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)

HUMIRA® 
AGIL 
Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
25.04.2017 LS 03337/17 
1 
+ 
Supplementary documentation AGIL-CV to record 
cardiovascular and metabolic risk factors in RA 
patients treated with adalimumab in routine clinical 
practice 
Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
This non-interventional study is to be conducted according to this observational plan. 
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NCT01076205

HUMIRA® 
AGIL 
Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
25.04.2017 LS 03337/17 
2 
 
 
Table of contents 
1 
Changes to the observational plan ................................................................ 4 
1.1 
Introduction ................................................................................................. 4 
1.2 
Rationale ..................................................................................................... 5 
1.3 
Research question .................................................................................... 5 
1.5 
Physician's selection criteria AGIL-CL .................................................... 6 
1.6 
Course of long-term AGIL-CV documentation ...................................... 6 
1.7 
Description of study activities .................................................................. 8 
1.8 
Calculation of CV risk model .................................................................... 9 
1.9 
Sample size estimation ........................................................................... 10 
1.10 
Biometrics concept of AGIL-CV ............................................................. 11 
1.11 
Time points of statistical analysis ......................................................... 11 
1.12 
References ............................................................................................... 12 
 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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Abbreviations and Definitions 
Extension of the list of AGIL abbreviations: 
 
 
dcrit 
Critical difference 
ESCCA 
EULAR Standing Committee for Clinical Affairs 
EULAR 
European League Against Rheumatism 
HDL cholesterol 
High-density lipoprotein cholesterol 
LDL cholesterol 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
SCORE 
Systematic Coronary Risk Evaluation 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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1 Changes to the observational plan 
 
1.1 
Introduction 
 
Introduction: AGIL-CV as a supplement to AGIL: 
 
Amendment I describes the collection and analysis of cardiovascular and metabolic 
risk parameters in patients with rheumatoid arthritis (RA) determined in the course of 
additional documentation to NIS AGIL. 
 
RA patients have increased cardiovascular morbidity and mortality as compared to the 
overall population. Furthermore, the majority of premature deaths in RA patients are 
attributable to cardiovascular disease (1), (2). RA patients show a higher 
cardiovascular risk, which can be put down to a higher prevalence of traditional risk 
factors (e.g. hypertension, dyslipidemia, smoking (3) as well as the underlying 
systemic inflammation, which play a key role in the development and progression of 
arteriosclerosis (4). Markers of inflammation are independent predictors of 
cardiovascular death (5). The systemic inflammation may even be the key process 
leading to myocardial infarction and premature death (6). RA is also associated with a 
pro-atherogenic lipid profile: Low HDL cholesterol levels are observed, which lead to 
an unfavorable cholesterol ratio (total cholesterol/HDL cholesterol) (7), (8). The 
prevalence of cardiovascular disease in RA is increased to an extent that is 
comparable to that of type 2 diabetes (9). Accordingly, RA should be regarded as an 
independent cardiovascular risk factor, and regular cardiovascular risk screening and 
management is therefore needed (1). 
 
As TNF plays a significant role in the development of inflammatory processes, the 
inflammatory process of arteriosclerosis may be interrupted by inhibiting this 
cytokine. Studies show that early initiation of effective therapy is associated with a 
decreased cardiovascular risk (6), (10), (11). 
 
The Standing Committee for Clinical Affairs of the European League Against 
Rheumatism ([EULAR], ESCCA) thus issued evidence-based recommendations for 
cardiovascular risk management in patients with rheumatoid arthritis that stress the 
implication of adequate control of disease activity and annual examinations to assess 
the cardiovascular risk (1). 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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Rheumatologists implementing these recommendations in everyday practice can 
routinely record their RA patients' cardiovascular and metabolic risks using this 
documentation. 
 
1.2 
Rationale 
 
Rationale and considerations regarding objectives of AGIL-CV in addition to AGIL: 
 
This supplementary documentation serves to record cardiovascular and metabolic risk 
factors in RA patients prior to starting adalimumab treatment in a routine clinical 
setting. In addition, the course of these risk factors and the impact of the disease 
activity on this course are to be documented during the 60-month adalimumab 
treatment. 
 
1.3 
Research question 
 
Description of study aims AGIL-CV as a supplement to AGIL: 
 
The primary research questions of AGIL-CV are 
 
 To determine baseline changes in Months 12, 24 and 60 after starting 
adalimumab treatment with regard to the following primary cardiovascular and 
metabolic parameters: 
 
o Lab chemistry blood parameters for glucose and lipid metabolism 
 
o Vital signs 
 
o Body measurements 
 
 The comparison between DAS28 responders and DAS28 nonresponders in 
terms of the primary parameters "lab chemistry blood parameters for glucose 
and lipid metabolism" and "vital signs" 
 
 Determination of the time point and frequency of cardiovascular events in the 
course of the entire documentation 
The secondary research question addresses the investigation of the impact of the 
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personal data and familial medical history recorded at baseline on the previously 
specified cardiovascular and metabolic parameters. The Systematic Coronary Risk 
Evaluation (SCORE) risk model is applied to determine the individual risk and 
changes thereof over time. 
 
1.4 
Number of patients to be included in AGIL-CV 
 
Patient number required for the AGIL-CV research question in addition to AGIL 
 
At least N=300 RA patients are required for the study to evaluate the cardiovascular 
and metabolic changes. This number takes premature therapy discontinuation by 50% 
of patients up to Month 60 into account (see Section 1.9). 
 
1.5 
Physician's selection criteria AGIL-CL 
 
Additional selection criteria for the conduct of AGIL-CV: 
 
The data for additional documentation of cardiovascular and metabolic risk factors are 
collected at selected sites that determine the cardiovascular risk profile as a routine 
measure for monitoring RA patients. All of these sites participate in NIS AGIL. 
 
1.6 
Course of long-term AGIL-CV documentation 
 
Additional supplement of AGIL-CV: 
 
This non-interventional study (including Amendment I) is conducted as a single-
arm, multi-center, prospective cohort study. 
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Table 1 "Physician's overview" is supplemented by the following sub-table that shows 
the process of medical documentation for AGIL-CV. 
Table 1 
Physician's overview – collection of cardiovascular and metabolic 
risk factors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Month 60 or last visit 
2 Height is only determined at Month 0. 
3 Data are incorporated into the SCORE risk model. 
4 Glucose (serum or plasma), lipid profile (HDL cholesterol, LDL cholesterol, total cholesterol, 
triglycerides, CRP) 
Month 
0 
3 
6 
12 
24 
36 
48 
601 
Body measurements (weight, height, waist 
and hip circumference) 2 
X 
X 
X 
X 
X 
X 
X 
X 
Familial medical history (diabetes, 
obesity, 
premature 
cardiovascular 
disease) 
X 
Tobacco use 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol consumption 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 3 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation of cardiovascular 
events (myocardial infarction, stroke) 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory parameters (fasted) 3,4 
X 
X 
X 
X 
X 
X 
X 
X 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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1.7 
Description of study activities 
 
Description of data to be documented for AGIL-CV as a supplement to AGIL: 
 
Baseline examination (Month 0) to determine cardiovascular risk factors 
Body measurements 
Weight, height 
Waist and hip circumference (waist measured 5 cm above anterior superior iliac 
spine) 
Familial medical history 
Parents' medical history: Diabetes mellitus and obesity Premature 
cardiovascular disease in the family 
Tobacco and alcohol 
Tobacco use  
Alcohol consumption 
Vital signs 
Blood pressure (in a sitting position, after 3-minute rest period) 
Pulse (in a sitting position, after 3-minute rest period) 
Laboratory parameters 
Glucose after fasting (serum or plasma) 
Lipid profile after fasting (HDL cholesterol, LDL cholesterol, total cholesterol, 
triglycerides) 
CRP 
Documentation of cardiovascular events 
Myocardial infarction 
Stroke 
 
Examinations over the course of the study (Month 3, 6, 12, 24, 36, 48, 60) to 
determine cardiovascular risk factors 
Body measurements (except height)  
Vital signs  
Laboratory parameters  
Tobacco use 
Documentation of cardiovascular events 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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1.8 
Calculation of CV risk model 
 
In addition to the documentation tools described in AGIL: 
 
SCORE (Systematic Coronary Risk Evaluation): The SCORE risk model is 
routinely used in European clinical practice to manage cardiovascular diseases. It 
permits a direct estimate of the absolute ten-year risk of fatal cardiovascular disease 
events. This ten-year risk calculation is based on the conditional probability of 
cardiovascular mortality within the next ten years, provided that the patient survives 
up to the index age (13). 
 
The estimate is based on the absolute cardiovascular disease risk rather than just on 
the risk of coronary heart disease. The following parameters are used to calculate the 
score: 
 
 Age 
 
 Sex 
 
 Currently smoker/non-smoker 
 
 Systolic/diastolic blood pressure (in a sitting position, after 3-minute rest period) 
 
 Cholesterol ratio (total cholesterol/HDL cholesterol) 
 
The overall risk of fatal cardiovascular disease is calculated by combining two 
different risk estimates: 
 
 Coronary heart disease 
 
 Non-coronary atherosclerotic vascular disease 
 
This calculation determines a probability score of fatal cardiovascular disease within 
the next ten years ranging from "< 1%" to "15% and over". 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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Risk models are to be modified for RA patients by applying a multiplication factor of 
1.5 if a patient meets at least two of the following three criteria (1): 
 
 Disease duration of over ten years 
 
 Positive RF or positive anti-CCP antibody result 
 
 Presence of certain extra-articular manifestations 
 
 
1.9 
Sample size estimation 
 
Sample size estimation for AGIL-CV as a supplement to AGIL: 
 
The sample size estimation is based on published data concerning the blood pressure 
of RA patients (14): 
 
Assuming an alpha and beta error of 5% each, the following minimum number of RA 
patients is required at the evaluation time points of Months 12, 24 and 60: 
 
 N=128 patients are required in order to detect a mean systolic blood pressure 
difference of 10 mmHg (given a mean systolic blood pressure of 128 mmHg 
with a standard deviation of 18 mmHg). 
 
 N=136 patients are required in order to detect a mean diastolic blood pressure 
difference of 5 mmHg (given a mean diastolic blood pressure of 74 mmHg 
with a standard deviation of 11 mmHg). 
 
In documentations with adalimumab, premature discontinuation has been observed 
for approx. 50% of patients in the course of a 60-month documentation duration. If 
this rate is taken into account; an overall number of N=300 patients is sufficient to 
address the primary research questions given the above-named estimations. 
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Amendment I (dated 06-Mar-2012) of the observational plan AGIL GER 08-05 (17-May-2010) 
 
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1.10 Biometrics concept of AGIL-CV 
 
Biometrics concept as an addition to AGIL-CV: 
 
Using stepwise regression analyses with forward and backward techniques, all partial 
correlations between the primary parameters and the other disease and patient 
characteristics are determined at baseline. The impact of disease and patient 
characteristics on the changes in each of the primary parameters is established by 
means of these regression analyses at Months 12, 24 and 60. In particular, the DAS28 
response (defined as the critical difference [dcrit] of ≤ -1.8 points, constituting an 
improvement of 1.8 points in DAS28) or DAS28 nonresponse was used as a coded 
variable. 
 
In addition, the observed difference between the DAS28 responders (patients with a 
dcrit of ≤ -1.8 at 5 of 7 visits) and the DAS28 nonresponders (dcrit > -1.8) is tested 
using the general linear model. Missing data are replaced using the Last observation 
carried forward (LOCF) method. 
 
1.11 Time points of statistical analysis 
 
Analysis time point of AGIL-CV as a supplement to AGIL: 
 
Statistical analyses for the primary research questions are planned for Months 12, 24 
and 60. For the secondary research questions, previous cardiovascular results are 
taken into account at these analysis time points. 
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1.12 References 
 
The following references are to be added to the list: 
 
(1) Peters, M.J.L., Symmons, D.P.M, Mcarey, D., et al. (2010). EULAR evidence-
based recommendations for cardiovascular risk management in patients with 
rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis; 
69(2), 325-331. 
(2) Del Rincon, I.D., Williams, K., Stern, M.P., et al. (2001). High incidence of 
cardiovascular events in a rheumatoid arthritis cohort not explained by 
traditional cardiac risk factors. Arthritis Rheum; 44(12), 2737-2745. 
(3) Han, C., Robinson, D.W.J., Hackett, M.V., et al. (2006). Cardiovascular 
disease and risk factors in patients with rheumatoid arthritis, psoriatic 
arthritis, and ankylosing spondylitis. J Rheumatol; 63(11), 2167-2172. 
(4) Ross, R. (1999). Atherosclerosis-an inflammatory disease. N Engl J Med; 
340(2), 115-126. 
(5) Maradit-Kremers, H., Nicola, P.J., Crowson, C.S., et al. (2005). 
Cardiovascular death in rheumatoid arthritis: a popular-based study. Arthritis 
Rheum; 52(3), 722-732. 
(6) Dixon, W.G., Watson, K.D., Lunt, M., et al (2007). Reduction in the incidence 
of myocardial infarction in patients with rheumatoid arthritis who respond to 
anti-tumor necrosis factor-alpha therapy: results from the British Society for 
Rheumatology Biologics Register. Arthritis Rheum; 56(9), 2905-2912. 
(7) Park, Y.B., Lee, S.K., Lee, W.K., (1999). Lipid profiles in untreated patients 
with rheumatoid arthritis. J Rheumatol; 26(8), 1701-1704. 
(8) Vis, M., Nurmohamed, M. T., Wolbink, G., et al (2005). Short term effects of 
infliximab on the lipid profile in patients with rheumatoid arthritis. J 
Rheumatol; 32(2), 252-255. 
(9) Van Halm, V.P., Peters M.J., Voskuyl, A.E., et al. (2009). Rheumatoid 
arthritis versus type 2 diabetes as a risk factor for cardiovascular disease: a 
cross- sectional study. Ann Rheum Dis; 68(9), 1395-1400. 
(10) Popa, C., Netea, M.G., Radstake, T. et al. (2005). Influence of anti-tumor 
necrosis factor therapy on cardiovascular risk factors in patients with active 
rheumatoid arthritis. Ann Rheum Dis; 64(2), 303-305. 
(11) Jacobsson, L.T., Turesson, C., Gulfe, A., et al. (2005). Treatment with tumor 
necrosis factor blockers is associated with a lower incidence of first 
cardiovascular events in patients with rheumatoid arthritis. J Rheumatol; 32(7), 
1213- 1218. 
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(12) Naranjo, A., Sokka, T., Descalzo, M.A., et al. (2008). Cardiovascular disease 
in patients with rheumatoid arthritis. Results from the QUEST-RA study. Arth 
Res Ther; 10(2), R30. 
(13) Conroy, R.M., Pyorala, K., Fitzgerald, A.P, et al. (2003). Estimation of ten-
year risk of fatal cardiovascular disease in Europe. The SCORE project. EIR 
Heart J; 24(11), 987-2003. 
(14) Mok CC, Ko GT, Ho LY, et al. (2011). Prevalence of atherosclerotic risk 
factors and the metabolic syndrome in patients with chronic inflammatory 
arthritis. Arthritis Care Res (Hoboken). Feb;63(2):195-202. 
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