatigue 
149

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
11 
x
The reduction of number and dose of concomitant medication 
x
Patient’s assessment of adalimumab therapy compared to previous therapies 
Target parameters for safety evaluation of adalimumab are: 
x
The evaluation of safety and tolerability by the documentation and analysis of 
serious adverse events (SAEs) and adverse events (AEs). 
x
Evaluation of safety and tolerability for subgroups of patients with common 
frequent concomitant diseases, especially diabetes type II, cardiovascular, liver, 
and renal insufficiencies, and related concomitant medications.  
150

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
12 
8 Investigational Plan 
8.1 Selection of Study Population 
This study population will consist of adult patients ( 18 years) with moderate to 
severe active rheumatoid arthritis (RA) who have failed other anti-rheumatic drugs 
including Methotrexat (MTX) and patients with a severe, active and progressive 
rheumatoid arthritis (with or without prior MTX).  
Patients who have been previously treated with other biologics (including TNF 
inhibitors) can be included in the NIS.
The inclusion and exclusion criteria adhere to the approved label as stated in the 
German Summary of Product Characteristics (SPC) “Fachinformation” for 
HUMIRA®. No additional inclusion and exclusion criteria are applicable since this 
project is non-interventional.
Patients to be included will be informed about the NIS and the use of their anonymous 
data. Patients willing to participate must provide their written informed consent to the 
investigator before entry into the NIS. The signed informed consent form will be 
added to the patient’s file. 
8.2 Number of Patients to be Enrolled 
The NIS will include about 2500 patients in order to provide for the final evaluation 
of missed working days a sample size of n = 850 employed patients who are 
temporarily on sick leave during the study (see also Section 12.1 “Sample Size 
Calculation”).
8.3 Investigator Selection Criteria 
The data for his NIS will be collected from rheumatology outpatient departments and 
office-based rheumatologists in Germany routinely treating patients with RA. 
Physicians from about 200 sites which are spread across all of Germany will 
participate in this NIS. 
151

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
13 
Principal Investigator: 
8.4 Study Duration 
The duration of the whole NIS is estimated to be about 9 years.  
Study start: March 2009
Recruiting phase: March 2009 – March 2012 
Data completion: March 2017 
Data analysis and final report: March 2017 – March 2018 
For each individual patient, the NIS starts with the enrollment in the long term 
documentation at the beginning of the treatment with adalimumab and ends either 
after 5 years or with the termination of the adalimumab therapy.  
8.5 Study Conduct 
8.5.1 Schedule of Observations 
This NIS 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). Adalimumab must not be prescribed for the purpose of including a 
patient in this NIS.  
152

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
14 
Patients will be informed about the type of therapy, alternate therapies, and risks, and 
they have to provide a written informed consent to the data collection on the 
documentation forms before the start of therapy. The presence of the written informed 
consent is documented on the base documentation from. Before enrollment in the 
NIS, the patients will be made anonymous. Abbott will only receive access to 
anonymous data. Abbott can only identify the patients via their patient number.
The visits are scheduled according to the recommendations of the Deutsche 
Gesellschaft für Rheumatologie (German Society for Rheumatology): The 
documentation consists of patient self-assessments as well as assessments by the 
physician. The following tables provide an overview of the observations to be 
documented by the physician (Table 1) and the patient (Table 2).
Due to long time intervals between the scheduled visits (one year after month 12), 
interim documentation forms will be provided for non-scheduled visits in order to 
document clinically significant events.  
153

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
15 
Table 1. Physician Schedule 
Month
0 
3 
6 
12 
24
36 
48 
601
Demographic data 
X 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
Indication HUMIRA®
X 
 
 
 
 
 
 
 
Medical history / change history 
X 
X 
X 
X 
X 
X 
X 
X 
Radiologic findings2
X 
 
 
X 
X 
X 
X 
X 
Previous RA therapies 
X 
 
 
 
 
 
 
 
Concomitant diseases and therapies3
X 
X 
X 
X 
X 
X 
X 
X 
Current HUMIRA® therapy4
X 
X 
X 
X 
X 
X 
X 
X 
RA-related concomitant medication4 
X 
X 
X 
X 
X 
X 
X 
X 
Disease activity5
X 
X 
X 
X 
X 
X 
X 
X 
Current joint status5
X 
X 
X 
X 
X 
X 
X 
X 
Morning stiffness 
X 
X 
X 
X 
X 
X 
X 
X 
Rheumatoid nodules 
X 
 
 
 
 
 
 
 
Joint (replacement) surgery 
X 
 
 
X 
X 
X 
X 
X 
Laboratory values: CRP, ESG, Hb-value, 6 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory values: RF, CCP6
X 
 
 
 
 
 
 
 
Laboratory values: Hepatitis B, Hepatitis C, 
tuberculosis screening, TB prophylaxis (if 
necessary)6
X 
X7 
X7 
X7 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Patient’s compliance 
 
X 
X 
X 
X 
X 
X 
X 
1 Month 60 or last visit 
2 after baseline visit (month 0) only if current radiograph is available or if indicated 
3 after baseline visit (month 0) only for newly developed diseases or changed therapy 
4 after baseline visit only for changes in therapy or dose 
5 Data are part of the DAS28 (Disease Activity Score) 
6 after baseline visit (month 0) only if data is available or if indicated 
7 only TB prophylaxis documented 
154

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
16 
Table 2. Patient Schedule 
Month
0 
3 
6 
12 
24
36 
48 
60 
Personal data  
X 
 
 
 
 
 
 
 
Education  
X 
 
 
 
 
 
 
 
Professional status 
X 
 
X 
X 
X 
X 
X 
X 
Missed working days  
(last 6 months) 
X 
 
X 
X 
X 
X 
X 
X 
Physician visits and hospitalization 
(last 6 months) 
X 
 
X 
X 
X 
X 
X 
X 
Days of impairment in non-occupational 
activities 
X 
 
X 
 
X 
X 
X 
X 
Work ability (WPAI) 
X 
X 
X 
X 
X 
X 
X 
X 
Exhaustion/fatigue (last 7 days) 
X 
X 
X 
X 
X 
X 
X 
X 
Pain (last 7 days) 
X 
X 
X 
X 
X 
X 
X 
X 
Functionality (HAQ) 
X 
X 
X 
X 
X 
X 
X 
X 
Health-realted quality of life (EQ-5D)  
X 
X 
X 
X 
X 
X 
X 
X 
Patient’s assessment of adalimumab ther-
apy compared to previous therapies 
 
X 
X 
X 
X 
X 
X 
X 
Participation Abbbott Care service program 
X 
X 
X 
X 
X 
X 
X 
X 
8.5.2 Description of Activities 
The following data will be documented (if assessed in routine care): 
Physician:
Baseline Visit (Month 0)
Demographics and History 
Demographic Data (age, gender, height, weight) 
Inclusion criteria (moderate to severe active RA and/or severe, active, and 
progressive RA, signed informed consent) 
Exclusion criteria according to Fachinformation (hypersensitivity, active 
tuberculosis, other severe infections [e.g. sepsis, opportunistic infections], 
moderate to severe heart insufficiency [NYHA calss III/IV]) 
155

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
17 
Indication for the current HUMIRA® therapy 
Radiological findings of affected joints 
History (including initial diagnosis of RA and tobacco use) 
Previous therapies: DMARD (MTX, SASP, leflunomid), glucocorticoids, biologics 
(infliximab, etanercept, rituximab, tocilizumab, abatacept), date of biologic 
discontinuation
Concomitant diseases and concomitant medication 
Current RA therapy 
Current HUMIRA® therapy 
Additional DMARD, systemic glucocorticoids, analgetics, NSAID, COX inhibitors  
Current status 
Disease activity, joint status (28 joints, tender, swollen), morning stiffness, 
rheumatoid nodules, previous joint surgery 
Laboratory values (RF, CCP, CRP, ESR, Hb-value, hepatitis B, hepatitis C, 
tuberculosis screening, TB prophylaxis, pregnancy test in women with 
childbearing potential) 
Follow-up Visits (Month 3, 6, 12, 24, 36, 48, 60)
Change history 
Current therapy (RA therapy and concomitant medication) 
Disease activity 
Joint status 
Morning stiffness 
Joint (replacement) surgery (beginning month 12) 
Radiographic findings (beginning month 12) 
Laboratory values (CRP, ESR, Hb-value, other laboratory values if indicated) 
(S)AE
Patient’s compliance 
Patient:
Baselince Visit (Month 0)
Personal data 
Education
Professional status 
Missed working days, days of impairment in non-occupational activities 
Physician visit, hospitalization 
WPAI, HAQ, and EQ-5D 
156

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
18 
Exhaustion/Fatigue, pain 
Participation in the Abbott Care service program 
Follow-up Visits (Month 3, 6, 12, 24, 36, 48, 60)
WPAI, HAQ, and EQ-5D 
Exhaustion/Fatigue, pain 
Patient’s assessment of adalimumab therapy 
Participation in the Abbott Care service program 
Follow-up Visits (Month 6, 12, 24, 36, 48, 60)
As above, additionally: 
Missed working days, days of impairment in non-occupational activities 
Physician visits, hospitalization 
Changes in the professional status 
8.5.3 Scales and Scores 
The following scores will be derived from the documented data: 
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 data documented on the physician form: 
x
Joint status: Number of swollen and tender joints (each with a maximum of 28) 
x
ESR (mm/1. h) or CRP (mg/l) 
x
Patient’s assessment of current disease activity (from 0 = inactive to 10 = highly 
active) 
The DAS28 is calculated by means of a validated algorithm (4), (5).  
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: 
x
Dressing & Grooming 
x
Arising
157

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
19 
x
Eating
x
Walking 
x
Hygiene
x
Reach
x
Grip
x
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 calculated into a mean value which indicates the degree of functional 
impairment (HAQ Disability Index: 0-3) (8). 
WPAI: The WPAI is a questionnaire for the self-assessment of work productivity and 
activity impairment. In this observational study, the WPAI-GH is used which 
measures work productivity and activity impairment with reference to general health 
problems. All dimensions relate to the past seven days. The following dimensions are 
measured: 
x
Assessment of employment status 
x
Assessment of hours missed from work due to health problems and other reasons 
such as vacation or holidays (total number of hours to be indicated) 
x
Assessment of hours the patient has actually worked (total number of hours to be 
indicated)
x
Assessment of impairment in work productivity and in regular daily activities 
(2 assessments with 10 levels each) 
The WPAI yields four types of scores:  
x
‘activity impairment’ 
x
‘absenteeism’ (work time missed) 
x
‘presenteeism’ (impairment at work/reduced on-the-job effectiveness) and  
x
‘work 
productivity 
loss’ 
(overall
work 
impairment/absenteeism 
plus 
presenteeism).  
158

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
20 
Scores were transformed into percentages. Higher scores indicate greater impairment. 
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 
consists of two parts. The first part includes statements for the following five areas 
(dimensions): 
x
agility/mobility  
x
self-care
x
usual activities  
x
pain, bodily discomfort  
x
anxiety, 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. 
The second part is a thermometer-scale (EQ-VAS) on which the patients rate their 
health on the current day between the endpoints “best health imaginable” (100) and 
“worst health imaginable” (0).  
8.5.4 Study Medication 
This is a non-interventional observational study with HUMIRA£. HUMIRA£ is used 
according to the approved label for rheumatoid arthritis and is prescribed by the 
attending physician. Abbott does not provide any study medication. 
HUMIRA£-injection is available as ready-to-use syringes and as pre-filled pen 
(injector, pre-filled/FertigPEN) and includes 40 mg adalimumab.  
The recommended dose of HUMIRA£ for adult patients with RA is 40 mg sc every 
other week. 
159

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
21 
9 Adverse Events 
9.1 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):
Death of Subject: An event that results in the death of a subject.  
Life-Threatening: An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been taken. This does 
not include an event that would have been fatal if it had occurred in a more severe 
form 
Hospitalization: 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.  
Prolongation of Hospitalization: An event that occurs while the study subject is 
hospitalized and prolongs the subject’s hospital stay.
Congenital Anomaly: An anomaly detected at or after birth that results in fetal loss. 
Persistent or Significant Disability/Incapacity: An event that results in a condition 
that substantially interferes with the activities of daily living of a study subject. 
Disability is not intended to include experiences of relatively minor medical 
160

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
22 
significance such as headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle). 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent 
Serious Outcome: An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-threatening, hospitalization,
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). 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. 
Spontaneous Abortion: Miscarriage experienced by study subject. 
Elective Abortion: Elective abortion performed on study subject.   
9.2 Severity 
The physician will use the following definitions to rate the severity for any adverse 
event being collected as an endpoint/data point in the study and for all serious adverse 
events: 
Mild: The adverse event is transient and easily tolerated by the subject. 
Moderate: The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities. 
Severe: The adverse event causes considerable interference with the subject’s usual 
activities and may be incapacitating or life-threatening. 
9.3 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: 
161

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
23 
Probably related: 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. 
Possibly related: 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. 
Probably not related: An adverse event has little or no temporal relationship to the 
study drug, and/or a more likely alternative etiology exists, 
Not related: An adverse event is due to an underlying or concurrent illness or effect 
of another drug an is not related to the study drug (e.g., has no temporal relationship 
to study drug or has a much more likely alternative etiology).  
If an investigator’s opinion of possibly, probably not, or not related to pharmaceutical 
product is given, an alternate etiology must be provided by the investigator.
9.4 Serious Adverse Event Collection Period 
Serious adverse events will be reported to Abbott from the time the physician obtains 
the patient’s authorization to use and disclose information (or the patient’s informed 
consent) until 30 days or 5 half-lives following the intake of the last dose of 
physician-prescribed treatment. 
162

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
24 
9.5 Serious Adverse Event Reporting 
In the event of a serious adverse event – whether or not related to Abbott product or 
comparator, if applicable – the physician will notify the Abbott drug safety identified 
below within 24 hours of the physician becoming aware of the event. The notification 
will be performed via fax on the form labeled “Bericht über Schwerwiegende 
Unerwünschte Arzneimittelwirkungen”: 
163

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
25 
9.6 Pregnancy Reporting 
In the event of a pregnancy, the physician will notify the Abbott drug safety identified 
below within 24 hours of the physician becoming aware of the pregnancy. The 
notification will be performed via fax on the base documentation form: 
Reported pregnancies will be reported like SAEs. 
164

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
26 
10 Ethics and Quality 
In accordance to the code of conduct of the German pharmaceutical industry, the 
German principal coordinating investigator
 will forward the 
NIS study protocol to the ethics committee for approval: 
The patient has to provide a written informed consent to use and/or disclose personal 
and/or health data before enrollment in the study. This written informed consent will 
be archived with the patient’s file and documented on the report forms. According to 
§ 67 section 6 AMG, the NIS will also be reported to the Kassenärztliche 
Bundesvereinigung (federal association of physicians), the umbrella organization of 
health insurance providers, and the responsible federal authority. 
All patient data entered in the patient's CRF will be forwarded to Abbott GmbH & Co 
KG for evaluation - without naming the patient. Each CRF bears a pre-printed patient 
identification number, which replaces the patient's initials. The date of birth will be 
replaced by the patient’s age at the start of the study. Accordingly, the patient’s 
identity will not be disclosed to Abbott GmbH & Co. KG. 
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.
Source data verification by the sponsor’s monitor at the physician’s site is planned for 
5% of the documented patients. Informed consent, in- and exclusion criteria, and all 
available source data will be inspected. 
165

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
27 
This NIS will be sponsored by Abbott GmbH & Co. KG, 
166

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
28 
11 Case Report Form 
All data specified in Section 8.5 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 five patients. 
Any observation of an adverse event in the time period up to 60 months, beginning 
with the initiation of HUMIRA® therapy, is to be documented on the "Adverse Event” 
form labeled 'Bericht über unerwünschte Ereignisse' and checked for severity. If the 
event fulfills the serious criterion (Serious Adverse Event), the "Adverse Drug 
Reaction Report” form labeled 'Bericht über Schwerwiegende Unerwünschte 
Arzneimittelwirkungen' is to be completed additionally. 
167

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
29 
12 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. 
12.1 Sample Size Calculation 
The primary parameter of this documentation is work productivity, which is captured 
by the number of missed working days. The sample size calculation is based on the 
results of an interim analysis of a documentation of adalimumab in RA with 4640 
patients, of whom 1417 patients had been employed part time or full time. The mean 
number of missed working days was 26 days (standard deviation of 55 days) during 
the last 12 month prior to adalimumab therapy. The correlation between baseline and 
follow-up report is estimated with r = 0.5. According to these numbers, 850 employed 
patients are required to detect a mean difference of 5 days within 12 months at the 
0.05 significance level (two-sided) with a power of 0.80. Since 30 % of patients are 
employed, a total number of about 2500 employed and non-employed patients are 
required in order to detect the specified difference in missed working days.  
12.2 Analysis Population(s) 
The data of all documented patients will be used in the statistical analysis of 
tolerability and safety of adalimuab. The data of patients whose RA had been treated 
with adalimuab previously will be excluded from the analysis of efficacy. 
12.3 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 SAP. 
All data will be analyzed on the basis of “observed cases”. For the statistical analysis 
of data concerning the course of disease, the health-related economic parameters and 
168

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
30 
the health-related quality of life (if related to changes from baseline values), an 
additional approach will be followed considering only patients with complete data at 
all visits.  
12.4 Level of Significance 
Inferential statistics will be performed at a nominal level of significance of 0.05 (two-
sided). Due to the exploratory character of the analyses, the resulting p-values will not 
be adjusted for multiple testing. 
12.5 Biometric Concept 
The general biometric approach consists of the realization of the analyses described in 
section 7 “Study Objectives”. The analysis principally uses descriptive statistical 
methods, supported by regression statistical methods and subgroup analysis. 
By forward and backward stepwise regression, those patient and disease 
characteristics (baseline values of all target parameters, disease duration, previous 
therapies, demographic and anthropometric data, health-related quality of life etc.) 
will be selected which show a statistically significant partial correlation with the 
parameters of therapeutic success at month 3 (improvements in the number of affected 
joints [DAS28], HAQ, number of missed working days, and WPAI). Due to the clear 
temporal relation between the baseline values and the treatment effects at month 3, the 
selected predictors can be interpreted both as causal explanation and as prognosing 
factors concerning therapy-modifying influencing variables (since an reactive 
influence of the 3-month values on the baseline values can be ruled out). Additionally, 
the strength of the relationship between the predictors and the parameters of 
therapeutic success will be determined. 
The impact of the features determined by regression analysis on the therapeutic 
success will be illustrated by subgroup analysis. Subgrouping will be done according 
to content-related considerations: Regarding disease activity, patients will be 
classified into groups with high or low DAS28 values (lower and higher 5.1 units, 
respectively). Regarding age, patients will be classified into groups with high or low 
age (lower and higher 40 years, respectively).
169

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
31 
The impact of adalimumab therapy on health-related quality of life (EQ-5D), the 
number of physician visits and hospitalizations, the days of impairment in non-
occupational activities, and the subjective symptoms (morning stiffness, pain, 
exhaustion/fatigue) will be descriptively evaluated and additionally analyzed by 
between-group comparison.  
The tolerability analysis will be based on MedDRA coded AEs and SAEs. Incidence 
rates will be reported on the “Preferred Term” and “System Organ Class” levels for 
all patients as well as for subgroups of patients with different degrees of disease 
activity as well as with different previous and concomitant therapies and diseases. 
12.6 Times of Statistical Analyses 
Interim analyses are planned after 3 and 5 years after the inclusion of the first patients, 
so that at month 12 and 24 sufficiently large groups of about 800 patients are 
available. The general analysis will be performed after closure of the follow-up of the 
last patient (8 years after starting the study).
170

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
32 
13 Final Report and Publications 
After the end of the NIS, an Integrated Final Report is generated in cooperation with 
the Principal Investigator, who also signs the report. 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 Abbott GmbH & Co. KG, 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 Abbott GmbH & Co. KG. The results of this NIS may be published by 
Abbott GmbH & Co. KG or any of the participating investigators after approval by 
Abbott GmbH & Co. KG. 
171

HUMIRA®
AGIL 
AGIL GER 08-05 (28-Okt-2008) 
33 
14 Literature 
(1)
Lee, D.M., Weinblatt, M-E. (2001). Rheumatoid arthritis. Lancet; 358, 903-
911.
(2)
Backman, C.L. (2004). Employment and work disability in rheumatoid arthri-
tis. Current Opinion in Rheumatology; 16, 148-152. 
(3)
Tony H.-P., Hein G., Richter C. et al. (2007). Adalimumab: Wirksamkeit und 
Sicherheit bei Patienten mit rheumatoider Arthritis in Deutschland: Zwischen-
auswertung der Langzeitdokumentation HUM03-1 im Alltag der rheumatolo-
gischen Praxis mit 4600 Patienten nach 24 Monaten Behandlung. Zeitschrift 
für Rheumatology, 60, Suppl. 1, S42.05. 
(4)
Van der Cruyssen, B., Van Looy, S., Wyns, B. et.al. (2005). DAS28 best re-
flects the physician’s clinical judgment of response to infliximab therapy in 
rheumatoid patients: validation of the DAS28 score in patients under inflixi-
mab treatment. Arthritis Research & Therapy; 7, R1063-R1071. 
(5)
Van der Heijde, D.M.F.M., van ‘t Hof, M.A., van Riel, P.L.C.M. et al. (1990). 
Judging disease activity in clinical practice in rheumatoid arthritis: first step in 
the development of a disease activity score. Annals of the Rheumatic Dis-
eases; 49, 916-920. 
(6)
Fries, J.F., Spitz, P., Kraines, R.G., Holman, H.R. (1980). Measurement of pa-
tient outcome in arthritis. Arthritis Rheum; 23, 137-145
172