A PROSPECTIVE, MULTICENTER NON-INTERVENTIONAL STUDY TO EVALUATE THE EFFICACY OF ENBREL (REGISTERED) (ETANERCEPT) OVER A PERIOD OF 12 MONTHS IN THE ROUTINE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS, AXIAL SPONDYLOARTHRITIS, PSORIATIC ARTHRITIS, OR PLAQUE PSORIASIS WITH PARTICULAR FOCUS ON THE CLINICAL STATUS IMPROVEMENTS STILL OBSERVABLE AFTER 12 WEEKS OF TREATMENT
Conditions: Rheumatoid Arthritis, Psoriatic Arthritis, Axial Spondyloarthritis, Plaque Psoriasis
Sponsor: Pfizer

Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
 
Title 
- ADEQUATE STUDY - 
A prospective, multicenter non-
interventional study to evaluate the efficacy 
of Enbrel® (etanercept) over a period of 12 
months in the routine treatment of patients 
with rheumatoid arthritis, axial 
spondyloarthritis, psoriatic arthritis, or 
plaque psoriasis with particular focus on the 
clinical status improvements still observable 
after 12 weeks of treatment. 
Study number: 
B1801385 
Version: 
 Final 1.3 
Date: 
 30.01.2015 
Name of active substance: 
Enbrel® (etanercept) 
Scientific question and goals 
The goal of this non-interventional study is 
to evaluate the efficacy of etanercept during 
routine clinical use over a maximum of 12 
months in patients with rheumatoid arthritis, 
psoriatic arthritis, axial spondyloarthritis, or 
plaque psoriasis. In so doing, particular 
attention will be paid to the proportion of 
those patients who only attain the desired 
treatment goal after 12 weeks of treatment. 
The primary efficacy end point for the study 
is the proportion of patients who attain the 
desired treatment goal after 12 and 24 
weeks, whereby data collection tools 
including DAS28, PASI, PGA, and ASDAS 
will be used to define the indication-specific 
treatment goal in accordance with the 
currently valid national/international 
treatment guidelines and -recommendations. 
The secondary efficacy end points for the 
study include not only objective measures of 
disease activity but also patient-reported 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
information regarding function. 
Safety and tolerability of the treatment are 
recorded based on the documentation of 
adverse events and the reasons for premature 
ending of treatment. 
Author 
Dr. 
 
Pfizer Pharma GmbH 
Linkstr. 10 
10785 Berlin 
 
 
 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................... 3 
1. LIST OF ABBREVIATIONS ............................................................................................ 5 
2. RESPONSIBILITIES ........................................................................................................ 7 
3. ABSTRACT ...................................................................................................................... 7 
4. AMENDMENTS AND UPDATES ................................................................................... 7 
5. MILESTONES .................................................................................................................. 7 
6. RATIONALE AND BACKGROUND INFORMATION................................................... 8 
6.1. Background information ........................................................................................ 8 
6.2. Study rationale ...................................................................................................... 8 
7. SCIENTIFIC QUESTION AND GOALS ........................................................................ 10 
8. STUDY METHODS ....................................................................................................... 10 
8.1. Study design ........................................................................................................ 10 
8.1.1. Design and study procedures ................................................................... 10 
8.1.2. Primary study end points ......................................................................... 12 
8.1.3. Secondary end points at weeks 12, 24, 36, and 52 .................................... 12 
8.2. Study setting........................................................................................................ 13 
8.2.1. Study conduct ......................................................................................... 13 
8.2.2. Inclusion criteria ..................................................................................... 14 
8.2.3. Exclusion criteria .................................................................................... 14 
8.3. Variable description ............................................................................................ 14 
8.4. Source documents ............................................................................................... 16 
8.5. Calculation of case numbers ................................................................................ 16 
8.6. Data management ................................................................................................ 17 
8.7. Data analysis ....................................................................................................... 17 
8.8. Quality control .................................................................................................... 17 
8.9. Strengths and limitations of the study methodology used ..................................... 18 
8.10. Other aspects ..................................................................................................... 18 
9. PROTECTION OF STUDY PARTICIPANTS ................................................................ 18 
9.1. Patient information and informed consent form ................................................... 18 
9.2. Ending the participation of a patient .................................................................... 19 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
9.3 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ....... 19 
9.4 
Ethical study conduct ................................................................................... 19 
10. MANAGEMENT AND REPORTS FROM ADVERSE EVENTS/ADVERSE 
DRUG REACTIONS ...................................................................................................... 20 
10.1. Summary of product characteristics ................................................................... 20 
10.2. Requirements .................................................................................................... 20 
10.3. Reporting period ................................................................................................ 21 
10.4. Causality assessment ......................................................................................... 21 
10.5. Definition of safety-relevant events ................................................................... 22 
10.5.1. Adverse events ...................................................................................... 22 
10.5.2. Serious adverse events ........................................................................... 23 
10.5.3. Scenarios which must be reported to Pfizer Pharmacovigilance 
within 24 hours ............................................................................................ 25 
10.6. Requirements for the reporting of claims and complaints for medical 
devices .................................................................................................................. 29 
11. COMMUNICATION AND PUBLICATION OF RESULTS ......................................... 29 
11.1. Publication plan ................................................................................................. 29 
11.2. Communication of safety problems ................................................................... 29 
12. REFERENCES .............................................................................................................. 31 
13. LIST OF TABLES ........................................................................................................ 32 
14. LIST OF IMAGES ........................................................................................................ 32 
ANNEX 1. LIST OF STANDALONE STUDY DOCUMENTS .......................................... 32 
ANNEX 2. ADDITIONAL INFORMATION ...................................................................... 32 
 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AMG 
Arzneimittelgesetz [German Drug Act] 
ASDAS  
Ankylosing Spondylitis Disease Activity Score 
AXSPA 
Axial spondyloarthritis  
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BSA 
Body Surface Area  
ESR 
Erythrocyte sedimentation rate 
CDAI 
Clinical Disease Activity Index 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DAS 
Disease Activity Score 
DLQI 
Dermatology Life Quality Index 
DSU 
Drug Safety Unit 
DVP 
Data Validation Plan 
EIU 
Exposure in Utero 
ETN 
Etanercept 
EULAR 
European League Against Rheumatism 
FDAAA 
Food and Drug Administration Amendments Act 
FFbH 
Hannover Functional Questionnaire 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practice 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and Outcomes Research 
LDAS 
Low Disease Activity Score 
LSLV 
Last Subject Last Visit 
MDA 
Minimal Disease Activity 
MTX 
Methotrexate 
PASI 
Psoriasis Area and Severity Index 
PCD 
Primary Completion Date 
PhRMA 
Pharmaceutical Research and Manufacturers of America 
PRO 
Patient-Reported Outcome(s) 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
PsA 
Psoriatic Arthritis 
PSARC 
Psoriatic Arthritis Response Criteria 
PsO 
Plaque Psoriasis 
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
SAP 
Statistical Analysis Plan 
SDAI 
Simple Disease Activity Index 
SAE 
Serious Adverse Event 
AE 
Adverse Event 
VAS 
Visual Analog Scale 
 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
2. RESPONSIBILITIES 
Scientific Director 
Name 
Title 
Office 
Address 
Dr. 
 
Study 
 
Pfizer Pharma GmbH 
Linkstrasse 10; 
10785 Berlin 
Dr.
 
Scientific 
 
Center for Innovative 
Diagnostics and Treatment 
- Rheumatology/ 
Immunology 
at the Goethe University 
Hospital, Frankfurt 
 
 Frankfurt am Main 
PD Dr. 
 
Scientific 
 Charite – Berlin 
University Medical Center 
 Berlin 
Dr. 
 
Scientific 
 Ruhrgebiet Rheumatology 
Center 
 
 Herne 
Prof. Dr. 
 
Scientific 
 
Schleswig-Holstein 
University Hospital, 
Lübeck Campus 
 
 Lübeck 
 
3. ABSTRACT 
An abstract is not required. 
 
4. AMENDMENTS AND UPDATES 
Currently not applicable. 
 
5. MILESTONES 
Milestone 
Planned date 
Start of data collection 
01. February 2015 
End of data collection 
31. July 2017 
Final study report 
30. June 2018 
 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
6. RATIONALE AND BACKGROUND INFORMATION 
6.1. Background information 
For patients with rheumatic diseases, attaining remission or at least low disease activity and 
close monitoring result in more favorable statuses which are visible in radiology findings and 
functionally measurable [1-3]. If remission cannot be attained, at least a low level of disease 
activity should be achieved, as is often the case especially with a long-persisting disease. The 
German treatment guidelines for rheumatoid arthritis indicate that the desired treatment goal 
should be attained after 3 months and in any case after no more than 6 months [4]. The same 
approach also applies accordingly for other indications. 
For psoriatic arthritis (PsA), criteria according to PSARC and the extent of body surface area 
(BSA) affected are also used to assess disease activity in patients with PsA [5]. For axial 
spondyloarthritis (axSpA), the most proven parameters for the assessment of disease activity 
are ASDAS or BASDAI [6]. The assessment of disease activity in plaque psoriasis (PsO) is 
usually performed using PASI, BSA, and DLQI [7, 8]. 
The COMET study has shown that RA patients who start treatment with etanercept early on 
are more likely to attain clinical remission. In this study, the DAS remission criteria were 
attained after 24 weeks by 50 % of the patients, which constituted a further 40 % increase 
versus the status attained at week 12. After 52 weeks, 57 % of the patients had attained the 
remission criteria [9]. 
In the PRISTINE study, Strohal was able to show that 37.2 % of the patients with PsO who 
were treated once weekly had attained a PASI75 after 12 weeks (62.4 % when treated with 
50 mg twice weekly). The number of patients who attained a PASI75 increased to 59.9 % 
after 24 weeks (78.2 % when treated with 50 mg twice weekly) [10]. 
These studies show clearly that it may be worth continuing treatment with etanercept beyond 
12 weeks even if the criterion for low disease activity has not yet been attained. 
6.2. Study rationale 
Approx. 20 - 30 % of patients end their treatment with etanercept during the first year of 
treatment, whereby the discontinuation of treatment is due to a lack of efficacy or side 
effects. The German and also the EULAR guidelines for the treatment of RA recommend a 
change of treatment after 3 and at most after 6 months if the criterion for low disease activity 
has not been attained [4, 11, 12]. The treatment guidelines for the other indications for which 
etanercept is approved are similar. 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
Clinical studies in the indications of RA, axSpA, PsA, and PsO show that it may be worth 
continuing treatment beyond a period of 12 weeks even if the criterion for low disease 
activity has not yet been attained, because the number of patients who only attain this 
criterion beyond the 12 weeks is increasing. 
In routine care, according to national and EULAR guidelines, the medical assessment of the 
treating rheumatologist or dermatologist and other criteria should be taken into consideration 
in addition to the purely numerical assessment of treatment goals. Therefore, the assessment 
as to whether the treatment goals were ultimately attained depends in everyday clinical 
practice not only on the numerical results from the DAS, ASDAS (or PSARC) or PASI tools, 
but also on the overall evaluation of the physician and the patient, as well as on the treatment 
outcomes reported by the patient (“patient reported outcomes,” PRO), treatment satisfaction, 
and other social and functional factors. 
In summary, it is therefore the primary goal of this study to check how many patients in 
everyday clinical practice benefit from the continuation of treatment with etanercept beyond 
12 weeks, even if the defined treatment goal has not yet formally been attained at that time 
but treatment is continued based on the judgment of the prescribing physician and the patient. 
In so doing, this rate is to be compared across the different indications. The variables which 
also reflect compliance with the treatment guidelines by physicians are to be examined in 
terms of additional influencing factors such as disease duration, concomitant medications, or 
PROs.  
Early treatment with biologics is recommended for all indications in order to attain improved 
quality of life and patient function and to exert a favorable effect on comorbidities, e.g. 
cardiovascular diseases. It is not yet known whether the burden of disease is comparable in 
the different indications at the start of treatment with etanercept. Here, a better understanding 
of these relationships could help doctors to determine the optimal time point for the start of 
treatment with etanercept. 
In this study, the variables are examined in a joint study setting (as far as is currently known, 
for the first time), which permits these variables to be compared directly across the different 
indications. Even though the treatment goals and the extent of disease activity in the different 
indications are determined based on different tools, it will still be possible to measure and 
compare PROs in particular, such as global assessment, pain, fatigue, mental health and - at 
least for the rheumatological indications - FFbH (comparable with the HAQ) and morning 
stiffness, regardless of the indication. The overall physician’s assessment will also be 
measured in all indications and compared between the individual indications. 
In addition to findings regarding relevance to practice and the reality of care according to 
treatment guidelines and recommendations, patient compliance with the treatment plan will 
be scientifically studied in detail. 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
The goal of Pfizer’s own “TOGETHER” program is to improve patient treatment compliance 
with training measures. This study is to investigate the extent to which participation in the 
“TOGETHER” program influences treatment compliance. 
7. SCIENTIFIC QUESTION AND GOALS 
The primary goal of this study is to determine how many patients treated under everyday 
conditions benefit from the continuation of treatment with etanercept beyond 12 weeks even 
if the desired treatment goal (see Table 2) has not yet been attained at that time point, as well 
as to compare these rates across the different indications. For this purpose, the following 
questions are to be answered based on a reliable data body collected during clinical routine: 
• Proportion of patients who have not attained defined treatment goals for each 
respective indication after 12 weeks, but do attain these between weeks 12 and 24.  
• Proportion of patients who have attained the desired treatment goal after 12 weeks, 
• Proportion of patients who continue treatment up to week 52 in the different 
indications, 
• Comparison of PRO results across indications, 
• How is the decision made in everyday clinical practice whether treatment with 
etanercept is continued or discontinued (i.e. which other parameters are taken into 
consideration, for example PRO or physician’s global assessment), 
• At what time point is the decision made to switch treatment (i.e. after 3 or 6 months, or 
even later), 
• Are there predictive factors for the continuation of treatment with etanercept, 
• What factors may influence treatment compliance (e.g. participation of the patients in a 
compliance program). 
 
8. STUDY METHODS 
8.1. Study design 
8.1.1. Design and study procedures 
This study is a prospective, multicenter, non-interventional study to evaluate the efficacy of 
etanercept in patients with RA, PsA, axSpA or PsO. 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
Efficacy data will be documented within a period of 12 months and health outcomes every 
quarter in the course of routine treatment. An overview of the documentation to be performed 
can be found in Table 1 below. 
Table 1: 
Overview of study procedures  
 
Visit 1 
Week 0 
Visit 2 
Week 12 
Visit 3 
Week 24 
Visit 4 
Week 36 
Visit 5 
Week 52 
  
 
 
 
 
 
Medical history 
X 
 
 
 
 
Inflammation in MRI 
(axSpA) 
X 
 
 
 
 
Radiological Sacroiliitis 
(axSpA) 
X 
 
 
 
 
Participation in the 
“Together” program 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Treatment/medications 
 
 
 
 
 
Prior treatment 
X 
 
 
 
 
Treatment with Enbrel 
X 
X 
X 
X 
X 
Concomitant treatment 
 
X 
X 
X 
X 
Safety parameters 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
Laboratory 
X 
X 
X 
X 
X 
AE documentation 
 
X 
X 
X 
X 
Efficacy 
 
 
 
 
 
Examination of joints 
X 
X 
X 
X 
X 
PASI (PsO) 
X 
X 
X 
X 
X 
Morning stiffness (RA, 
axSpA, PsA) 
X 
X 
X 
X 
X 
Patient and physician global 
assessment 
X 
X 
X 
X 
X 
Pain 
X 
X 
X 
X 
X 
Fatigue  
X 
X 
X 
X 
X 
Occiput-to-wall distance 
(axSpA) 
X 
X 
X 
X 
X 
Dactylitis (PsA) 
X 
X 
X 
X 
X 
Nail involvement (PsO, PsA) 
X 
X 
X 
X 
X 
Enthesitis (PsA, axSpA) 
X 
X 
X 
X 
X 
Pruritus (PsO) 
X 
X 
X 
X 
X 
Health outcomes 
 
 
 
 
 
FFbH (RA, axSpA, PsA) 
X 
X 
X 
X 
X 
BASDAI (axSpA) 
X 
X 
X 
X 
X 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
DLQI (PsO) 
X 
X 
X 
X 
X 
PHQ-2 
X 
X 
X 
X 
X 
 
8.1.2. Primary study end points 
- 
Patients with RA: Proportion of patients who attain the desired treatment goals (see 
Table 2) at the week 12 and week 24 time points under monotherapy or in combination 
with MTX and maintain these long-term over a period of 52 weeks. 
- 
Other indications: Proportion of patients who attain the desired treatment goals 
according to guidelines (see Table 2) in each respective indication at the week 12 and 
week 24 time points. 
8.1.3. Secondary end points at weeks 12, 24, 36, and 52 
All patients: 
- 
Proportion of patients who continue treatment with etanercept, 
- 
Occurrence of adverse events, 
- 
Remission, 
- 
Patient global assessment, 
- 
Fatigue, 
- 
Pain (VAS), 
- 
Physician global assessment, 
- 
PHQ-2 
- 
Comparison of the parameters “patient global assessment,” “fatigue,” “pain,” 
“physician global assessment,” and “ PHQ-2 across all indications, 
- 
Comparison of FFbH and morning stiffness among patients with RA, axSpA, and PsA, 
- 
Discontinuation of treatment due to a lack of efficacy or adverse events, 
- 
Nature of further treatment if treatment has been discontinued, 
 
Additionally for RA patients: 
- 
FFbH 
- 
CDAI 
- 
SDAI 
Additionally for axSpA patients: 
- 
BASDAI, 
- 
FFbH 
- 
Enthesitis 
- 
Occiput-to-wall distance 
Additionally for PsA patients: 
- 
BSA 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
- 
Dactylitis 
- 
Enthesitis 
- 
FFbH 
Additionally for PsO patients: 
- 
PASI, median time to PASI75, body segment (head, trunk, upper and lower 
extremities) and component-related subscales (erythema, induration, flaking) over 
24 weeks, 
- 
DLQI, 
- 
Pruritus 
- 
BSA. 
The following indication-related laboratory tests will be documented if they are available as 
part of a routine assessment: 
- 
Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) 
 
 
In addition, the following laboratory tests will be documented for patients with RA, PsA, 
and axSpA if they are available as part of a routine assessment: 
 
- 
Rheumatoid factor (RF) and anti-CCP antibodies. 
- 
HLA-B27 at Visit 1 (just axSpA). 
 
8.2. Study setting 
8.2.1. Study conduct 
The planned recruitment period is 18 months. With a planned observation duration of 12 
months per patient, the entire study would thus last for 30 months. The study is to start in 
Q1/2015 and will be ended in Q3/2017. In all, about 2100 patients in 300 centers are to be 
included in this non-interventional study, of whom about 1200 will have a diagnosis of RA 
and about 300 each will have a diagnosis of axSpA, PsA, and PsO. 
After regular initiation on treatment with etanercept, patients will be documented for a period 
of up to 12 months. In accordance with section 67, paragraph 6 of the AMG, notice of the 
conduct of the study will be made to the National Association of Statutory Health Insurance 
Physicians, the Central Federal Association of Health Insurance Funds, and the competent 
central federal authority. Logistics, database creation, data input, and evaluation and 
reporting will be performed by a CRO Winicker Norimed. 
Due to the high number of participating centers and patients throughout Germany, it is 
expected that the results from the study will have a representative nature. Another advantage 
of the study design lies in the fact that the 4 different indications will be examined within one 
study setting, which should improve the comparability of the study results across indications. 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
8.2.2. Inclusion criteria 
Patient eligibility should be checked and documented by the treating physician before 
patients are included in the study. The decision to commence treatment with etanercept shall 
be made in advance and independently of any participation in this study. 
Proof of a personally signed and dated informed consent form stating that the patient (or 
legal representative, if applicable) has been informed of all concrete aspects of the study is a 
prerequisite for inclusion in this study. 
Patients eligible for documentation must meet the following criteria,: 
1. Confirmed diagnosis of RA, axSpA, PsA or PsO, 
2. No prior treatment with etanercept and eligibility for treatment with etanercept according 
to the summary of product characteristics, 
3. Patient age >18 years, 
8.2.3. Exclusion criteria 
The contraindications, special warnings, and precautions according to the summary of 
product characteristics for etanercept shall apply. The additional documentation of the patient 
in another post-marketing study with etanercept is not permitted. 
8.3. Variable description 
The primary and secondary end points are listed in section 8.1.2 and section 8.1.3. 
All of the indication-specific efficacy measures used in this study, such as DAS28, BASDAI 
or PASI, are clearly defined and meet the current international scientific standard. The 
definitions for “desired treatment goals” in the individual indications were based on 
recommendations, including from national and international treatment guidelines. An 
overview of these recommendations can be found in Table 2 below. 
 
 
 
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Etanercept 
 OBSERVATIONAL PROTOCOL FOR A NON-INTERVENTIONAL DRUG STUDY 
Final   1.3 (30. January 2015) 
 
Table 2: 
Overview of desired treatment goals and minimum efficacy criteria in the 
different approved etanercept indications, based on the current latest 
treatment guidelines  
Indication 
Desired treatment 
goal 
Minimum 
efficacy 
Source 
PsO 
• PASI75 
or  
• PGA (“clear” or 
“almost clear”) 
and 
• DLQI 0 or 1 
• PASI50 
and 
• DLQI <5 or 
improvement of at 
least 5 points 
S3 Guidelines for the 
systemic treatment of PsO 
[7, 8] 
RA 
• DAS28 <2.6 
• DAS28 ≤3.2 
or  
• Physician assessment, 
e.g. based on 
radiology findings 
S1 Guidelines of the DGRh 
[4] 
axSpA 
• ASDAS <1.3 
 
• BASDAI: 50% 
relative difference or 
absolute difference of 
2 points (scale from 
0 -10) 
and 
• Expert opinion on 
continuation: yes/no  
Kiltz et al. 2014 [13] 
PsA 
• DAS28 <2.6 
or  
• MDA criteria 
met a 
• DAS28 ≤3.2 
or  
• Physician assessment, 
e.g. based on 
radiology findings 
a) Mease 2011 [5] 
 
Selected parameters, such as remission, low disease activity, or continuation of treatment, 
will be analyzed for potential influencing variables (e.g. duration of disease, clinical 
outcomes, PRO). 
Detailed information on the calculation of variables and on data evaluation in general will be 
set forth in a separate statistical analysis plan (SAP) before the start of the evaluation. 
 
 
 
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Etanercept 
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8.4. Source documents 
The data will be recorded using a case report form (CRF) for each patient included. The CRF 
contains the queries and questionnaires required for all four indications; the indication-
specific queries and questionnaires are to be completed for each indication and must be 
handed out to the patients. The completed original CRFs are the sole property of Pfizer and 
must not be provided to third parties in any format without the written approval of Pfizer, 
with the exception of authorized representatives of Pfizer or the appropriate competent 
authorities. 
The treating physician is ultimately responsible for the collection and reporting of all clinical 
data, safety and laboratory data entered on the CRFs and other forms for data collection 
(source documents) and must guarantee that they are accurate, authentic/original, traceable, 
complete, consistent, legible, timely (contemporaneous), permanent, and available as 
required. The CRFs must be signed by the treating physician or authorized personnel. All 
corrections of entries on the CRFs and source documents must be dated, signed off, and 
explained (if required) and must not obscure the original entry. 
In most cases, the source documents are patient records in the hospital or at the doctor’s 
office. In these cases, the data collected on the CRFs must match the data in these records.  
In some cases, the CRF or part of the CRF can also serve as a source document. In these 
cases, a document must be available at the doctor’s study site and at Pfizer and must clearly 
identify the data recorded in the CRF and for which the CRF is considered a source 
document. 
The clinical parameters recorded, especially those used to assess efficacy, are usual, known 
and recognized variables within each respective indication. All questionnaires used in the 
study have been validated. 
8.5. Calculation of case numbers 
It is assumed that the RA patients included in this study who are receiving a combined 
treatment (ETN + MTX) will be similar to those patients included in the randomized, double-
blind DOSERA study in terms of the proportion of patients continuing treatment beyond 
week 12 (i.e. adequate efficacy - defined based on the DAS28 and the patient and physician 
global assessment of disease progression - has been attained). In that study, 22 - 26 % of the 
patients on combined treatment had attained no adequate efficacy after 12 weeks and 
continued treatment with etanercept (open-label), while conversely, adequate efficacy from 
treatment had been attained for 74 - 78 % of the patients at week 12. The sample size for this 
non-interventional study was calculated with the primary focus on the indication of RA. 
 
 
 
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Assuming that 74% of the patients under treatment with ETN + MTX and 66% of the 
patients under ETN monotherapy exhibit adequate response to treatment after 12 weeks 
(odds ratio of 0.682), 1200 patients (with a 2:1 ratio, this equals 800 patients under combined 
treatment and 400 patients under monotherapy) will be sufficient to detect a significant 
difference in the primary end point “proportion of patients attaining the desired treatment 
goal” with a power of 80% using a two-sided test with a significance level of 5%. 
A logistic regression quoting the odds ratio and the corresponding 95% confidence interval is 
the appropriate statistical methodology for the analysis of this binary variable. As a 
sensitivity analysis, a GEE (generalized estimating equation) analysis can also be performed 
as a repeat method to obtain the binary response variable. 
Because the combination with MTX is not recommended for the indications axSpA, PsO, 
and PsA, the inclusion of 300 patients in each of these indications appears sufficient for 
analysis of efficacy and tolerability. 
8.6. Data management  
The completed CRFs will be sent by mail from the center to the CRO. Data will be entered at 
the CRO into an SAS-based database. All entries will be recorded in an audit trail file. 
8.7. Data analysis 
Absolute and relative adjusted frequencies are determined for categorical data. Numerical 
data are expressed using the sample statistics mean and standard deviation, as well as 
minimum, 1% percentile, 5% percentile, lower quartile, median, upper quartile, 95% 
percentile, 99% percentile and maximum. 
The primary end point “proportion of patients attaining the desired treatment goal” will be 
analyzed using a logistic regression for the subgroups “RA patients with ETN+MTX” and 
“RA patients with ETN monotherapy”. 
A detailed description of the statistical analysis of the data collected will be included in the 
SAP which will be dated, stored, and maintained by the sponsor. The SAP may modify the 
analyses described here. Every substantial amendment to the definition and analysis of the 
primary end point would take place in the form of a protocol amendment. 
8.8. Quality control 
Plausibility checks for the data entered will be defined in a data validation plan (DVP). As 
far as possible, these checks will be performed with software support and in the event of 
deviations, queries will be sent by the CRO to the centers. The sending and return of queries 
 
 
 
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will be tracked and if necessary, data changes will be performed in the database. All of the 
changes performed will be recorded in an audit trail file. 
Furthermore, there it is provisionally planned that 30 monitoring visits will be performed at 
randomly selected centers to ensure data quality and to verify the documented patient data. 
8.9. Strengths and limitations of the study methodology used 
An inherent disadvantage of a non-controlled observational study is the potential risk of 
selection bias. Furthermore, patients who have withdrawn prematurely from the study, whose 
missing observations are not usually replaced, may skew the time point results toward the 
end of the study. Also, no proof of efficacy is possible in the classical sense as the data from 
a randomized parallel group are not available as a control. 
However, these limitations are balanced by advantages associated with the methodology. For 
example, the design of an observational study usually permits the inclusion of a substantially 
larger number of patients that would be usual in randomized, controlled studies. Furthermore, 
in randomized clinical studies, only strictly selected patient groups are studied, which limits 
the applicability of these studies in terms of the patients who are ultimately treated in routine 
clinical practice. In the case of RA, it was shown based on evaluation of the German 
biologicals registry RABBIT that only 21 - 33% of the registry patients treated in routine 
clinical practice with TNF blockers would also have been eligible for participation in the 
pivotal randomized, controlled studies [14]. The patient groups selected from the clinical RA 
studies this reflect are only a small proportion of the patients who are routinely treated with 
biologicals in the postmarketing phase. As such, non-interventional observational studies, 
despite the limitations mentioned above, are capable of providing valuable supplemental 
information on the effects of a medication in everyday clinical practice. 
8.10. Other aspects 
Not applicable. 
9. PROTECTION OF STUDY PARTICIPANTS 
9.1. Patient information and informed consent form 
All parties guarantee the protection of the patient’s personal data and will not include the 
name of the patient in any forms from Pfizer, reports, publications or other disclosures unless 
required by law. In the event that data is forwarded, Pfizer will maintain high standards of 
confidentiality and the protection of the patients’ personal data. 
The informed consent form used in this study and all changes made in the course of the study 
must be approved in advance by Pfizer and submitted to the IRB/IEC for review before use. 
 
 
 
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The treating physician must guarantee that every study patient or her/his legal representative 
is informed fully of the characteristics and goals of the study and the potential risks 
associated with participation. The treating physician or a person assigned by her/him shall 
obtain a written informed consent form from every patient or patient’s legal representative 
before study-specific activity is performed. The treating physician shall keep the original of 
every informed consent form signed by the patient. 
9.2. Ending the participation of a patient 
The patient can withdraw her/his consent to participate in the non-interventional study at any 
time or the treating physician may decide to end the participation of the patient on grounds of 
safety, problems with compliance, or for administrative reasons. In any case, the patient’s 
clinical status should be documented if possible. The physician should ask the patient about 
the reasons for her/his decision and continue to track all unresolved adverse events. 
If the patient withdraws her/his consent for further data collection, data will no longer be 
recorded from her/him as part of the non-interventional study.  
9.3 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The observational protocol and the patient information and informed consent form will be 
submitted to the competent ethics committee for review before patients are included. 
9.4 Ethical study conduct 
This study is a multicenter, prospective, non-interventional study in accordance with section 
4, number (23), clause 3 of the AMG. Furthermore, the vfa recommendations for the 
improvement of quality and transparency in non-interventional studies apply, as do the 
guidelines of the “Good Pharmacoepidemiology Practices” (GPP), issued by the 
“International Society for Pharmacoepidemiology” (ISPE), the guidelines of the 
“International Society for Pharmacoeconomics and Outcomes Research” (ISPOR), and the 
guidelines of the “Pharmaceutical Research and Manufacturers of America” (PhRMA).  
The patient shall provide her/his written informed consent form for the study, which will 
have been submitted to the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for review beforehand. 
Based on the the vfa recommendations for the improvement of quality and transparency in 
non-interventional studies and in order to satisfy the requirement for publication of notice of 
NISs, this non-interventional study will be registered in a publicly accessible registry.  
 
 
 
 
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10. MANAGEMENT AND REPORTS FROM ADVERSE EVENTS/ADVERSE DRUG 
REACTIONS 
10.1. Summary of product characteristics 
Etanercept shall be used in accordance with the summary of product characteristics. The 
specified contraindications, warnings and precautions for use, undesirable effects, 
interactions, and information on posology and method of administration must be followed. 
All drug safety-relevant cases reported by the participating physician to the CRO contracted 
by Pfizer, Winicker Norimed, in the course of this non-interventional study will be evaluated 
based on the summary of product characteristics. 
10.2. Requirements 
The table below summarizes the requirements for the recording of safety-relevant events on 
the reporting form for adverse event monitoring (AEM) in non-interventional studies to 
Winicker Norimed. These requirements are described for three types of events: (1) serious 
adverse events (SAEs); (2) non-serious adverse events (if applicable) and (3) scenarios under 
which drug exposure occurs, including exposure during pregnancy, exposure during 
lactation, medication errors, overdose, misuse, extravasation, and job-related exposure. These 
events are defined in the section “Definitions of safety-relevant events”. 
safety-relevant event 
Notation in the case report form 
Reporting on the NIS-AE 
reporting form to  Winicker 
Norimed within 24 hours after 
discovery 
SAE 
All 
All 
Non-serious AE 
all  
 all 
Scenarios under which drug 
exposure occurs, including exposure 
during pregnancy, exposure during 
lactation, medication errors, 
overdose, misuse, extravasation, and 
job-related exposure. 
All  
All (regardless of whether they are 
associated with an AE) 
 
For each adverse event (AE) the physician must track and collect information suitable for 
determining the outcome of the adverse event and for assessing whether it meets the 
classification criteria for an SAE (see the section “Serious adverse events” which follows). 
Safety-relevant events from the above table must be reported by the physician to Winicker 
Normied  within 24 hours after s/he becomes aware of the event, regardless of whether s/he 
sees any causal relationship with the medication being studied. Especially when the 
serious 
 
 
 
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adverse event is fatal or life-threatening, the report to Winicker Normied  must be made 
immediately, regardless of the scope of information available about the event. 
These deadlines also apply for additional new information (follow-up) regarding reports of 
safety relevant events already submitted. 
In the rare case that the physician is not immediately aware of the occurrence of a safety-
relevant event, the physician must report the event within 24 hours after s/he becomes aware 
of it and must document the time at which s/he discovered the adverse event. 
For safety-relevant events categorized as serious or listed in the right-hand column of the 
above table, which must be reported to Winicker Normied  within 24 hours after they are 
discovered, the physician is obligated to track information and report it to  Winicker Normied 
within the 24-hour deadline. Furthermore, a physician may be asked by  Winicker Normied 
to expedite the collection of certain additional information. Such information may go beyond 
the scope and detail of the information about adverse events recorded in the case report form. 
Generally, this will involve the description of the adverse event in sufficient detail to permit a 
comprehensive medical evaluation of the case and independent determination of the possible 
causality. Also, all additional relevant information about the event, e.g. concomitant 
medications and illnesses, must be provided.  
If a patient dies, a summary of any available autopsy findings must be submitted to Winicker 
Normied  as soon as possible. 
10.3. Reporting period 
For each patient, the reporting period for reporting adverse  events starts with the time of first 
use or with the time of informed consent if he/she is already using etanercept. The reporting 
period will last until the end of the observation period for the study and at least 28 calendar 
days after the last administered dose of the medication being observed. All safety-relevant 
events from the above table occurring within this reporting period must be reported to 
Winicker Norimed and its authorized representative. 
In most cases, the date of informed consent is the same as the date of inclusion of the patient 
in the NIS. In some situations, there might be a time gap between the date of informed 
consent and the inclusion date. If in such cases a patient provides informed consent but is 
never included in the study (e.g. the patient changes her/his mind regarding participation, 
then the reporting period will end with the date of the decision not to include the patient.  
Serious adverse events occurring after the end of the non-interventional study (NIS) and the 
observation period must also be reported to DSU if the physician sees a causal relationship 
with etanercept.  
 
10.4. Causality assessment 
The physician must assess and document the causal relationship. For all AEs, the physician 
must collect sufficient information to determine the causality of each adverse event. For an 
AE with a causal relationship with etanercept, the physician must track this until the event 
 
 
 
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and/or its sequelae have resolved or have stabilized at an acceptable level for the physician 
and Pfizer agrees with this assessment.  
The physician’s causality assessment shall include determination whether there is a 
possibility that etanercept has caused the adverse event or contributed thereto. Even if the 
final causality assessment by the physician is “unknown” and the physician cannot determine 
whether the event was caused by etanercept, the safety-relevant event must be reported 
within 24 hours.  
If the physician is unable to identify the cause of the event but decides that etanercept has not 
caused the event, this fact must be documented clearly on the NIS AE reporting form. 
10.5. Definition of safety-relevant events 
10.5.1. Adverse events 
An adverse event (AE) is any adverse medical incident occurring with a patient who is using 
a medicinal product. The event does not necessarily have to be causally related to the 
treatment or use. The same definition applies for medical devices and nutritional supplements 
(including baby and children’s foods [hereinafter - pediatric preparations].  
Examples of adverse events include in particular but are not limited to:  
• Abnormal test findings (see below for circumstances in which an abnormal test finding 
counts as an adverse event) 
• Clinically relevant signs and symptoms 
• Changes in findings from physical examination 
• Hypersensitivity and allergic reactions 
• Lack of efficacy 
 
• Drug abuse  
 
• Drug dependency  
 
In addition, symptoms or findings may be included which are attributable to the following: 
 
• Overdose of a substance 
• Drug withdrawal  
• Misuse  
• Use outside the approved indication (off-label use) 
 
 
 
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• Drug interactions 
• Extravasation 
• Exposure in utero 
• Exposure during lactation 
• Medication error 
 
• Job-related exposure  
 
 
Abnormal test findings 
An abnormal objective test finding must be reported as an adverse event if:  
• the test finding is accompanied by symptoms and/or 
• the test finding requires further diagnostic tests or medical/surgical intervention and/or 
• the test finding results in a change to the dose of the medicinal product being observed or 
in the ending of the study for the study participant concerned, in substantial additional 
concomitant drug treatment, or in other treatment and/or 
• the test finding is categorized as an adverse event by the physician or sponsor. 
The mere repetition of an abnormal test for which none of the above conditions apply is not 
considered an adverse event. Abnormal test findings which are interpreted as erroneous do 
not need to be reported as adverse events. 
 
10.5.2. Serious adverse events 
 
A serious adverse event is any adverse medical incident after the administration of a 
medicinal product or nutritional supplement (including pediatric preparations) or after the use 
of a medical device which, regardless of the dose: 
 
• Results in death 
• Is life-threatening  
• Requires hospitalization of the patient or prolongation of hospitalization (see below for 
circumstances which do not count as an adverse event) 
• Results in permanent or substantial disability/loss of work capacity (substantial 
impairment of the ability to perform everyday activities)  
 
 
 
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• Results in a congenital deformity/birth defect. 
Furthermore, medically significant adverse events must be categorized as “serious”. It must 
be reviewed in accordance with medical and scientific discretion whether an event must be 
evaluated as medically significant. Events are medically significant if they are not 
necessarily immediately fatal or life-threatening or do not lead to hospitalization but may 
pose a substantial threat to the patient. Adverse events are also medically significant if they 
require intervention/treatment to prevent a condition which meets the criteria specified in the 
above definition for “serious adverse events”.  
Medically significant events must be reported like serious adverse events. 
Examples of such events are intensive treatment in an emergency room or at home due to 
allergic bronchospasm, blood diseases or seizures which do not result in hospitalization, or 
the development of drug dependency or -abuse. 
In addition, all suspected cases of the transmission of infectious germs (pathogenic and non-
pathogenic germs) by a Pfizer product must be categorized as serious. The suspicion of this 
event is suggested if clinical symptoms or laboratory findings are present which indicate an 
infection in a patient who was exposed to a Pfizer product. In these cases, the wording 
“suspected transmission” and “transmission” must be treated as synonymous. These cases are 
categorized by pharmacovigilance personnel as unexpected and processed as a “serious case 
requiring immediate reporting.” If applicable, these cases are additionally categorized as 
product defects. 
Hospitalization 
A hospitalization is defined as an inpatient admission (even if for fewer than 24 hours) to a 
hospital or equivalent healthcare institution or a prolongation of an existing hospital stay. 
Inpatient admission also includes transfer within a hospital to an acute/intensive care ward 
(e.g. from the psychiatric department to a general medicine department, from a general 
medicine department to a cardiac department, from a neurological department to a 
tuberculosis unit). An emergency room visit does not necessarily count as hospitalization. An 
event which results in a visit to the emergency room should however be assessed in terms of 
its medical significance 
A hospitalization without a medical adverse event is not in itself an adverse event and must 
not be reported. Examples include:  
• hospitalization due to a social indication (e.g. for homeless patients) 
• hospitalization for administrative reasons (e.g. for an annual examination) 
• Optional hospitalization which is not caused by an adverse event (e.g. for an elective 
cosmetic surgery) 
• hospitalization for observation without a medical adverse event 
 
 
 
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• hospitalization for the treatment of a pre-existing illness which is not related to a new 
adverse event or the worsening of a pre-existing illness (e.g. for the diagnostic 
investigation of pre-existing abnormal laboratory values) 
• Hospitalization required by the observational protocol during the study (e.g. for a 
procedure required in the observational protocol).  
 
10.5.3. Scenarios which must be reported to Winicker Norimed within 24 hours 
Below is an explanation for scenarios under which drug exposure occurs, including exposure 
 
 
 
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during pregnancy, exposure during lactation, medication errors, overdose, misuse, 
extravasation, and job-related exposure. 
Exposure in utero 
Exposure during pregnancy (also called exposure in utero [EIU]) occurs when: 
• a woman under treatment with or when in direct contact with etanercept (e.g. 
environmental exposure) becomes pregnant or is found to be pregnant under these 
circumstances, or the woman following the discontinuation or after direct contact with 
etanercept becomes pregnant or is found to be pregnant under these circumstances 
(maternal exposure). 
An example of environmental exposure would be a case in which a pregnant woman 
comes into direct contact with Pfizer product: a nurse reports that she is pregnant and has 
come into contact with a chemotherapy product. 
• a man had contact with etanercept due either to treatment or environmental exposure 
before or around the time of conception and/or during the pregnancy of his partner 
(paternal exposure) 
Generally, all cases of exposure identified prospectively and retrospectively during 
pregnancy must be reported, regardless of whether or not an adverse event has occurred. 
Such instances of exposure must be reported like serious adverse events. 
If a female study participant or partner of a study participant becomes or is pregnant during 
study treatment with etanercept, this information must be reported to Winicker Norimed 
using the NIS AE reporting form and the EDP supplemental form (EDP: Eng. exposure 
during pregnancy), regardless of whether an adverse event has occurred.  
In addition, all information regarding environmental exposure with etanercept involving a 
pregnant woman must be submitted using the NIS AE reporting form and the EDP 
supplemental form. This must occur regardless of whether or not an AE has occurred (e.g. a 
female study participant reports that she is pregnant and has had contact with a cytotoxic 
product by inhalation or spillage).  
The information submitted should include the expected delivery date (see information below 
on termination of pregnancy). 
Follow-up will be performed to obtain general information about the pregnancy. 
Furthermore, follow-up observation will take place to gather information about the outcome 
of the exposure during pregnancy (EDP) for all EDP reports for which the outcome of the 
 
 
 
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pregnancy is unknown. A pregnancy will be tracked to the end or termination of the 
pregnancy (e.g. induced abortion) and Winicker Norimed will be informed of the outcome. 
This information will be reported as a follow-up to the initial EDP report. In the event of a 
live birth, the external integrity of the neonate at the time of birth may be evaluated. In the 
event of a termination, the reason/s for the termination should be stated and, if clinically 
possible, the integrity of the fetus evaluated by cursory visual inspection (unless the test 
findings before the termination conclusively show a congenital anomaly and the findings are 
reported). 
If the outcome of the pregnancy meets the criteria for an SAE (e.g. ectopic pregnancy, 
spontaneous abortion, intrauterine fetal death, neonatal death, or congenital anomaly [in case 
of a live birth, aborted fetus, intrauterine fetal death, or neonatal death]) the procedure for 
reporting SAEs must be followed. 
Additional information on the pregnancy outcome reported as an SAE follow:  
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths occurring within 1 month of birth should be reported as SAEs 
regardless of causality. In addition, infant deaths occurring after the age of 1 month 
should be reported as SAEs if the physician identifies or presumes a connection 
between the infant death and exposure with the investigational product. 
Additional information regarding exposure in utero may be requested. Further tracking of the 
outcome of the birth will be handled on a case to case basis (e.g. tracking of premature 
infants to identify developmental delays).  
In the event of the father being exposed, the study participant will be given the form for the 
release of information about the pregnant partner for his partner. It must be documented that 
the study participant has received this letter for his partner. 
Exposure during lactation 
Scenarios for exposure during lactation must be reported regardless of the presence of an 
associated AE. A report regarding exposure during lactation shall not be prepared if a 
medication from Pfizer approved specifically for use in lactating women (e.g. vitamins) is 
being administered in accordance with the approved indication. However, if the infant 
experiences an AE associated with the administration of such a medication, the AE is 
reported together with the exposure during lactation. 
 
 
 
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Medication error 
A medication error is any accidental error with the prescription, dispensing, or administration 
of a product by healthcare professionals, patients, or users themselves, which may result in 
improper use or in injury to the patient. 
Such events may be related to medical/pharmaceutical practice, the healthcare products 
themselves and with processes or systems, such as with the prescription, ordering, product 
information and labeling, packaging, product name and product description (nomenclature), 
composition of the medication, dispensing, sales, administration, training, monitoring, and 
use. 
Medication errors include: 
• Near-errors, regardless of whether a patient was directly affected or not (e.g. 
accidental/improper use i.e. accidental use of the product outside the approved indications 
or prescription by a healthcare professional or the patient/user)  
• Confusion regarding the trade name (e.g. trade name, product name) 
The physician must report the following medication errors to Winicker Norimed, regardless 
of whether a corresponding (serious) adverse event occurs: 
• Medication errors with exposure of the patient to the drug, regardless of whether the 
medication error involves an AE or not 
• Medication errors (including potential medication errors or near-errors) in which no 
patient is directly involved. If a medication error does not include the exposure of a 
patient to the drug, the following minimum criteria shall apply for a medication error 
report: 
o Identifiable reporter 
o Suspected drug 
o Medication error 
Overdose, misuse, extravasation 
Reports regarding overdose, misuse, and extravasation associated with a Pfizer product shall 
be reported to Winicker Norimed by the physician regardless of whether they involve an 
AE/SAE.  
 
 
 
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Lack of efficacy 
Reports regarding a lack of efficacy from a Pfizer product shall be reported to Winicker 
Norimed by the physician regardless of whether they involve an AE/SAE and regardless of 
the indication for use of the Pfizer product. 
Job-related exposure 
Reports regarding job-related exposure with a Pfizer product shall be reported to Winicker 
Norimed by the physician regardless of whether they involve an AE/SAE. 
10.6. Requirements for the reporting of claims and complaints for medical devices 
All complaints for medical devices are documented on the corresponding pages of the CRF, 
regardless of whether they involve an adverse event. This includes potential near-incidents or 
the malfunction of a medical device if these are associated with the use of a medical device. 
A near incident or malfunction of the medical device is an event which could have resulted in 
death or severe health impairment or could result in death or severe health impairment should 
they recur. 
The physician must notify Winicker Norimed of all complaints regarding medical devices 
within 24 hours of becoming aware of them. 
 
11. COMMUNICATION AND PUBLICATION OF RESULTS 
11.1. Publication plan 
It is planned that 4 interim analyses will be performed and their results presented as an 
abstract at the appropriate national (DGRh) and international (EULAR, EADV, ACR) 
specialist conferences in 2015 and 2016. Formal interim reports are not envisaged. The final 
study results are then to be published in the 2nd half of 2017 in a German (Z Rheumatol) and 
2 international journals (ARD, JEADV). 
The final CSR is envisaged for  June 2018. 
11.2. Communication of safety problems 
In the event of an imposed ban or imposed restriction (e.g. suspension of the study) from any 
competent authority, or if the treating physician becomes aware of new information which 
could influence the risk/benefit assessment for a Pfizer product, Pfizer should be informed 
immediately. 
In addition, the treating physician will inform Pfizer of any measures s/he has taken to 
protect study patients from an immediate hazard to their health. S/he will also inform Pfizer 
 
 
 
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of all serious violations of the observational protocol for this non-interventional study of 
which s/he becomes aware. 
 
 
 
 
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12. REFERENCES 
1. 
Bakker MF, Jacobs JW, Welsing PM, Vreugdenhil SA, van Booma-Frankfort C, 
Linn-Rasker SP, et al. Early clinical response to treatment predicts 5-year outcome in 
RA patients: follow-up results from the CAMERA study. Annals of the rheumatic 
diseases [2011]; 70(6): 1099-103. 
2. 
Emery P, Breedveld F, van der Heijde D, Ferraccioli G, Dougados M, Robertson D, 
et al. Two-year clinical and radiographic results with combination etanercept-
methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, 
double-blind, randomized study. Arthritis and rheumatism [2010]; 62(3): 674-82. 
3. 
Klarenbeek NB, Guler-Yuksel M, van der Kooij SM, Han KH, Ronday HK, Kerstens 
PJ, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year 
outcomes of rheumatoid arthritis patients in the BeSt study. Annals of the rheumatic 
diseases [2011]; 70(6): 1039-46. 
4. 
Kruger K, Wollenhaupt J, Albrecht K, Alten R, Backhaus M, Baerwald C, et al. 
[German 2012 guidelines for the sequential medical treatment of rheumatoid arthritis. 
Adapted EULAR recommendations and updated treatment algorithm]. Zeitschrift fur 
Rheumatologie [2012]; 71(7): 592-603. 
5. 
Mease PJ. Measures of psoriatic arthritis. Arthritis care & research [2011]; 63 Suppl 
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6. 
Eder L, Chandran V, Shen H, Cook RJ, Gladman DD. Is ASDAS better than 
BASDAI as a measure of disease activity in axial psoriatic arthritis? Annals of the 
rheumatic diseases [2010]; 69(12): 2160-4. 
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Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, et al. European S3-
guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European 
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Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, et al. [S3-
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Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison 
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active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, 
double-blind, parallel treatment trial. Lancet [2008]; 372(9636): 375-82. 
10. 
Strohal R, Puig L, Chouela E, Tsai TF, Melin J, Freundlich B, et al. The efficacy and 
safety of etanercept when used with as-needed adjunctive topical therapy in a 
randomised, double-blind study in subjects with moderate-to-severe psoriasis (the 
PRISTINE trial). The Journal of dermatological treatment [2013]; 24(3): 169-78. 
 
 
 
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11. 
Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. 
EULAR recommendations for the management of rheumatoid arthritis with synthetic 
and biological disease-modifying antirheumatic drugs: 2013 update. Annals of the 
rheumatic diseases [2014]; 73(3): 492-509. 
12. 
Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et 
al. EULAR recommendations for the management of rheumatoid arthritis with 
synthetic and biological disease-modifying antirheumatic drugs. Annals of the 
rheumatic diseases [2010]; 69(6): 964-75. 
13. 
Kiltz U, Sieper J, Kellner H, Krause D, Rudwaleit M, Cheno JF, Stallmach A, Jaresch 
S, Braun J. Zeitschrift für Rheumatologie [2014]; Suppl. 2 (73): 78-96 
14. 
Zink A, Strangfeld A, Schneider M, Herzer P, Hierse F, Stoyanova-Scholz M, et al. 
Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an 
observational cohort study: comparison of patients according to their eligibility for 
major randomized clinical trials. Arthritis and rheumatism [2006]; 54(11): 3399-407. 
 
13. LIST OF TABLES 
Not applicable. 
14. LIST OF IMAGES 
Not applicable. 
ANNEX 1. LIST OF STANDALONE STUDY DOCUMENTS 
Not applicable. 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable. 
 
 
 
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