TREATMENT SATISFACTION COMPARISON IN RHEUMATOID ARTHRITIS PATIENTS BETWEEN TOFACITINIB CITRATE AND ADALIMUMAB, EACH USED IN RHEUMATOID ARTHRITIS TREATMENT
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Comparison 
of 
treatment 
satisfaction 
between patients with rheumatoid arthritis on 
tofacitinib citrate and adalimumab treatment
Protocol number
A3921304
Protocol version identifier
Version 3.2
Date of last version of protocol
10 December 2019
Active substance
Anatomical Therapeutic Chemical (ATC) 
code category: Selective immunosuppressant 
(L04AA29)
Medicinal product
Tofacitinib citrate
Research question and objectives
This study aims
to compare treatment 
satisfaction and quality of life between 
patients who have been using tofacitinib 
citrate and those using adalimumab for 6
months or more and less than 2 years in the 
treatment of rheumatoid arthritis. 
Author
 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................4
2. RESPONSIBLE PARTIES....................................................................................................5
3. AMENDMENTS AND UPDATES.......................................................................................7
4. MILESTONES.....................................................................................................................10
5. RATIONALE AND BACKGROUND................................................................................10
6. RESEARCH QUESTION AND OBJECTIVES .................................................................11
7. RESEARCH METHODS ....................................................................................................11
7.1. Study design ............................................................................................................11
7.2. Setting......................................................................................................................11
7.2.1. Study population.........................................................................................11
7.2.2. Inclusion criteria .........................................................................................11
7.2.3. Exclusion criteria........................................................................................12
7.3. Variables..................................................................................................................13
7.3.1. Propensity score methods ...........................................................................14
7.3.2. Treatment satisfaction questionnaire for medication version 1.4...............15
7.3.3. EuroQoL-5 dimension-3 level index and EuroQoL-visual analogue 
scale..................................................................................................................15
7.4. Data sources ............................................................................................................16
7.5. Study sample size....................................................................................................16
7.6. Data management....................................................................................................18
7.6.1. Data collection............................................................................................18
7.6.2. Data collection method...............................................................................18
7.6.3. Data management .......................................................................................19
7.7. Data analysis ...........................................................................................................19
7.7.1. Patient’s characteristics and outcomes in total patients..............................20
7.7.2. Outcomes comparison using propensity score methods.............................20
7.8. Quality control.........................................................................................................20
7.9. Limitations of the research methods .......................................................................21
7.10. Other aspects .........................................................................................................21
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................21

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8.1. Patient information..................................................................................................21
8.2. Patient consent.........................................................................................................22
8.3. Patient withdrawal...................................................................................................22
8.4. Institutional review board (IRB)/Independent ethics committee (IEC)..................22
8.5. Ethical Conduct of the Study ..................................................................................23
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................23
9.1. Single reference safety document............................................................................32
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........32
11. REFERENCES ..................................................................................................................32
12. LIST OF TABLES.............................................................................................................34
13. LIST OF FIGURES ...........................................................................................................34
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................34
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................34
ANNEX 3. ADDITIONAL INFORMATION.........................................................................34

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
EULAR
The European League Against Rheumatism
RA
Rheumatoid Arthritis
TNF
Tumor Necrosis Factor
DMARD
Disease modifying antirheumaticdrug
MTX
Methotrexate
DAS
Disease Activity Score
CRP
C-reactive protein
PSM
Propensity Score Method
PS
Propensity Score
IPTW
Inverse Probability of Treatment Weighting
SMD
Standardized Mean Difference
TSQM
Treatment Satisfaction Questionnaire for 
Medication
QoL
Quality of Life
EQ-5D
EuroQoL-5Dimensions
EQ-VAS
EuroQoL-Visual Analogue Scale
PRO
Patient Reported Outcome

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2. RESPONSIBLE PARTIES
Name, 
degree(s)
Title
Affiliation
Address
/ M.D.
Professor
 
/ M.D
Professor
/ M.D
Professor
 / M.D
Professor
 
/ M.D
Professor
 
/ M.D
Professor
 / 
M.D
Professor
 
/ M.D
Professor
 / 
M.D
Professor
 / M.D
Professor
/ M.D
Professor
/ 
M.D
Professor
 / 
M.D
Professor
 / 
M.D
Professor
/ M.D
Professor
/ M.D
Professor
./ 
M.D
Professor
 / 
M.D
Professor
 / 
M.D
Professor
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/ M.D
Professor
/ M.D
Professor
/ M.D
Professor
 / M.D
Professor
/ MS
OR/RWD team
lead
/ 
MS
OR/RWD 
Specialist
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3. AMENDMENTS AND UPDATES
Amendment 
number
Date
Substantial or 
administrative 
amendment
Protocol 
section(s) 
changed 
Summary of amendment(s)
Reason

18.05.11
Substantial
P 4, 5
2. RESPONSIBLE PARTIES 
 
 
 
 
 
-
removed and
 
 added
 
 
 
Change in author
P 7, 8
6. Research Questions and 
Objectives
7.2.1. Inclusion Criteria
- Inclusion criteria modified from 
more than 3 months and less than 2 
years to more than 6 months and less 
than 2 years
Modified as subjects who have been 
taking tofacitinib citrate for 3 months 
and adalimumab for 6 months are more 
likely to be included in the study 
clinically.
DAS28 from the clinical records was 
measured at 6 months, and this was 
applied.
P 10
7.3. Variables
Graph 1. Assessments [15, 20-21]: 2. 
Clinical characteristics
- tofacitinib citrate or adalimumab 
added to DMARD
- changed measuring units to the 
dose unit (mg/month)
To specify DMARD types, those in 
parenthesis have been added.
Prescribing patterns are very different; 
therefore, the measuring unit was 
changed to include all variations.
P 19
8.4. Ethical conduct of the study
- Recent Declaration of Helsinki 
added
Most recent Declaration of Helsinki 
added

2019.01.
31
Substantial
P 5
2. RESPONSIBLE PARTIES
 
 
7.6.2. Data Collection Method
- according to the included 
institutions, the number of 
institutions was changed to 23
According to the institutions added
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P 6 
P 17
4. Milestones
- End date of data collection changed 
to Sep 30, 2019
7.6.2. Data Collection Method
- Data collected dates changed to 
September 30, 2019.
Followed data collection extension
P 9–11
7.2.2. Exclusion criteria
- Modified and added
7.3. Variables
Graph 1. Assessments [15, 20-21]: 2. 
Clinical characteristics
Followed physician’s advice that 
csDMARDs co-administered with 
bDMARDs can include items other 
than MTX and that there are no 
differences between csDMARD types.
P 6, 14, 18 
3. Amendments and Updates
- reason for ver 2.0 modification: ~ 
patients who have been taking 
tofacitinib citrate for 3 months ~
7.4 Data Sources
- patients through a chart review and 
subject questionnaires 
7.7.1 Outcome Comparisons Using 
PSMs
- when the assumption for the 
parametric hypothesis is not 
satisfied- ~ when the assumptions for 
parametric hypothesis is not 
satisfied, non-parametric~
Changed to more appropriate term, and 
errors corrected.
P 20
8. Study subject protection
Pfizer protocol template 
 

2019.09.
02
Administrative
P 9
P 18
4. Milestones
- End date of data collection changed 
to December 31, 2019.
7.6.2. Data Collection Method
- Data collected dates changed to 
December 31, 2019.
Followed data collection extension

2019.12.
10
Administrative
P 9
P 18
4. Milestones
Followed data collection extension
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- End date of data collection changed 
to March 31, 2020.
7.6.2. Data Collection Method
- Data collected dates changed to 
March 31, 2020.

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4. MILESTONES
Milestone
Planned date
Study start-up
Request for proposal approval date
Completion of feasibility assessment
Participating institutions and 
investigators confirmation date
Start of data collection 
Site visit training date
End of data collection
March 31, 2020
Final study report
12 months from the last patients
5. RATIONALE AND BACKGROUND
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint 
destruction and leads to loss of function, decreased quality of life [1], and ultimately death [2] 
from complications. It is characterized by an excessive increase in pro-inflammatory cytokines
that causes abnormal inflammation [3]. Therefore, the American Arthritis Foundation has 
recommended early diagnosis and appropriate treatment targeting maintenance of low disease 
activity or remission of RA, prevention or delay of joint damage, and recovery of physical 
abilities and improvement in the quality of life [4].  
According to the 2016 Update of the European League Against Rheumatism (EULAR)
recommendation, the basic principle of the RA treatment goal is to provide the best care for 
the patients, and that treatment should be discussed and agreed between the two parties [5]. 
Therefore, patient evaluation of the treatment is an important factor for its success. 
Recently, the development of new treatments with various mechanisms and diagnosis 
criteria for early detection have allowed diagnosis and treatments in earlier stages of RA than 
previously possible [6]. However, it is a chronic condition that is still difficult to cure, and 
various complications [7-10] and decreased quality of life [1] can occur with insufficient 
treatment or a prolonged disease presence. Within 2 years of diagnosis, irreversible bone 
erosion has been observed in more than 50% of patients [7], and it was shown that patients 
with prolonged disease period have a high risk for widespread complications, such as 
cardiovascular conditions [8], infection [9], and malignant tumor [10]. 
According to the 2015 American College of Rheumatology Guideline, patients who have 
insufficient response to or who do not have tolerance to the conventional synthetic disease-
modifying antirheumatic drugs (csDMARDs) as the 1st line treatment are recommended to 
switch to biologic DMARDs (bDMARDs) or the small molecular target therapy JAK 
suppressor (tofacitinib citrate) to minimize disease activity or to expedite remission [11]. Most 
patients who receive csDMARDs suffer from a prolonged disease period, and it is important 
to assess quality of life and treatment satisfaction in this population. 

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bDMARDs are injectibles, and they have been reported to have low compliance [12] owing 
to invasive administrations and loss of therapeutic effects from immunogenic response [13, 
14]. On the contrary, tofacitinib citrate, which has been developed recently and used as an 
antirheumatic drug, is reported to have similar efficacy [15] and safety [16-18] as those of the 
bDMARDs and has a higher patient preference owing to its oral route of administration [19]. 
In a comparison using a RCT, non-inferior effects [15] and safety [20] of tofacitinib citrate 
were shown when compared to commonly used the bDMARD adalimumab, and both agents 
showed a higher quality of life than the placebo [21]. However, most clinical treatment success 
reports compare bDMARDs [22-24], and there are few reports that compare JAK suppressors 
with bDMARDs and their effects on patient treatment satisfaction and quality of life. 
Therefore, the purpose of this study is to compare the two most common clinically used 
antirheumatic agents, adalimumab and tofacitinib, in terms of treatment satisfaction and quality 
of life among Korean patients to assess treatment success from patients’ perspectives. 
6. RESEARCH QUESTION AND OBJECTIVES
This study aim to compare treatment satisfaction and quality of life between patients who 
have been using tofacitinib citrate and patients who have been using adalimumab for 6 months 
or more and less than 2 year in treatment of rheumatoid arthritis. The specific objectives are as 
follows:
Primary objective
To compare the treatment satisfaction between tofacitinib citrate users and adalimumab 
users.
Secondary objective
To compare the quality of life between tofacitinib citrate users and adalimumab users.
7. RESEARCH METHODS
7.1. Study design
This study is a multi-center, non-interventional cross-sectional study.
7.2. Setting
7.2.1. Study population
The study population is patients with RA who have been using tofacitinib citrate or 
adalimumab for 6 months or more and less than 2 years in RA treatment at the participating 
institutions.
7.2.2. Inclusion criteria
Study populations must satisfy the following inclusion criteria for enrollment:

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1. ≥ 19 years of age
2. Patients who satisfy the 2010 American College of Rheumatology/European League 
Against Rheumatism diagnosis criteria a)
3. Treatment groups:
1) Tofacitinib citrate users: patients who have been taking tofacitinib citrate for more 
than 6 months
2) Adalimumab users: patients who have been taking adalimumab for more than 6 
months
4. Patients who can read and write the questionnaire forms in Korean
7.2.3. Exclusion criteria
Study population who satisfy the exclusion criteria listed below will be excluded from the 
study:
1
Patients who are taking tofacitinib citrate or adalimumab for more than 2 years
2
Patients who are taking tofacitinib citrate or adalimumab along with azathioprine or 
cyclosporine
3
Patients who are participating in clinical research with other investigational products
4. Patients who are taking bDMARDs for diseases other than RA
a)
*The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a 
history compatible with prior fulfilment of the 2010 criteria should be classified as having RA.
Patients with long-standing disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, 
have previously fulfilled the 2010 criteria should be classified as having RA.
†Differential diagnoses differ in patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis 
and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.

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‡Although patients with a score of less than 6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled 
cumulatively over time.
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal 
interphalangeal joints, first carpometacarpal joints and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are 
classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint 
involvement.
¶’Large joints’ refers to shoulders, elbows, hips, knees and ankles.
**’Small joints’ refers to the metacarpophalangeal joints, proximal interphalangeal joints, second to fifth metatarsophalangeal joints, thumb 
interphalangeal joints and wrists.
††In this category, at least one of the involved joints must be a small joint; the other joints can include any combination of large and additional small 
joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).
‡‡Negative refers to international unit (IU) values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-
positive refers to IU values that are higher than the ULN but three of less times the ULN for the laboratory and assay; high-positive refers to IU values 
that are more than three times the ULN for the laboratory and assay. When rheumatoid factor (RF) information is only available as positive or negative, a 
positive result should be scored as low-positive for RF.
§§Normal/abnormal is determined by local laboratory standards.
¶¶Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (eg, pain, swelling, tenderness) of joints that are 
clinically involved at the time of assessment, regardless of treatment status.
ACPA, anti-citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
7.3. Variables
The information detailed below will be collected from medical records and patient 
questionnaires during the study from those who satisfy the inclusion criteria. 
Table 1. Evaluation Criteria [15,20-21]
Evaluation 
Criteria
Information
Evaluation 
Method
1. Demographics
•
Age
•
Gender
Medical Chart
•
Educational level
•
Financial status
•
Employment status
Patient 
Questionnaire
2. Clinical 
Characteristics
•
Body mass index 
•
Comorbidities
•
Initial RA diagnosis date 
•
DMARD types used previously
•
Current use of DMARD (tofacitinib citrate or 
adalimumab), treatment numbers/duration/doses 
(mg/month)
Co-administered drug types, numbers, dosage 
(csDMARDs/NSAIDs/steroid; mg/month)
•
DAS28 components
Medical Chart
3. 
Treatment
Satisfaction
•
Treatment 
satisfaction 
questionnaire 
for 
medication, (TSQM)
Patient 
Questionnaire

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4. Quality of Life •
EuroQoL-Visual Analogue Scale, EQ-VAS
•
EuroQoL-5 Dimensions index, EQ-5D index
Patient 
Questionnaire
7.3.1. Propensity score methods
The purpose of the propensity score is to create conditions similar to those of randomized 
trials by balancing the covariates in subjects between the groups. The propensity score 
adjustment method reduces multidimensional covariates into a one-dimensional score, or the 
propensity score. The computed propensity score can be used for bias reduction through 
restriction, matching, stratification, covariate adjustment, and weighted methods. It can also 
be used to estimate the mean treatment effect of two groups or the mean treatment effects of 
the active group compared to those of the control group. 
-
Propensity score use of the propensity score in the cross-sectional studies [26-
30]
The propensity score is used in the cross-sectional studies to remove or minimize effects 
from the disturbance variable. Analytical methods using propensity scores are considered 
superior to the average covariate analysis method of the one-dimensional study. Therefore, 
the analytical method using propensity score will be used in this study. 
1) Propensity score matching [25]

Propensity score matching can restrict variations between the covariates by matching 
subjects with similar propensity scores from groups 1 and 2. 

Duplicates not allowed: Once a subject from group 2 is matched with a subject from 
group 1, he/she cannot be considered for a match to a subject from another group, and 
therefore, the subject from group 2 can be matched for a maximum of one time. 

Greedy matching (nearest matching method): Subject from group 1 is randomly 
selected; then the subject with the closest propensity score is selected from group 2 
(caliper matching is also an option), and 1:1 matching will be considered. 

If too many subjects are eliminated from the analysis after matching, this method will 
not be considered as the analytical method, and only the methods described below will 
be considered and reported. Standards for the decision will be described in the SAP in 
detail. 
2) Propensity score adjustment [28]
This method uses all patients enrolled in the study, 

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•
Propensity score adjustment: A method for including the treatment variable and the 
PS itself as a covariate in a multiple model estimating a treatment effect.
3) Propensity score based weighing [28]
This method also uses all patient data.
•
Propensity score weighting: A method of using IPTW (inverse probability of 
treatment weighting) method to estimate a mean treatment effect of the two drug 
groups. The weight makes the characteristics of treatment groups similar to the target 
population.
4) Propensity score based stratification [28]
This method also uses all patient data.
•
Propensity score stratification: A method of stratifying patients according to the 
quintiles or deciles of their propensity score, and evaluate a treatment effect within 
each stratum. A pooled treatment effect will then be obtained across strata.
7.3.2. Treatment satisfaction questionnaire for medication version 1.4
TSQM version 1.4 is a self-report questionnaire for investigating treatment satisfaction. 
TSQM version 1.4 is the original version created with domain scoring for effectiveness, 
convenience, global satisfaction, and side effects with 14 items. Then each domain is scored 
by formula. The formula for TSQM scoring will be stated in Statistical Analysis Plan. TSQM 
scores range from 0 to 100 by each domain, higher scores indicate that the patient is in a greater 
satisfaction.
7.3.3. EuroQoL-5 dimension-3 level index and EuroQoL-visual analogue scale
EuroQoL-5 dimension (EQ-5D) is a standardized measure of health status, such as quality of 
life. The EuroQoL-5 dimension-3 level (EQ-5D-3L) essentially consists of 2 pages – the EQ-
5D descriptive system and EuroQoL-visual analogue scale (EQ-VAS). 
The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no 
problems, some problems, extreme problems. The respondent is asked to indicate his/her health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each 
of the 5 dimensions. 

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The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable health 
state’. This information can be used as a quantitative measure of health outcome as judged by 
the individual respondents. The scale is 0 to 100, higher scores imply that the patient is in a 
better health state.
The formula for EQ-5D scoring will be stated in Statistical Analysis Plan.
7.4. Data sources
Once a subject satisfies the inclusion criteria and voluntarily consents to participate in the 
study, subject data will be collected through review of medical records and patient 
questionnaires. Variables collected from the medical chart include demographic and clinical 
characteristics. Educational status, total income for the past year, and the current employment 
status will be collected from the questionnaires. Treatment satisfaction and the quality of life 
questions will be collected using the TSQM questionnaires and EQ-5D measurements, and the 
subject will self-record these.
7.5. Study sample size
The purpose of this study is to compare treatment satisfaction and quality of life in patients 
with RA who are receiving adalimumab or tofacitinib citrate. It is essential to identify the 
minimum sample size required to obtain statistically significant differences between the two 
groups. The equation below was used to calculate the sample size in this study [31].
ࡺൌ
૛࣌૛
ሺࣆ૚െࣆ૛ሻ૛ൣࢠ૚ିࢻ/૛൅ࢠ૚ିࢼ൧
૛

ો: Standard deviation from the overall satisfaction pooled ൎ14.58 (SD1: 16 [18], SD2: 
13 [24])
σ ൌටሺߪଵ
ଶ൅ߪଶଶሻ/2

ࣆ૚: Average of the overall satisfaction measured (larger) = 83 [24]

ࣆ૛: Average of the overall satisfaction measured (smaller) = 79 [24]

ࢠ૚ିࢻ/૛: 95% confidence interval (double-sided) significance = 1.96

ࢠ૚ିࢼ: 80% power threshold = 0.842

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Sample size was calculated based on literature that compared the median general satisfaction 
number between two drugs from the TSQM and the EQ-5D index score [24]. 
Jobanputra P et al. (2010) reported that the median EQ-5D index score and the median overall 
satisfaction score from TSQM (interquartile range) at 3 months after taking the medication in 
the adalimumab group were 0.62 (0.59–0.76) and 83 (67–100), respectively. In contrast, these 
scores were 0.62 (0.52–0.76) and 79 (58–92), respectively, in the etanercept group. Based on 
the sample number calculated in this study, we assumed that the average scores for the EQ-5D 
index or TSQM would be similar to the median scores from this measurement tool. This is 
because the interquartile ranges were almost symmetrical to the median value. We also 
assumed that the difference between the 3rd interquartile and median values (or the difference 
between the median and the 1st interquartile values) would replace the deviation from the 
general EQ-5D index or TSQM scores. This is because approximately 67% of the normal 
distribution data falls within the average ± 1 standard deviation, whereas 50% of uniform 
distribution data falls within median ± interquartile (in other words, within the interquartile 
range: Q1–Q3) values. Based on these assumptions, the standard deviations for the EQ-5D 
index scores were from 0.03 (= 0.62–0.59) to 0.14 (= 0.76–0.62) in adalimumab and from 0.1 
(= 0.62–0.52) to 0.14 (=0.76–0.62) in etanercept. Under the same assumption, the standard 
deviations for the TSQM scores were from 16 (= 83–67) to 17 (= 100–83) in adalimumab and 
from 13 (= 92–79) to 21 (= 79–58) in etanercept. 
We assumed 0 (= 0.62–0.62) and 4 (= 83–79) points as the difference in the average EQ-5D 
and TSQM scores between patients receiving adalimumab and tofacitinib citrate. We also 
assumed the standard deviations as 0.03–0.14 and 16–17 points for the EQ-5D index and
TSQM, respectively, in patients receiving adalimumab and in patients receiving tofacitinib 
citrate, the EQ-5D index and TSQM as 0.1–0.4 points and 13–21 points, respectively. Through
various combinations of standard deviations, we assumed that the minimum pooled standard 
deviation is 0.07 (= ඥሺ0.03ଶ൅0.1ଶሻ/2 and 14.58 (= ඥሺ16ଶ൅13ଶሻ/2), and the maximum 
pooled standard deviation is 0.14 (= ඥሺ0.14ଶ൅0.14ଶሻ/2) and 19.1 (= ඥሺ17ଶ൅21ଶሻ/2) in 
the EQ-5D index and TSQM, respectively. 
It was calculated that a total of 32 subjects in each group will be needed to detect the average 
difference of 0.05 points in EQ-5D with an 80% power at 5% significance, and a standard 
deviation of 0.07. The average difference of EQ-5D between the groups from a previous study 
was 0, which could not be used to calculate the sample size. Therefore, we voluntarily selected 
a small number, 0.05, as the average difference for the calculation. If 0.14 is used as the pooled 
standard deviation, a total of 125 per group will be needed.
When 14.58 is set as the pooled standard deviation for TSQM, a total of 209 subjects will be 
needed for each group for an 80% power with 5% significance. If 19.1 is set as the pooled 
standard deviation, a total of 359 subjects will be needed for each group. 
Based on the above calculations of the range of sample sizes for each group, the most number 
needed for each group, conservatively, is 360 subjects. Considering 10–20% of subjects not 
consenting, the actual sample size would be 400–450 subjects per group. Therefore, 

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approximately 420 subjects will be identified from each group from the total of 840 subjects 
in this study. 
Considering the geographic distribution and the number of patients as well as the clinical 
experiences and the academic success of the physicians, institutions participating in this study 
are deemed representative hospitals to care for patients with RA in Korea. Therefore, we 
believe that subjects who are screened from these institutions and undergo inclusion/exclusion 
criteria and the consent process are representative of Korea’s patients with rheumatoid arthritis 
who either use tofacitinib citrate or adalimumab.  
7.6. Data management
7.6.1. Data collection
As used in this study protocol, the term case report form should be considered a paper docu
ment record in accordance with the data collection method used in this study. A case report 
form should be prepared for each patient included in the study. The original case record form 
should not be disclosed in any form to Pfizer's authorized representative or any third party ex
cept the regulatory authority without the written consent of Pfizer.
The investigators should collect and report all clinical and laboratory data entered in the cas
e report form and other data collection forms (evidence documents). And the researcher have 
ultimate responsibility for ensuring their accuracy, authenticity / originality, attributability, co
mpleteness, consistency, readability, timely collection (concurrency), continuity and, where n
ecessary, availability. In order to verify accuracy of  the information contained in the case rec
ord, the case report form should be signed by the researcher or a delegated researcher. All mo
difications to the case report form and the grounds document should include the date and initi
als, the reason (if necessary), and do not cover the original content.
In most cases, the supporting documentation is the patient's medical chart record. In this cas
e, the data collected in the case report form should match the data recorded in the chart.
In some cases, the case report form or part of the case report form may also be the evidence 
document. In this case, the document should be kept in the investigator's center and Pfizer, an
d clearly stated in the documentation that the case report from, along with the data recorded i
n the case report form, is the basis document.
7.6.2. Data collection method
Data will be collected based on the study timeline. The study will be conducted at a total of 
23 institutions from the start date until March 31, 2020 according to the treatment timelines in 
patients with RA. Patients who satisfy inclusion and exclusion criteria and voluntarily consent 
to participate in the study will be enrolled. Patient information will be retrieved from medical 
charts. Information that cannot be obtained from medical charts will be collected from patient

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questionnaires, and treatment satisfaction and quality of life will be self-reported using 
authorized tools (TSQM and EQ-5D-3L). 
7.6.3. Data management 
Data management will be performed concurrently with data collection. A questionnaire will 
be issued to the researcher in charge of the research institute regarding the contents that are 
collected by mistake. Repeat this process until the final database is confirmed by reviewing 
the contents of the questionnaire that has been resolved by the researchers in charge of each 
research institute. The range of invalid values of each question will be fully described in data 
management plan.
After the completion of data collection, de-identified data will be aggregated in central 
database. Database lock will be conducted prior to the statistical analyses.
7.7. Data analysis
Data analysis will be undertaken using SAS software, version 9.4 of the SAS® system for 
Windows (Cary, NC, USA).
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan, which will be dated, filed and maintained by the 
sponsor. The Statistical Analysis Plan may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a protocol 
amendment.
The subjects of this study are as follows.
- All patients enrolled as study subjects who were eligible for two treatment groups.
The general principles of statistical analysis in this study are as follows:
- Complete statistical analysis plan before DB lock is done. The details of the data analysis 
methodology of this study are specified in the statistical analysis plan.
- If a statistical test is required, it should be carried out at the two-side significant level 5%.
- When multivariable analysis is performed, independent variables used for actual analysis 
can be added or subtracted considering the structure of collected data and general charac
teristics of study subjects.
- In the case of data that do not have a bias in the interpretation of the results, the analysis i
s carried out based on only the observed data without adjusting the missing values. If it i
s deemed that significant bias is imposed on the interpretation of the results when the an
alysis is carried out with only the observed data, the analysis is carried out by statisticall
y adjusting the missing values using the following appropriate missing value imputation 
method. As a method of replacing missing values, methods such as mean imputation, me

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dian imputation, probability imputation, regression imputation, ratio imputation, or mult
iple imputation are used depending on the pattern of missing values.
- Other inconsistent data may be excluded from the analysis under the responsibility of the 
investigator.
7.7.1. Patient’s characteristics and outcomes in total patients
For data on the demographic and clinical characteristics, the continuous data will provide 
mean, standard deviation, median, and range (min, max). If the form of the data is not normally 
distributed, the median, range, and quartile range are suggested. Categorical data will provide
frequency and percentages. Comparison between groups will be performed by the Student's t-
test. If normality assumption is not met, a nonparametric method is used. At this time, as a 
review of the assumption of normality, the histogram of each continuous variable will be
evaluated based on the results of the parametric tests. If the form of the data is not normally 
distributed, the logarithm transformed data will be used for comparison between the groups. 
Categorical variables will be tested using the chi-square test, but Fisher's exact test will be used 
when the assumptions required for parametric testing are not met.
The score of each domain in generic tools (TSQM and EQ-5D) will be presented by the mean 
and standard deviation. The difference of score at each domain according to the patient’s
characteristics will be evaluated by Student t-test or ANOVA. If the score does not satisfy the 
assumptions required for the parametric test, nonparametric method will be used.
7.7.2. Outcomes comparison using propensity score methods
Differences in treatment satisfaction and quality of life between the two groups will be 
compared after adjusting for the demographic characteristics. Of the propensity score methods, 
we will be utilizing the matching, weighted, covariate-adjusted, and stratified methods. The 
propensity score will be estimated and used to balance the covariates between the groups. After 
the quality evaluation to assess whether the covariates are well balanced, treatment satisfaction 
and quality of life score with propensity score adjustment will be compared. Along with the 
various propensity score methods, multivariate linear regression will also be used to compare 
the results between the groups. 
7.8. Quality control
It is performed in accordance with the Study Plan and the Good Outcomes Research Practices 
of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and may 
be monitored regularly by Pfizer or its agents during the study to confirm this. Here, monitoring 
includes its own in-house monitoring.

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7.9. Limitations of the research methods
This non-interventional, multicenter, and multi-dimensional observation study has the
following limitations. 
First, there can be causality problems. A cross-sectional study has practicality or 
convenience given its snapshot characteristic. However, it is difficult to use this as evidence 
for establishing causality. This can be explained as the case of two variables being related when 
measured from the same perspective, but it being difficult to determine that there is causality
between the two. 
Second, there is a limitation in controlling disturbance variables. Disturbance variables are 
those measured variables that can affect the relationships between variables of interest;
however, they do not affect the major variables. There is the limitation of unmeasured 
disturbance variables, which cannot be considered during the adjustment. 
Third, there can be a recall bias. Even when the investigator uses the same patient 
questionnaires as those that have been confirmed for their validity, patients are unable to report 
the answers accurately in relation to the past history. This can increase or decrease the effects 
of a particular variable, and therefore, as a result, affect the study outcomes. 
7.10. Other aspects
Not applicable
8. PROTECTION OF HUMAN SUBJECTS
8.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in [encrypted electronic and/or paper] form 
and will be [password protected or secured in a locked room] to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.

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The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
8.2. Patient consent
The informed consent documents and any patient recruitment materials must be in 
compliance with local regulatory requirements and legal requirements, including applicable 
privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the institutional 
review board (IRB)/independent ethics committee (IEC) before use, and available for 
inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the patient’s personal 
data.  The investigator further must ensure that each study patient is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
8.3. Patient withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
patient outcome, if applicable. The investigator would inquire about the reason for 
withdrawal and follow-up with the patient regarding any unresolved adverse events. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
8.4. Institutional review board (IRB)/Independent ethics committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 

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the IRB/IEC should be retained by the investigator. Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
8.5. Ethical Conduct of the Study
This study is conducted in accordance with the general principles set out in the Regulations 
and Regulatory Requirements, the Good Outcomes Research Practices of the International 
Society for Pharmacoeconomics and Outcomes Research (ISPOR), and the Declaration of 
Helsinki (World Medical Association 1996, 2008 and 2013).
9. MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE 
REACTIONS 
REQUIREMENTS
The following table summarizes the requirements for recording safety events on the data 
collection tools and for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety.  These requirements are delineated for 
three types of events: (1) serious adverse events (SAEs); (2) non-serious adverse events (AEs) 
(as applicable); and (3) scenarios involving drug exposure, including exposure during 
pregnancy, exposure during breast feeding, medication error, overdose, misuse, extravasation, 
lack of efficacy, and occupational exposure.  These events are defined in the section 
“Definitions of safety events.”
Safety event
Recorded 
on 
the 
data 
collection tool
Reported on the NIS AEM 
Report Form to Pfizer Safety 
within 24 hours of awareness
SAE
All
All
Non-serious AE
All
None
Scenarios involving exposure to a 
drug 
under 
study, 
including 
exposure 
during 
pregnancy, 
exposure during breast feeding, 
medication 
error, 
overdose, 
misuse, extravasation, lack of 
efficacy, 
and 
occupational 
exposure
All 
(regardless 
of 
whether 
associated with an AE), except 
occupational exposure
All (regardless of whether 
associated with an AE)

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For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(refer to section "Serious Adverse Events” below). 
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness 
of the event by the investigator regardless of whether the event is determined by the 
investigator to be related to a drug under study.  In particular, if the SAE is fatal or life-
threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information.  This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports.  In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events.
For those safety events that are considered serious or that are identified in the far right column 
of the table above that are reportable to Pfizer within 24 hours of awareness, the investigator 
is obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe.  In addition, an investigator may be requested by Pfizer to obtain 
specific follow-up information in an expedited fashion.  This information is more detailed than 
that recorded on the data collection tools. In general, this will include a description of the AE 
in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Any information relevant to the event, such as 
concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
Reporting period 
For each patient, the safety event reporting period begins at the time of  the patient’s first dose 
of tofacitinib citrate and adalimumab or the time of the patient’s informed consent if s/he is 
already exposed to tofacitinib citrate and adalimumab, and lasts through the end of the 
observation period of the study, which must include at least 28 calendar days following the last 
administration of a drug under study; a report must be submitted to Pfizer Safety (or its 
designated representative) for any of the types of safety events listed in the table above 
occurring during this period.  If a patient was administered a drug under study on the last day 
of the observation period, then the reporting period should be extended for 28 calendar days 
following the end of observation. Most often, the date of informed consent is the same as the 
date of enrollment.  In some situations, there may be a lag between the dates of informed 
consent and enrollment.  In these instances, if a patient provides informed consent but is never 
enrolled in the study (e.g., patient changes his/her mind about participation, failed screening 
criteria), the reporting period ends on the date of the decision to not enroll the patient.  

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If the investigator becomes aware of a SAE occurring at any time after completion of the study 
and s/he considers the SAE to be related to tofacitinib citrate and adalimumab, the SAE also 
must be reported to Pfizer Safety. 
Causality assessment
The investigator is required to assess and record the causal relationship.  For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of each AE.  For 
AEs with a causal relationship to tofacitinib citrate and adalimumab, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment.  
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that tofacitinib citrate and adalimumab caused or contributed to an AE.  If the 
investigator’s final determination of causality is “unknown” and s/he cannot determine whether 
tofacitinib citrate and adalimumab caused the event, the safety event must be reported within 
24 hours. 
If the investigator cannot determine the etiology of the event but s/he determines that 
tofacitinib citrate and adalimumab did not cause the event, this should be clearly documented 
on the data collection tool and the NIS AEM Report Form. 
DEFINITIONS OF SAFETY EVENTS
Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product.  The 
event need not necessarily have a causal relationship with the product treatment or usage. 
Examples of AEs include but are not limited to:  
•
Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE);
•
Clinically significant symptoms and signs;
•
Changes in physical examination findings;
•
Hypersensitivity;
•
Progression/worsening of underlying disease; 

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•
Lack of efficacy; 
•
Drug abuse; 
•
Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:
•
Drug overdose;
•
Drug withdrawal;
•
Drug misuse; 
•
Off-label use; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy;
•
Exposure during breast feeding;
•
Medication error;
•
Occupational exposure.
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
•
Test result is associated with accompanying symptoms, and/or
•
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

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•
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or
•
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
Serious adverse events
A SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional 
product (including pediatric formulas) at any dose that:
•
Results in death;
•
Is life-threatening;
•
Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs);
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a Pfizer product.  
The terms “suspected transmission” and “transmission” are considered synonymous.  These 

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cases are considered unexpected and handled as serious expedited cases by pharmacovigilance 
(PV) personnel.  Such cases are also considered for reporting as product defects, if appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable.  For 
example, the following reports of hospitalization without a medical AE are not to be reported. 
•
Social admission (e.g., patient has no place to sleep)
•
Administrative admission (e.g., for yearly exam)
•
Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery)
•
Hospitalization for observation without a medical AE
•
Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (e.g., for work-up 
of persistent pre-treatment lab abnormality)
•
Protocol-specified admission during clinical study (e.g., for a procedure required by 
the study protocol)
Scenarios necessitating reporting to Pfizer Safety within 24 hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below.
Exposure during pregnancy

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An exposure during pregnancy (EDP) occurs if:
1.
A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) tofacitinib citrate and adalimumab, or the female becomes, or 
is found to be, pregnant after discontinuing and/or being exposed to tofacitinib citrate and 
adalimumab (maternal exposure).
An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed 
to chemotherapeutic products).
2.
A male has been exposed, either due to treatment or environmental exposure to 
tofacitinib citrate and adalimumab prior to or around the time of conception and/or is exposed 
during the partner pregnancy (paternal exposure).
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed.
If a study participant or study participant’s partner becomes, or is found to be, pregnant during 
the study participant’s treatment with tofacitinib citrate and adalimumab, this information must 
be submitted to Pfizer, irrespective of whether an AE has occurred using the NIS AEM Report 
Form and the EDP Supplemental Form. 
In addition, the information regarding environmental exposure to tofacitinib citrate and 
adalimumab in a pregnant woman (e.g., a subject reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) must be submitted using the NIS AEM 
Report Form and the EDP Supplemental Form.  This must be done irrespective of whether an 
AE has occurred.  
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up 
is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(e.g., induced abortion) and Pfizer is notified of the outcome.  This information is provided as 
a follow up to the initial EDP report.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for 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 demise, neonatal death, or congenital anomaly [in a 

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live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the procedures 
for reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
•
Spontaneous abortion includes miscarriage and missed abortion;
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure to 
investigational product.
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm 
infants to identify developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE.  An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in accord 
with authorized use.  However, if the infant experiences an AE associated with such a drug’s 
administration, the AE is reported together with the exposure during breastfeeding.
Medication error
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may be 
related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.  
Medication errors include:

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•
Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription on 
the part of the healthcare provider or the patient/consumer);
•
Confusion with regard to invented name (e.g., trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE:
•
Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE.
•
Medication errors that do not involve a patient directly (e.g., potential medication errors 
or near misses).  When a medication error does not involve patient exposure to the product the 
following minimum criteria constitute a medication error report:
•
An identifiable reporter;
•
A suspect product;
•
The event medication error.
Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE. 
Lack of Efficacy
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product.
Occupational Exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE.

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9.1. Single reference safety document
The 
 SAFETY REPORTING LANGUAGE: OTHER PRIMARY DATA 
COLLECTION STUDY (A type) will serve as the single reference safety document during the 
course of the study, which will be used by Pfizer safety to assess any safety events reported to 
Pfizer Safety by the investigator during the course of this study. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The study results will be submitted to domestic or international academic journal.
COMMUNICATION OF ISSUES
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of any 
serious breaches of this NI study protocol that the investigator becomes aware of.
11. REFERENCES
1
McInnes IB, Liew FY. Cytokine networks—towards new therapies for rheumatoid 
arthritis. Nat ClinPractRheumatol 2005;1:31-39.
2
Matcham F, et al. The impact of rheumatoid arthritis on quality-of-life assessed using the 
SF-36: A systematic review and meta-analysis. Semin Arthritis Rheum 2014;44(2):123-
130.
3
Sokka 
T, 
et 
al. 
Mortality 
in 
rheumatoid 
arthritis: 
2008 
update. 
ClinExpRheumatol2008;26(5 Suppl 51):S35-S61.
4
Arthritis 
Foundation; 
Home>About 
Arthritis>Types>Rheumatoid 
Arthritis> 
Treatment;http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php
5
Scott DL et al., Rheumatoid arthritis. Lancet 2010;376:1094-108.
6
Smolen JS et al., EULAR recommendations for the management of rheumatoid arthritis 
with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann 
Rheum Dis 2014;73:492-509.
7
van der Heijde D, et al. Biannual radiographic assessments of hands and feet in a three-
year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum
CCI

<A3921304>NON-INTERVENTIONAL STUDY PROTOCOL
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1992;35(1):26-34.
8
Naranjo A, et al. Cardiovascular disease in patients with rheumatoid arthritis: results from 
the QUEST-RA study. Arthritis Res Ther 2008;10(2):R30
9
Doran M, et al. Frequency of infection in patients with rheumatoid arthritis compared with 
controls: a population-based study. Arthritis Rheum 2002;46(9):2287-2293.
10 Smitten A, et al. A meta-analysis of the incidence of malignancy in adult patients with 
rheumatoid arthritis. Arthritis Res Ther2008;10:R45.
11 Singh JA, et al. 2015 American College of Rheumatology Guideline for the Treatment of 
Rheumatoid Arthritis. Arthritis Care Res 2015;1-25.
12 Curtis JR, Hobar C, Hansbrough K. Injection-site burning and stinging in patients with 
rheumatoid arthritis using injectable biologics. Curr Med Res Opin 2011; 27:71–78.
13 Radstake TR, et al. Formation of antibodies against infliximab and adalimumab strongly 
correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann 
Rheum Dis 2009;68(11):1739-1745.
14 Bartelds GM, et al. Development of antidrug antibodies against adalimumab and 
association with disease activity and treatment failure during long-term follow-up. JAMA
2011;305(14):1460-1468
15 Alten R et al., Examining patient preferences in the treatment of rheumatoid arthritis using 
a discrete-choice approach. Patient preference and adherence 2016;10:2217-2228.
16 van Vollenhoven R, et al. Tofacitinib or adalimumab versus placebo in rheumatoid 
arthritis. N Engl J Med 2012;367-508-519.
17 Kawalec P, et al. The effectiveness of tofacitinib, a novel Janus kinase inhibitor, in the 
treatment of rheumatoid arthritis: a systematic review and meta-analysis. ClinRheumatol: 
Published online 23 July 2013.
18 Strand V et al., Tofacitinib or adalimumab versus placebo: patient-reported outcomes from 
a phase 3 study of active rheumatoid arthritis. Rheumatology 2016;55:1031-1041.
19 Sylwestrzak G et al., Considering Patient Preferences When Selecting Anti–Tumor 
Necrosis Factor Therapeutic Options. Am Health Drug Benefits 2014;7(2):71-81.
20 Pope JE et al., Treating to a Target in Established Active Rheumatoid Arthritis Patients 
Receiving a Tumor Necrosis Factor Inhibitor: Results From a Real-World Cluster-
Randomized Adalimumab Trial. Arthritis Care & Research 2013;65(9):1401–1409.
21 Jobanputra P et al., A randomised efficacy and discontinuation study of etanercept versus 
adlimumab (RED SEA) for rheumatoid arthritis: a pragmatic, unblinded, non-inferiority 
study of first TNF inhibitor use: outcomes over 2years. BMJ Open 2012;2:1-9.
22 Rosenbaum PR & Rubin DB. The central role of the propensity score in observational 
studies for causal effects. Biometrika1983;70(1):41-55.
23 Virchow JC et al., Impact of ocular symptoms on quality of life (QoL), work productivity 
and resource utilisation in allergic rhinitis patients – an observational, cross sectional study 

<A3921304>NON-INTERVENTIONAL STUDY PROTOCOL
<Version3.2>,<10 December 2019>
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in four countries in Europe. Journal of Medical Economics 2011;14(3):305-314.
24 Rajavashisth TB et al., Decreased prevalence of diabetes in marijuana users: cross-
sectional data from the National Health and Nutrition Examination Survey (NHANES) III. 
BMJ Open 2012;2:1-9
25 Fusaro M et al., Long-Term Proton Pump Inhibitor Use is Associated with Vascular 
Calcification in Chronic Kidney Disease: A Cross-Sectional Study Using Propensity Score 
Analysis. Drug Saf2013;36:635–642.
26 Ekundayo OJ et al., Association of diuretic use and overactive bladder syndrome in older 
adults:Apropensity score analysis. Archives of Gerontology and Geriatrics 2009:64–68.
27 Nickolas TL et al., Relationship between Moderate to Severe Kidney Disease and Hip 
Fracture in the United States. J Am SocNephrol2006;17: 3223–3232.
28 Jang EJ et al.,Methods for the control of measurd confounders in outcomes research. 
National Evidence-based Healthcare Collaborating Agency (2013), 1-272.
29 Chow S et al., Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & 
Hall/CRC Biostatistics Series (2008), page 58
30 Goren A et al., Patient reported health outcomes and non-adherence in psoriasis patients receiving 
adalimumab or ustekinumab for moderate to severe plaque psoriasis, Journal of Dermatological 
Treatment, 2016; 27:1, 43-50
12. LIST OF TABLES 
Table 1. Evaluation Criteria [15,20-21]
13. LIST OF FIGURES
None
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Not applicable