RHYTHM (RHeumatoid Arthritis studY of THe Myocardium): How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Sponsor: Columbia University

NCT01548768 
 
Columbia University Human Subjects Study Description Data Sheet 
 
Protocol: IRB-AAAI1026(Y1M02) 
Modiﬁcation 
Protocol Status: Approved 
Effective Date: 01/19/2012 
Expiration Date: 05/03/2012 
 
Originating Department: 
MEDICINE (527-18) 
Submitting To: 
Medical Center 
Title: 
ESCAPE II Myocardium: How RA and TNF inhibitors affect the myocardial 
structure and function. 
Sponsor Protocol Version#: 
Abbreviated title: 
ESCAPE II Myocardium 
IRB of record: 
Columbia University Medical Center 
IRB number used by the 
IRB of record: 
 
Afﬁliated Institutions: 
-Standard Columbia Submission 
Protocol Begin Date: 
03/15/2011 
Protocol End Date: 
03/15/2014 
 
Principal Investigator: 
Joan Bathon (527) 
 
Study Description 
1. STUDY PURPOSE AND RATIONALE 
 
Patients with Rheumatoid Arthritis (RA) are at increased risk for developing heart failure (HF) compared to matched 
non-RA controls. In addition, HF is one of the main causes for premature death and a major contributor to the reduced 
- compared to the general population - lifespan of RA patients. 
Preliminary data show that patients with RA have a lower LV mass than non-RA controls, and that this decrease in LV 
mass is associated with a lower cardiac output. Assuming that the decrease in the cardiac output could be indicative of 
pre-clinical HF, this is in contrast with what is observed in the non-RA patients, where the development of HF is 
preceded by an increase in LV mass. The reasons for a decreased LV mass in RA, and how this may be linked or lead 
to a compromised LV function are not known. Furthermore, based on preliminary data that associate the presence of 
speciﬁc RA characteristics (such as the presence of CCP antibodies) with a decrease in the LV mass, we can 
hypothesize that RA related inflammation within the myocardium may be causing myocardial cell death or apoptosis. In 
addition, based on data showing diffuse subendocardial hypoperfusion in patients with RA we can hypothesize that 
inflammation may affect the endothelium of the myocardial microvasculature, and interfere with myocardial perfusion 
leading to myocardial atrophy. 
 
The ﬁrst aim of this study is to evaluate and identify factors that are associated with the phenotype of low LV mass. We 
will enroll 150 RA patients in the study. Some of the potential low LV mass predictors to be studied include: RA 
associated characteristics (e.g., anti-CCP antibody titers), duration of articular disease, the degree of systemic and 
myocardial inflammation, and alterations in myocardial perfusion. LV structure and function will be assessed by 
cardiac PET-CT scan and 3-dimensional echocardiography (3D ECHO). 
 
TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment 
(usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the 
standard of care management of RA. It is estimated that currently up to 20% of patients with RA are being treated with 
TNF inhibitors. More than 10 years of experience with these agents support the use of these agents for RA patients 
who do not respond to initial treatment. While TNF inhibitors have revolutionized the treatment of articular RA, their 
effects on heart failure (HF) has not been elucidated. Clinical trials in non-RA patients with advanced HF showed that 
these medications are not beneﬁcial and may even be detrimental. Even though similar robust studies have never been 
performed in RA patients, product information sheets for all of the TNF inhibitors warn against their use in RA 
patients with advanced HF. However, their use is allowed for the treatment of RA in patients with moderate or mild HF 
with careful monitoring. Animal data, recent RA cohort data, and our preliminary data in RA patients suggest that TNF 
 
 
Printed On: 01/19/2012 at 13:20 
page 1 of 123 
05/03/2012 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 2 of 23 
 
 
inhibitors may prevent HF and/or improve LV function in RA. So far, no studies have investigated the direct effect of 
this class of drugs on myocarcial function and structure. The hypothesis that TNF inhibitors may have a differential 
effect on the failing myocardium - depending on whether patients have RA or not - would reconcile the contradictory 
literature. Assuming that systemic or myocardial inflammation may be the primary force leading to HF in RA, we 
hypothesize that TNF inhibitors may be beneﬁcial in preventing or improving HF in patients with RA. We will address 
this hypothesis ﬁrst by examining the effect of TNF inhibitor treatment in RA patients without heart failure. If safe, 
further studies can direct attention to RA patients with heart failure. 
 
The second aim of the study will target 50 of the 150 RA patients enrolled in aim 1, and will evaluate the effect of 
treatment with TNF inhibitors on left ventricular (LV) structure and function, and also myocardial inflammation and 
perfusion. In this aim we will investigate the effect on TNF inhibitor treatment directly on the myocardium in patients 
without HF, or other known cardiovascular disease. Thus we will not enroll any patients with HF, but only patients free 
of any cardiovascular disease. Participants in need of treatment to control their disease activity despite methotrexate will 
be randomized to receive treatment with either a TNF inhibitor or other equivalent FDA approved treatment. The direct 
effect on the myocardial function, structure, LV mass, and subendocardial hypoperfusion will be evaluated over 
6 months of observation. In this aim as already noted above - we will utilize only FDA approved drugs for RA, and 
the study will be conducted and monitored in the context of usual care. 
 
 
 
2. STUDY DESIGN AND STATISTICAL PROCEDURES 
 
2a. Study Design 
(this section includes references) 
 
For aim 1, the proposed studies will be performed in 150 patients with RA and 15 subjects without RA who will 
function as controls. The 150 patients will be recruited from the rheumatology clinics at New York Presbyterian 
Hospital of the Columbia University. The 15 control subjects will be recruited from the internal medicine clinics at the 
same institution or among friends of the recruited RA patients. 
 
The 150 participants should have RA fulﬁlling established diagnosed criteria and not have a history of cardiovascular 
disease as indicated in the section for inclusion/exclusion criteria 
 
These patients (150) will undergo the evaluations shown in the table below - and in more detail in Appendices I, II and 
III - during an initial visit (Visit I). 
 
Visit I 
Evaluations 
September/2011 - August/ 2014 
 
 
 
Cardiac PET-CT scan* 
X 
3D Echocardiogram 
X RA 
& CV Questionnaires 
   X 
Joint examination 
 X 
Phlebotomy 
 X 
Anthropometry 
  X 
DEXA scan (body composition)** 
    X 
 
*including 3 transverse CT slices (mid-chest, L4-L5, mid-thigh) and cardiac CT for evaluation of coronary artery 
calciﬁcation (CAC). 
**only for the 50 participants who will be recruited for aim 2. (see below) 
 
During the ﬁrst PET scan a cardiac CT scan will be obtained in order to quantify coronary artery calcium (Agatston 
Score). Three additional CT Slices will be obtained (mid chest, lumbar, and mid thigh) to evaluate for visceral fat 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 3 of 23 
 
 
accumulation as a risk factor for cardiovascular disease. 
 
Controls will undergo only the PET-CT scan, 3D Echo, anthropometry evaluations, phlebotomy, and will complete 
abbreviated cardiovascular related questionnaires as outlined in Appendices I, II and III. 
 
The PET-CT scan will occur on the same day or within one week of Study visit I. 
We expect that the vast majority of the 150 enrolled patients will already be on treatment with methotrexate at the time 
of enrollment. Methotrexate is the cornerstone of treatment for RA and almost all patients are started on methotrexate 
upon diagnosis of RA as part of standard of care. However only approximately 50% of patients reach a state of RA 
remission or low disease activity with methotrexate. The other 50% of patients with RA do not respond adequately to 
methotrexate and need treatment with additional agents in order to reach remission or low disease activity. In usual 
care patients who do not respond to methotrexate are frequently prescribed medications such as sulfasalazine and 
plaquenil in addition to methotrexate (triple therapy) or a TNF inhibitor in addition to methotrexate. Whether a patient 
receives one (TNF inhibitor) or the other (triple therapy) treatment is a matter of physician and patient preferences most 
of the time. Published guidelines provide only initial treatment recommendations (for example: methotrexate for all RA 
patients once diagnosis is established) and do not comment on whether one therapeutic agent should be preferred over 
an other for patients who do not respond to methotrexate (1). 
 
For aim 2, we will identify 50 of the patients enrolled in aim 1 who are in need for further treatment due to increased 
RA activity despite methotrexate treatment. These patients will be recruited to continue in the study for an additional 
24 (+/- 2) weeks (6 months). The patients will be randomized to receive one of the FDA approved options in an open 
label protocol for increased disease activity; either a TNF inhibitor or triple therapy and in the context of standard of 
care as already noted above. For more information regarding inclusion/exclusion criteria please refer to the appropriate 
IRB/RASCAL application section below. 
 
Although treatment with TNF inhibitor and methotrexate is slightly superior in slowing radiographic joint damage, 
triple therapy has comparable efﬁcacy and multiple clinical trials (COBRA and Best) robustly support the ability of the 
regimen to effectively reduce disease activity and slow radiographic damage (2,3). 
 
After the escalation in their treatment at baseline (Study Visit I) these patients will return for a second (24 weeks) 
study visit respectively and the set of evaluations shown in the table below - and in more detail in Appendices I, II and 
III - will take place. A window of +/- 2 weeks will be allowed in scheduling the study visits. 
 
Visit II 
Evaluations 
Mar/2012-Jan/2015 
 
 
 
Cardiac PET-CT scan* 
X 
3D Echocardiogram 
X RA & 
CV Questionnaires 
  X 
Joint examination 
 
 X 
DEXA scan (body composition) 
   
 X 
Phlebotomy 
   
X 
Anthropometry 
  X 
 
*including 3 transverse CT slices (mid-chest, L4-L5, mid-thigh) and low dose radiation chest CT 
 
During PET-CT scans a low dose CT imaging of the chest is always obtained for attenuation correction as part of the 
usual PET-CT protocol. Although we will not need a repeat coronary artery calcium score at visit 2, low dose radiation 
CT imaging of the chest is always obtained for attenuation correction as part of the usual PET protocol. During this CT 
imaging acquisition 3 additional slices (CT cuts) will be again obtained (mid chest, lumbar, and mid thigh) to evaluate 
for change in visceral fat following treatment initiation. 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 4 of 23 
 
 
The 3-dimensional Echocardiogram (3D Echo) will be performed to provide a measure of LV mass and will be 
performed in every study visit. 
The 15 controls will also be asked to have a repeat set of evaluations 6 months (24 +/- 2 weeks) after their ﬁrst 
evaluation without any therapeutic or other intervention in between the two visits. The inclusion of non-RA controls 
will provide important data on the normal variation of cardiac PET-CT and 3D Echo parameters over time. Further 
evaluations for the control participant visits are outlined in appendices I, II and III. 
 
Every subject (RA patient or non RA control) will have a urine pregnancy test prior to tests involving radiation 
exposure (PET-CT scan and DEXA) and on the same day. 
 
The screening and consent process of a patient to receive randomized escalation of treatment will be made at the time 
they are consented for the ﬁrst study visit. It is possible that all 150 patients will qualify for randomization of their 
treatment but only the ﬁrst 50 of those will be selected to return for study visit II. The rest of the patients will exit the 
study and will continue their regular care with escalation of their treatment by their treating rheumatologist outside the 
study. 
 
Standard of care entails that patients who undergo escalation of their treatment need to be evaluated every 6-8 weeks 
to evaluate response to treatment, the need for further treatment escalation, and toxicity monitoring. Thus in between 
Study Visits I and II patients will return every 6-8 weeks for safety visits which will mirror standard of care 
management and which will be focused on toxicity monitoring as it would happen even if the patients did not 
participate in the study. An exit safety visit will occur 6-8 weeks after visit II. The incorporation of safety visits in the 
study and the related procedures/tests are shown in Appendices I and II. 
 
It is possible that patients randomized to receive either the triple therapy or treatment with a TNF inhibitor and 
methotrexate may not respond to treatment. Disease activity will be evaluated using the Clinical Disease Activity Index 
(CDAI) score at the time of every safety and study visit and treatment will be modiﬁed until they reach the state of low 
disease activity or remission as deﬁned by a CDAI score of less than or equal to 10. CDAI score takes into 
account the number of swollen and tender joints and the evaluation (using a Visual Analog Scale) of disease activity by 
both the patient and the physician. CDAI is an extensively validated disease activity tool. 
 
The treatment algorithm followed in this study is described below. A study flow chart describing the algorithm is 
provided in appendix XXI. 
 
i. Randomization to the non TNF inhibitor arm: Patients on triple therapy will be started on 1 gram of sulfasalazine 
(SSZ) twice daily along with weight adjusted daily Hydroxychloroquine (Plaquenil). Methotrexate treatment will be 
continued. It takes approximately 6 weeks before an effect of this therapeutic regimen is experienced. In the ﬁrst safety 
visit (which will happen approximately 8 weeks after the ﬁrst study visit) the need to increase the SSZ to 3 grams daily 
will be evaluated based on whether the patient has reached low disease activity status or remission. In the subsequent 
safety visit (safety Visit 2) which will occur 8 week after Safety Visit 1, if disease activity remains moderate or high, 
SSZ and Hydroxychloroquine will be stopped and patients will be switched to Leflunomide (Arava) 10 mg plus 
methotrexate. 
 
Patients will then return at 24 weeks for their second Study Visit (Study Visit 2) for completion of the study and further 
management as per standard of care. 
 
An additional Safety Visit (Safety Visit 3) will take place at 32 weeks and will serve as an exit safety visit. 
 
ii. Randomization to the TNF inhibitor arm: For patients randomized to receive treatment with a TNF inhibitor, 
disease activity will also be evaluated at the time of every visit. The effect of TNF inhibitors on arthritis activity may 
be observed as early as in 2 weeks but sometimes may take up to 14 weeks (approx. 3 months). At the time of the ﬁrst 
safety visit tolerability and safety will be evaluated. At the time of Safety Visit II if CDAI is still >10 (indicative of 
moderate disease activity) an increase in the dose or frequency of the TNF inhibitor (in the case of agents such as 
infliximab or adalimumab where escalation of dosage is an option) or a switch to treatment to an alternative TNF 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 5 of 23 
 
 
inhibitor will take place. 
 
Patients will then return at 24 weeks for their Second Study Visit (Study Visit 2) for completion of the study and 
further management as per standard of care. 
 
An additional Safety Visit (Safety Visit 3) will take place at 32 weeks and will serve as an exit safety visit. 
 
The treatment algorithm described above is similar to the care patients would receive even if they did not participate in 
the study. The only difference is that patients will be randomized to receive one of the two standard of care treatments. 
The need for prednisone to temporarily control disease activity will be decided by the investigators according to usual 
standards of care. 
 
As already mentioned decisions to escalate treatment will be based on CDAI score which is a composite disease activity 
score consisting of counts of swollen and tender joint counts and evaluation of disease activity by both the patient and 
the physician using a visual analog scale. The joint counts will be performed by a blinded trained joint assessor. Either a 
faculty member or a senior rheumatology fellow, also not aware of the patient treatment will perform the joint 
examinations and the assessment of disease activity. The same joint assessor will perform the joint counts for 
a given patient throughout the study. Every time CDAI is >10, then a change in the treatment according to the 
algorithm described above will be mandated to ensure patients' well being. 
 
As already mentioned, the goal of this study is to investigate the "low LV mass phenotype" in patients with RA and its 
contributors in an attempt to elucidate the pathophysiology pathways that may connect RA with alterations in the 
myocardium and the evolution to heart failure. 3D-Echo will be used to measure the LV mass. Cardiac PET-CT 
imaging will be used to evaluate myocardial function (cardiac output, ejection fraction), microvasculature function 
(myocardial perfusion) and myocardial inflammation (F18-FDG uptake). 
 
 
 
The research questions to be addressed with the study visit I are the following: 
 
i) Are anti-CCP antibodies or other RA­speciﬁc characteristics (e.g., disease duration, activity, severity) associated 
with lower LV mass (or other LV parameters of structure/function)? 
 
ii) What is the prevalence, the degree and correlates of microvascular dysfunction in RA? Is it associated with low LV 
mass or reduced global or regional contractility? Is it associated with systemic, articular and/or myocardial 
inflammation? 
 
iii) What are the prevalence, patterns, distribution and severity of inflammation as measured by F18-FDG uptake in 
myocardial PET imaging? Are intensity and/or distribution of F18-FDG uptake correlated with low LV mass or global 
or regional contractility? Does the severity/distribution of F18-FDG uptake correlate with levels of systemic and/or 
articular inflammation? 
 
For the second aim of this study the goal is to evaluate the effect of TNF inhibitors on the myocardium. For the 50 
patients undergoing randomization and the controls the questions to be addressed will be the following: 
 
i) Are global measures of LV structure (e.g., mass) or contractility (e.g., ejection fraction) affected (reduced or 
increased) by treatment with TNF antagonists? Is there a different effect compared to alternative therapy? 
 
ii) If microvascular dysfunction and/or inflammation are present before treatment, do they improve with treatment with 
TNF compared to alternative treatment? If parameters improve only with TNF inhibitor, this would suggest that TNF 
inhibitors exert a local anti-inflammatory effect on the myocardium mechanistically different compared to alternative 
treatment. 
 
iii) If treatment-induced improvements in microvascular dysfunction and/or inflammation (F18-FDG uptake) are 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 6 of 23 
 
 
observed with TNF inhibitor treatment and not with alternative treatment, do they correlate with (or mediate) global 
(or regional) changes in LV structure or function? If so, this would suggest a causal relationship between regional 
myocardial vasculopathy and/or inflammation with LV dysfunction. 
 
iv) Do treatment-induced improvements in systemic inflammation (e.g., CRP) and RA disease activity correlate with 
changes in myocardial microvascular perfusion and/or inflammation If so, this would suggest a relationship between 
systemic and myocardial inflammation. 
 
In preliminary exploratory data analyses, summary statistics for the continuous and categorical variables will be 
calculated, including means, standard deviations, quartiles and ranges, and for the categorical variables, counts and 
percentages. In initial analyses, statistical comparison of continuous variables will be conducted using the t-test or 
nonparametric method, as appropriate. The comparisons of the prevalence of categorical CV risk factors will be 
conducted using the Chi-square test or the Fisher's exact test, as appropriate. All comparisons will be conducted at the 
alpha=0.05 level of signiﬁcance using two-tailed tests, unless otherwise noted. To account for the potential for multiple 
comparisons artifact: a) First, signiﬁcance testing will be based on a priori hypotheses and not spurious signiﬁcant p- 
values; b) Second, if multiple comparisons are undertaken, adjustments in the threshold for statistical signiﬁcance will 
be made as necessary. If multiple and collinear variables are detected, appropriate techniques will be utilized to 
minimize the impact of collinearity on the statistical efﬁciency of the derived parameter estimates. 
 
To explore the associations of anti-CCP antibody, which can be analyzed as a dichotomous or continuous variable, other 
characteristics of RA (e.g. duration; activity; severity), and myocardial FDG uptake with continuous measures of global 
LV structure (e.g. LV mass) and function (e.g. ejection fraction, end-systolic volume stroke volume), we will perform 
descriptive analyses and potential data transformation as needed required to meet the requirement for statistical tests 
involved. LV structural and functional outcomes for those with presence/absence of anti-CCP antibody, longer/shorter 
RA duration, or more/less severe RA will be compared using t-tests or an appropriate non-parametric test. Association 
between LV structural and functional outcomes and anti-CCP antibody level and other RA characteristics as continuous 
predictors will be examined using nonparametric approach such as Loess plots to explore the natural form of the 
associations. Multivariate regression models (linear, polynomial, or piecewise regression, as appropriate) will be used 
to evaluate whether associations are independent of potential confounders. This will include explicitly adjusting for 
conventional CV risk factors in the investigation of associations of LV mass/contractility with RA characteristics to 
studying the degree in which these associations are independent of these risk factors. 
 
Linear mixed effects (MIXED) regression models will be used to assess trends in LV structure and functional 
outcomes over time between the two visits for the patients who will undergo randomization reevaluation with PET-CT 
and 3D Echocardiogram, while controlling for potential confounders. The data will include PET-CT studies for 25 RA 
patients receiving TNF antagonists and 25 RA patients receiving alternative treatment, and PET-CT studies for 15 non- 
RA patients. The data are longitudinal since LV outcomes are measured for each person at 2 different time points. 
Since repeated measures tend to be correlated within a person, mixed models with both ﬁxed and random effects will be 
used to adjust for this correlation. We will use unstructured correlation structure given that each visit will occur roughly 
around a ﬁxed time since study visit I, and use robust standard error estimates to conduct statistical inferences. To study 
the TNF inhibitor effects on LV structure or functional outcomes, visit­speciﬁc indicators, RA status, TNF treatment 
status, and visit x TNF treatment interaction will form the bases for the mean model. The visit­speciﬁc indicators will 
capture the time trend of LV outcomes over the study period, the RA status will delineate the overall mean difference in 
LV outcomes between RA and non-RA, with the TNF treatment status indicator and its interaction with visit indicators 
capturing the baseline difference in LV outcomes between TNF treated and non-treated groups and the potential TNF 
treatment effect on LV outcome over time, respectively. Actual TNF inhibitor dosage could be used 
in place of TNF status indicator in the model if necessary, and other potential covariates could be added into the model 
for confounding adjustment. For example, inflammation markers could be added into the model to examine whether any 
TNF treatment effect is mediated through the change in systemic inflammation. Similar modeling approaches can be 
used to study all research questions of interest using the corresponding outcomes and their hypothesized predictors 
listed in those questions to be addressed. For any binary outcomes in this type of regression analysis, e.g. indicator of 
whether a LV outcome exceeding certain critical value, generalized linear mixed effects models (GLIMMIX) can be 
used to study the odds of such outcome as a function of the independent variables. 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 7 of 23 
 
 
 
 
All analyses will be performed with STATA statistical software, version 9.0 (STATA Corp, College Station, TX) and 
PLINK (http://pngu.mgh.harvard.edu/ purcell/plink). In all tests, a two-tailed alpha error of 0.05 will be deﬁned as the 
level of statistical signiﬁcance. 
 
References: 
1. Saag KG, Teng GG, Patkar NM, et al: American College of Rheumatology 2008 recommendations for the use of 
nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008,59 
(6):762-84. 
2. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allart CF, et al: Clinical and radiographic outcomes of four 
different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled 
trial. Arthritis Rheum. 2005, 52:3381-3390 
3. Van Tuyl LH, Lems WF, Voskuyl AE, et al. Tight control and intensiﬁed COBRA combination treatment in early 
rheumatoid arthritis: 90% remission in a pilot trial. Ann Rheum Dis. 2008, 67(11):1574-7 
 
 
 
2b. Sample size and power calculations 
 
To investigate the dose-response association between two continuous variables in cross-sectional analyses, we will ﬁrst 
categorize the sample into 4 equal sized groups based on the quartiles of the continuous predictor and study the dose 
response association pattern using one-way ANOVA. With a total sample size of 150 for study Visit I, thus N=37 per 
group, in such a one-way ANOVA we will have 80 % power to detect a dose response pattern with a difference of 0.25 
SD or high in any two adjacent quartiles. When linear association is a good measure to characterize the dose response 
association between a continuous outcome and a continuous predictor, we will have 80% power to detect a correlation 
level of 0.227 or higher, in either direction, with a total N=150 and a two-sided alpha error of 0.05. 
 
We will obtain valuable information on LV structure/function outcomes for the cross-sectional visit, as well as for 
change in these outcomes over 6 months, for 3 groups of study participants, 25 RA patients treated with TNF- 
antagonist, 25 RA patients treated with triple treatment or alternative, and 15 non-RA participants with otherwise 
similar characteristics. For continuous outcomes we will obtain mean, standard deviations, and skewness (to inform us 
whether certain variables may need transformation before analyses so that sample size/power evaluation for future 
studies may need to be based on transformed data) for cross-sectional as well as the change over time measurements, 
and the correlations between two consecutive measurements over time. For binary variables we will obtain prevalence 
estimates and odds ratios as estimates of association between two repeated binary measures over time. Even 
accounting for a possible 15% drop out rate of participants, the correlation estimate will have precision ranged 
approximately between within +/- 0.33 for a correlation of 0.50 and within +/- 0.09 for a correlation of 0.90. For 
prevalence of binary outcomes, our estimate will be ranged approximately from within +/- 17.9% for a prevalence of 
50% to +/-10.7% for a prevalence of 90%. To estimate the power of detecting a 24 week (6 month) change in an LV 
myocardial outcome within the TNF treated RA group, with a 2-sided alpha of 0.05 and N=22 (accounting for possible 
drop out), we calculated the minimal detectable change based on cross-sectional SDs and various values for within 
person correlation between outcome measures at subsequent visits based on data from previous studies performed by the 
same investigator group. For example with a conservative SD of 1.8 L/min for cardiac output (CO) and 4.2 mL/m2 for 
stroke volume (SV) and the correlation between subsequent visits being 0.2 we will have 80% power to detect a 24 
week (6 month) change of 1.47 l/min for CO or 3.42 ml/m2 for SV or more in the TNF inhibitor treated RA group. 
Similarly in order to estimate power for comparing changes between the TNF inhibitor treated group, the triple therapy 
treated group and the normal control group  we based our calculations with comparing the changes between those 
groups with one way ANOVA assuming a 15% drop out and a 2-sided alpha of 0.05. We will have 80% power to 
detect any set of 3 group differences/changes if the SD of the changes is 0.444 or greater. We will have 80% power to 
detect a difference through the 3 group-one-way-ANOVA if the mean 24 week (6 month) change in SV for the TNF 
inhibitor group is 5.2ml/m2 or higher while the mean change for the other two groups is 0. To provide a context 
regarding the number used above as an expected change in SV we would like to mention here that in our pilot data we 
observed a change in SV of 12.5mL/m2 or higher with TNF inhibitor treatment in patients with RA. 
Based on preliminary data RA patients had an LV mass of 120± 27 grams while normal people had an LV mass of 147 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 8 of 23 
 
 
±40 gram. For a change in left ventricle mass from 120 to 147 grams over the 6 month period we will have an 80% 
power to detect this improvement of LV mass in 25 patients treated with TNF inhibitor with a one sided alpha of 0.05 
assuming a correlation of 0.35. We will have more than 85% power to detect a difference of 27 grams of mass between 
the TNF inhibitor treated group and the triple therapy treated group. 
For changes in FDG uptake indicative of myocardial inflammation we assume that according to AHA guidelines a 
signiﬁcant change in the intensity of FDG uptake would be equal to a decrease of 50%. We will have more than 80% 
power to detect such a difference between the TNF inhibitor treated group and the triple therapy treated group after 6 
months of treatment with a 2 sided alpha of 0.05. 
 
3. STUDY PROCEDURES (See Appendices I,II and III) 
 
Study procedures that are done outside the context of usual care for patients with RA are the following: 
 
i. 
 
Cardiac PET-CT imaging will be used to evaluate myocardial perfusion, myocardial inflammation and myocardial 
function. 
 
(this section includes references) 
PET Perfusion Imaging: 
The demonstration and quantiﬁcation of myocardial hypoperfusion/ischemia with nuclear imaging techniques is a 
well-established method to predict cardiovascular disease progression risk in cardiac patient populations (1). 
Myocardial hypoperfusion is a powerful predictor of cardiac endpoints such as nonfatal myocardial infarction and 
death. Myocardial blood flow determined by quantitative PET is an independent predictor of the coronary circulatory 
dysfunction in cardiac clinical events and shows superiority to conventional methods. In a recent review, Schindler et 
al report that functional alterations in cardiac circulation measured by PET imaging appear to be prognostically 
superior to structural assessments of coronary vessel disease (i.e. coronary angiography, calciﬁcation) in predicting 
future cardiac events. PET measurement of coronary flow reserve provides a sensitive index for evaluating changes in 
coronary disease severity. A review of a series of seven studies involving more than 1000 patients indicates that 
perfusion imaging with PET is a sensitive and speciﬁc method to diagnose severity of coronary disease (1). These 
studies found an average sensitivity and speciﬁcity of approximately 90% (1,2). 
PET measurement of myocardial perfusion is an ideal measure of coronary and microvascular involvement for the 
purposes of this study, and is preferable to other available techniques. In addition to prognostic signiﬁcance, there are 
several reasons for the choice of quantitative PET for myocardial perfusion. The use of PET addresses common 
limitations of other methods such as coronary angiography. That is, percent diameter stenosis of coronary vessels 
obtained by means of coronary angiography is poorly related to flow capacity or coronary flow reserve of the coronary 
arteries. Gould and colleagues have reported that progression or regression of coronary vessels stenosis may involve 
complex changes in which the integrated hemodynamic effects, absolute arterial lumen area, and length are not 
accounted for by any single geometric measurement such as percent stenosis. Furthermore, quantifying single focal 
stenoses on coronary arteriograms does not account for multiple stenoses, diffuse anatomic lesions, or disorders of 
arterial vasomotion. Therefore, coronary angiography, including quantitative coronary angiography, does not reflect 
the perfusion capacity of the integrated coronary artery circulation that is diseased in atherosclerosis. It has thus been 
suggested that the measurement of size and severity of myocardial perfusion abnormalities by PET-CT better reflects 
changes in the integrated flow capacity of the coronary circulation that are more relevant to long-term clinical outcomes 
and more sensitive to modest changes in lifestyle modiﬁcation interventions than other diagnostic methods (1,2). 
PET-CT imaging also provides accurate information about microvascular blood flow and endothelial dysfuction. 
 
PET Imaging Protocol: 
 
PET utilizes radiolabeled agents (such as [13N] ammonia) for the measurement of myocardial blood flow at rest and 
during pharmacological stress using agents such as the vasodilator adenosine. The percent increase in blood flow from 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 9 of 23 
 
 
rest to stress provides a measure of coronary blood flow reserve, including microvascular flow. Normal subjects 
without cardiovascular disease or risk factors have a coronary flow reserve on the order of 4. They are capable of a 4 
fold increase in blood flow with pharmacological stress, while patients with coronary artery disease demonstrate 
attenuations in coronary flow reserve. 
We will perform PET myocardial perfusion imaging using [13N] ammonia for the measurement of myocardial blood 
flow at rest and during pharmacological stress using the vasodilator adenosine. PET imaging will be performed in a 
blinded procedure in all subjects under the supervision of Dr. Bokhari, Investigator and Director of the Columbia 
University Medical Center Cardiac Positron Emission Tomography Center. Dr Bokhari will otherwise have no contact 
with the study subjects and will not be aware of participants' clinical info collected during the study. The PET data will 
be acquired on the Siemens Biograph Truepoint 40 PET/CT scanner. The camera has 4mm resolution and scan time 
performance superior to the prior generation of PET imaging devices. The Siemens biograph uses computed 
tomography (CT) acquisition for attenuation correction as well as co-registration with the emission image. PET data 
are collected in 47 planes 3.375 mm thick that cover a range of 16 cm. A dose of 10 mCi of [N13] ammonia is injected 
and a 10 min dynamic acquisition is started. The process is repeated, including a second attenuation scan, for the stress 
study. The injections of ammonia are separated by at least 40 minutes to allow the ﬁrst injection to decay to a level 
where it will not interfere with the second study. All scanning is performed in 2D gated mode and reconstructed with 
ﬁltered back projection using a Hann ﬁlter cutoff at 1 cycle/cm. 
 
PET-CT Flow Measures: 
 
To calculate coronary flow reserve, measurements of regional myocardial blood flow at rest and during adenosine 
stress will be obtained. For this purpose, list mode data will be formatted into dynamic frames of variable length (12 
frames x 5 sec, 3 frames x 20 sec, 1 frame x 300 sec). The last frame is used as a template for sectorial region of 
interest (ROI) analysis of the dynamic images. The input function is generated by drawing an ROI in the LV chamber 
on a mid-ventricular slice. This procedure yields PET absolute flow measurements in dL/min per 100 gms. The left 
ventricle is sampled radially from 40 different angles and 40 samples of flow are obtained for each short axis slice. The 
resulting hundreds of samples are grouped into 17 segments. Since the number of slices is variable, the total number of 
ﬁnal samples will vary. Thus, for each segment we will obtain between 520 samples, from which means and standard 
deviations will be computed for each of the 17 regions. This procedure of repeated sampling allows a greater precision 
in the flow data. Coronary flow reserve is the ratio of maximum flow during stress to flow at rest. An overall measure 
of coronary flow reserve for the entire myocardium (across all the 17 regions) will be calculated. Secondarily, regional 
flow reserve will be calculated according to vascular territories designated by standard techniques, i.e., left anterior 
descending (LAD), left circumflex (LCX), and right coronary artery (LCA). Additionally, base to apex myocardial 
perfusion gradients will also be quantiﬁed according to methods described by Gould and colleagues. From territorial 
areas, additional segmentation dividing mid and mid to apical circumferences of the left ventricle will be assigned 
within each polar map. Within each area, relative myocardial tracer concentrations will be quantitated by comparison to 
a normal database. 
 
Myocardial Perfusion Defect Score: 
 
In addition to the flow measures described above, we will construct a quantitative summed stress and rest score 
describing the extent and the severity of the perfusion defects across 17 segments of the myocardium. In each region, 
the defect severity is quantiﬁed on a 4 point scale from normal to absent perfusion. The regional severity scoring is then 
summed up across the 17 segments yielding a total score. Separate total scores are obtained for the rest and stress 
conditions, with the rest score assessing ﬁxed or irreversible defects. A reversible defect score will be obtained by 
subtracting the rest score from the stress score (i.e., summed difference score). For each of the summed rest, stress, and 
difference scores, each patients score will be divided by the highest possible score to yield a % myocardial involvement. 
These scores will represent secondary outcome for statistical analysis. 
 
PET for inflammation: 
 
F18 fluorodeoxyglucose (FDG) is a glucose analog that is taken up in metabolically active cells including myocytes 
and tumor cells. It is also taken up in regions of inflammation. Uptake into myocytes depends on substrate, insulin 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 10 of 23 
 
 
levels and GLUT4 transporter. Uptake by tumor and by regions of inflammation presumably uses GLUT1, a non 
insulin dependent transporter. Positron emission tomography will be performed on all patients from the base of the 
skull to the chest cavity after injection of F18 FDG and CT scan for neck and chest will be performed. Images will be 
obtained one to two to three hours after injection. Glucose levels will be checked at the time of injection using a 
standard clinical protocol. Uptake of tracer will be reported as global or focal and scored. Intensity of uptake will be 
scored according to a scale from 0 to 3. Level 0 will be no myocardial uptake. Level 1 will be myocardial uptake less 
than the mediastinal uptake. Level 2 will be uptake in the myocardium equal to mediastinal uptake. Level 3 will be 
uptake in the myocardium that is greater than mediastinal uptake. Extent of uptake will be assessed as number of 
speciﬁc regions of increased intensity. 
A computerized program will also be utilized to assess for the standardized uptake value (SUV) which will give a 
continuous variable based on quantitative uptake. 
 
CT scan images of the neck and/or chest will be fused with PET scan images to correlate the regions with regions of 
increased uptake. 
 
PET-CT for the evaluation of ventricular function: 
 
PET assessment of ventricular function is performed during gated myocardial perfusion imaging. With gated PET, 
accurate measurements are made of LV end-diastolic and end-systolic volumes as well as of LV ejection fraction. 
Additionally this method allows for assessing regional and global ventricular function both at rest and stress. 
 
Reliability of Cardiac PET Image Reading: 
 
The analysis of cardiac PET scans is largely automated and subject to minimal operator input. Nevertheless, we will 
monitor reliability of the analysis process. Inter rater and test retest reliability for analysis of cardiac PET scans will be 
performed prior to the start of the study with two research physicians; using 20 prior scans from previous imaging 
procedures. These scans will be analyzed independently while blinded to subject identity and diagnosis. For inter rater 
and test retest reliability, an intra-class correlation coefﬁcient (ICC) >.9 will be considered acceptable. The process will 
be repeated until this threshold is met. These readings will not be used in the ﬁnal data analysis. All scans will be 
analyzed at the conclusion of the study by one of the physician raters blinded to subject identity and treatment group 
who will not have had contact with the study subjects or involvement in any clinical aspect of the study. Having scans 
read by a single rater ensures consistency of the measurement. The PET scans will be randomly sequenced for reading 
by subject group and treatment phase. 
 
3 transverse CT images for the distribution of visceral fat: 
 
Adipose tissue distribution provides an assessment of risk  for the development of cardiovascular disease depending on 
whether is predominantly accumulated as visceral fat or not. Since patients will undergo CT imaging of the chest as 
part of the cardiac PET-CT imaging protocol we will take the opportunity to obtain 3 additional transverse CT images 
at the level of the liver, lumbar region and mid-thigh. These images will be obtained within seconds while the patient is 
having the PET-CT cardiac evaluation and with minimal additional exposure radiation. Fat distribution will be used in 
our analyses as a potential mediator or confounder of alterations in myocardial perfusion and structure. 
 
CT imaging for Coronary Artery Calciﬁcation (CAC): 
 
Coronary artery Calciﬁcation (CAC), a subclinical measure of atherosclerosis measured by Computer Tomography 
(CT) is associated with the degree of atherosclerotic plaque, and is strongly predictive of cardiovascular events 
including those at low risk. Coronary arterial calciﬁcation is part of the development of atherosclerosis, occurs almost 
exclusively in atherosclerotic arteries, and is absent in the normal vessel wall. Coronary artery calciﬁcation occurs in 
small amounts in the early lesions of atherosclerosis that appear in the second and third decades of life, but it is found 
more frequently in advanced lesions and in older age. 
All subjects (RA patients and controls) will undergo cardiac CT scanning at the same time as the PET examination 
during study visit 1 only. Electron-beam computed tomography (EBCT) and multi-detector computed tomography 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 11 of 23 
 
 
(MDCT) are the primary fast CT methods for CAC measurement at this time. Both technologies employ thin slice CT 
imaging, using fast scan speeds to reduce motion artifact. Thirty to 40 adjacent axial scans usually are obtained. A 
calcium scoring system has been devised based on the X-ray attenuation coefﬁcient, or CT number measured in 
Hounsﬁeld units, and the area of calcium deposits. For our study we will quantify CAC using the Agatson method, with 
a phantom of known calcium density scanned along with the participant to ensure standardization across scans. A CT 
study for coronary artery calcium measurement is completed within 10 to 15 min, requiring only a few seconds of 
scanning time. 
The methodology to be used used has been extensively described and standardized and can be reviewed in the 
reference literature below (3-5). 
 
 
 
References: 
 
1. Klocke, FJ, Baird, MG, Lorell, BH, Bateman, TM, Messer, JV, Berman, DS, O'Gara, PT, Carabello, BA, Russell, 
RO, Jr., Cerqueira, MD, St John Sutton, MG, DeMaria, AN, Udelson, JE, Kennedy, JW, Verani, MS, Williams, KA, 
Antman, EM, Smith, SC, Jr., Alpert, JS, Gregoratos, G, Anderson, JL, Hiratzka, LF, Faxon, DP, Hunt, SA, Fuster, V, 
Jacobs, AK, Gibbons, RJ , Russell, RO, ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide 
imaging-executive summary: a report of the American College of Cardiology/American Heart Association Task 
Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of 
Cardiac Radionuclide Imaging). Circulation 2003; 108: 1-15 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? 
cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14522503 
2. Schindler, TH, Zhang, XL, Vincenti, G, Mhiri, L, Lerch, R , Schelbert, HR, Role of PET in the evaluation and 
understanding of coronary physiology. J Nucl Cardiol 2007; 14(4): 589-603 http://www.ncbi.nlm.nih.gov/entrez/ 
query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17679069 
3. Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs DR Jr, Sidney S, Bild DE, Williams OD, Detrano 
RC: Calciﬁed coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol 
of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk 
Development in Young Adults (CARDIA) study. Radiology 2005, 234:35-43. 
4. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R: Quantiﬁcation of coronary-artery 
calcium using ultrafast computed-tomography. J Am Coll Cardiol 1990, 15:827-832. 
5. Nelson JC, Kronmal RA, Carr JJ, McNitt-Gray MF, Wong ND, Loria CM, Goldin JG, Williams OD, Detrano R: 
Measuring coronary calcium on CT images adjusted for attenuation differences. Radiology 2005, 235:403-414. 
 
 
 
ii. 
 
3-Dimensional Echocardiography (3D Echo) will be used to evaluate LV mass. 
(this section includes references) 
3D Echo for evaluation of LV mass 
 
3D Echo has demonstrated incremental value about LV mass over conventional echocardiographic modalities (M- 
mode, 2D Echo) in different patient populations [1,2]. The major strength of 3D Echo is the accurate imaging of 
cardiac structures avoiding the need for geometric assumptions in order to calculate outcomes such as the mass of the 
left ventricle. 
Conventional echocardiographic modalities are limited mainly by inaccuracies and variations caused by use of 
geometric assumptions in case of asymmetric LV geometry and unintended use of oblique planes. 3D Echo, based on 
the assessment of a larger number of tomographic views, resolves these limitations. 3D Echo correspondingly has the 
advantage of reducing dependence on geometric models and reducing error based on angulated images [3, 4]. Thus, 
3D Echo offers LV mass determination substantially comparable to cardiac magnetic resonance (CMR) imaging, as for 
global LV volumes [5]. This correlation between 3D Echo and CMR has also been stronger than that has been between 
conventional echocardiography and CMR [6]. Interobserver variability of real-time 3 dimensional echocardiography 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 12 of 23 
 
 
(RT3DE) was additionally reported to be signiﬁcantly lower than that of 2D Echo, supporting its superiority [7]. 3D 
Echo accuracy, has been veriﬁed using autopsy ﬁndings [4]. 3D Echo and CMR also produce comparable results in 
terms of LV mass with similar interobserver variability [8]. Moreover, 3D Echo is less dependent on operator practice 
and help to compensate operator inexperience when compared to conventional echocardiography. 
3D Echo is feasible in the clinical setting and provides fast and accurate assessment of LV mass, which is superior to 
conventional echocardiographic methods, especially in distorted hearts. This leads to greater sensitivity and reduced 
sample size. As 3D Echo is less costly than CMP, it is modality of choice for the proposed study. 
 
References: 
 
1. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, Morehead A, Kitzman D, Oh J, Quinones 
M, Schiller NB, Stein JH, Weissman NJ: American Society of Echocardiography. American Society of 
Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004, 
17:1086-119. 
2. Yao J, Cao QL, Masani N, Delabays A, Magni G, Acar P, Laskari C, Pandian NG: Three-dimensional 
echocardiographic estimation of infarct mass based on quantiﬁcation of dysfunctional left ventricular mass. Circulation 
1997, 96:1660-6. 
3. Natori S, Lai S, Finn JP, Gomes AS, Hundley WG, Jerosch-Herold M, Pearson G, Sinha S, Arai A, Lima JA, 
Bluemke DA: Cardiovascular function in multiethnic study of atherosclerosis: normal values by age sex and ethnicity. 
AJR Am J Roentgenol 2006, 186(6 Suppl 2):S357-65. 
4. Qin JX, Jones M, Travaglini A, Song JM, Li J, White RD, Tsujino H, Greenberg NL, Zetts AD, Panza JA, Thomas 
JD, Shiota T: The accuracy of left ventricular mass determined by real-time three-dimensional echocardiography in 
chronic animal and clinical studies: a comparison with postmortem examination and magnetic resonance imaging. J 
Am Soc Echocardiogr 2005, 18:1037-43. 
5. Jenkins C, Marwick TH: Baseline and follow-up assessment of regional left ventricular volume using 3- 
Dimensional echocardiography: comparison with cardiac magnetic resonance. Cardiovasc Ultrasound 2009, 7:55. 
6. Nikitin NP, Constantin C, Loh PH, Ghosh J, Lukaschuk EI, Bennett A, Hurren S, Alamgir F, Clark AL, Cleland JG: 
New generation 3-dimensional echocardiography for left ventricular volumetric and functional measurements: 
comparison with cardiac magnetic resonance. Eur J Echocardiogr 2006, 7:365-72. 
7. Caiani EG, Corsi C, Sugeng L, MacEneaney P, Weinert L, Mor-Avi V, Lang RM: Improved quantiﬁcation of left 
ventricular mass based on endocardial and epicardial surface detection with real time three dimensional 
echocardiography. Heart 2006, 92:213-9. 
8. Pouleur AC, le Polain de Waroux JB, Pasquet A, Gerber BL, Gérard O, Allain P, Vanoverschelde JL: Assessment of 
left ventricular mass and volumes by three-dimensional echocardiography in patients with or without wall motion 
abnormalities: comparison against cine magnetic resonance imaging. Heart 2008, 94:1050-7. 
 
iii. Phlebotomy - laboratory examinations (See Appendix II) 
 
Participants will undergo laboratory testing and related procedures according to standard of care for monitoring of 
patient with Rheumatoid arthritis on arthritis medications. Part of the blood obtained will be for usual patient care and 
part for research purposes as shown in the list below. The exact distribution of testing according to the visit can be 
viewed in Appendix II. 
For study visit I standard of care tests and procedures will not be duplicated if they have already been performed prior 
to study entry and if results are available in patients records. 
 
LABS TO BE PERFORMED AS PART OF REGULAR CARE 
Rheumatoid factor 
CCP antibodies 
Complete blood count with differential (CBC) 
Comprehensive metabolic panel (CMP) 
CRP (CRP), ESR 
Fasting lipid panel 
G6PD 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 13 of 23 
 
 
HCV Ab 
HBVsAg and HBVsAb 
 
LABS FOR PURELY RESEARCH PURPOSES 
Blood for processing, storage, and future biomarker evaluation 
 
OTHER PROCEDURES THAT ARE CONSIDERED STANDARD OF CARE 
(this section includes references) 
Urine pregnancy test during every study visit involving radiation exposure (prior to the imaging and on the same day) 
PPD placement (1) for latent tuberculosis 
Pneumococcus vaccination (1) 
Influenza (seasonal and H1N1) vaccination (1) 
Opthalmologic examination prior or within one year from initiation of treatment with Plaquenil (hydroxychloroquine) 
according to standard of care, as Plaquenil may rarely cause retinal toxicity (1) 
 
As noted earlier this procedures will not be duplicated if they have taken place as part of usual care prior to 
participation in the study. 
The total volume of blood for the purely research tests is 65 ml in study visits. In addition labs as part of usual care 
will add 21.4 ml of blood draw volume in Study Visit I and 9.4 ml in study visit II. The maximum amount of blood to 
be drawn including both research and usual care tests (at visit I) will be 86.4 ml in study visit I and 74.4 ml in study 
visit II. 9.4 ml of blood will be drawn in safety visits. 
Blood samples for research purposes will be stored in Rheumatology divisional freezers at Columbia University in a 
de­identiﬁed manner indicated only by a numeric patient ID. 
 
References: 
1. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, et al: American 
College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying 
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008,59(6):762-84. 
 
iv. Clinical examination including joint examination, anthropometry and vital signs (See also Appendix I) 
A musculoskeletal comprehensive examination to obtain counts of swollen and tender joints will take place in every 
visit. In addition as shown in appendix I other evaluations including seated blood pressure, waist circumference and 
height and weight will be obtained. 
 
v. DEXA scan 
A whole body DEXA scan will be performed on the 50 RA patients who will be randomized to escalation of treatment. 
As shown in appendix I it will be performed at the time of Study Visit I and II. The purpose will be to evaluate the 
amount and the pattern of adipose tissue distribution in the body which is an important parameter and risk factor for 
atheromatous and cardiovascular disease. Radiation exposure is minimal (0.001 rem) per study per patient and there are 
no risks associated with this study. Pregnancy test as noted earlier will be performed prior to DEXA for every female 
participant with child bearing potential. 
 
vi. Questionnaire completion (See also Appendix III) 
Patients will be asked to complete questionnaires at the time of their study visits as indicated in Appendix III. The 
questionnaires will be administered in English and Spanish and with the assistance of a research coordinator. The 
questionnaire list is included below 
 
SF36 
HAQ 
Health and life questionnaire 
Physical activity questionnaire 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 14 of 23 
 
 
Medical history 
Prednisone history 
RA history 
Oral Health 
Medication history 
RA medication history 
Joint Count 
Personal history 
RA LTRC respiratory symptoms 
RA LTRC Occupational and environmental exposures 
400m Walk Test 
 
4. STUDY DRUGS OR DEVICES 
 
The drugs that will be prescribed to subjects in this study, listed below, are FDA approved for the indicated use, at the 
prescribed dose(s), and in the patient populations being studied. 
TNF INHIBITORS 
ENBREL® (etanercept) 
REMICADE® (infliximab) 
SIMPONI® (golimumab) 
HUMIRA® (adalimumab) 
CIMZIA ( certolizumab) 
 
OTHER RA MEDICATIONS 
PLAQUENIL® (Hydroxychloroquine sulfate) 
ARAVA® (leflunomide) 
Methotrexate 
Sulfasalazine 
Folic Acid 
Prednisone 
 
5. STUDY INSTRUMENTS 
 
SF 36 (Appendix IV): The SF 36 questionnaire is the most widely used tool for measuring patient-reported quality of 
life. It captures practical, reliable, and valid information about functional health and well-being from the patient's point 
of view. This surveys is for adults 18 years of age and older, and can be self-administered or interview-administered. Is 
extensively validated and standardized. 
 
HAQ (Appendix V): The Health Assessment Questionnaire (HAQ) was developed originally in 1978 by James F. 
Fries, MD, and colleagues at Stanford University. It was designed to represent a model of patient-oriented outcome 
assessment. The HAQ has been administered and validated in patients with a wide variety of rheumatic diseases, 
including rheumatoid arthritis. 
It is one of the ﬁrst self­report functional status (disability) measures, and is widely used throughout the world. 
Although it measures functional status it was found to be the best predictor of mortality in patients with RA. The HAQ 
has become a de facto mandated outcome measure for clinical trials in rheumatoid arthritis and some other diseases. Is 
extensively validated and standardized. 
 
Health and life questionnaire (Appendix VI): This questionnaire includes several instruments designed to measure 
psychosocial characteristics that may be important in understanding the causes of cardiovascular disease. These 
psychosocial factors may themselves lead to increased risk of cardiovascular disease or may interact with other 
traditional risk factors, such as diet or sedentary lifestyle. The areas assessed as part of this questionnaire include 
neighborhood, characteristics, depression, stress, and social support. This is a self-administered form. The terms used 
in the questionnaire should require no explanation, because they are used in the way they tend to be used by most 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 15 of 23 
 
 
people in everyday life. This questionnaire has been extensively used in research before and also during the Multi- 
Ethnic Study of Atherosclerosis (MESA). 
 
Physical activity questionnaire (Appendix VII): The International Physical Activity Questionnaires (IPAQ) is a 
standardized questionnaire that will be used to evaluate levels of physical activity. It can be used for  either telephone or 
self-administered methods are available. The purpose of the questionnaires is to provide common instruments that can 
be used to obtain internationally comparable data on health related physical activity. The development of an 
international measure for physical activity commenced in Geneva in 1998 and was followed by extensive reliability and 
validity testing undertaken across 12 countries (14 sites) during 2000. The ﬁnal results suggest that these measures have 
acceptable measurement properties for use in many settings and in different languages, and are suitable for national 
population-based prevalence studies of participation in physical activity. 
 
Medical history, Prednisone history, RA history, Medication history (Appendices VIII, IX, X, XI): these questionnaires 
only collect history information from the patient, do not require a scoring system and do not need to be standardized or 
validated as they are used  only as history taking tools. However they have been used in our previously federally funded 
study (ESCAPE I) in the context of MESA (Multi-Ethnic Study of Atherosclerosis) 
 
Oral Health Assessment (Appendix XII): this questionnaire collects information about oral conditions, dental and 
periodontal disease. RA can affect the oral cavity causing xerostomia (dry mouth) which may predispose to dental 
disease. In addition a theory linking RA pathogenesis with periodontal disease is under investigation by the research 
community. This questionnaire does not provide an "oral health score" and is not a standardized data collection tool. It 
is a symptom and personal history collection form. 
 
RA medication (Appendix XIII) and Joint count (Appendix XIV) questionnaires: these questionnaires only collect 
history information from the patient, do not require a scoring system and do not need to be standardized or validated as 
they are used only as history taking tools. Appendix XIII collects information on medications for the treatment of 
rheumatoid arthritis (not other medications). Appendix XIV collects information about the number of joints that are 
affected by RA since numbers of affected joints inform therapeutic decisions. 
 
Personal history (Appendix XV): The Personal History questionnaire is used to collect information on socio-economic 
status (SES) and smoking and drinking habits, all of which are related to an individuals risk of cardiovascular disease. 
It has been used in previous studies such as in ESCAPE I and in the Multi-Ethnic study of atherosclerosis (MESA) 
 
Lung Tissue Research Consortium (LTRC) respiratory symptom questionnaire (Appendix XVI) and LTRC occupational 
and environmental exposure (Appendix XVII): Respiratory involvement is the second cause of mortality in patients 
with RA and symptoms overlap with those from cardiovascular disease. We will use these questionnaires to investigate 
the risks for respiratory involvement and the prevalence of respiratory symptoms in our research subjects. This 
questionnaires are used extensively in pulmonary disease related research by entities such as the Lung Tissue Research 
Consortium (LTRC) and the American Thoracic Society. 
 
400m Walk Test (Appendix XVIII)): Participants will be asked to walk a short distance (400m). This will happen under 
supervision by the research coordinator and after cardiovascular contraindications have been ruled out by the attached 
questionnaire. Vital signs will be recorded prior to and after the completion of the test. All information will be recorded 
in the attached questionnaire. The purpose of this test is to evaluate the tolerance to mild exercise and the response of 
the cardiovascular system (Heart Rate and Blood pressure) to brisk walking. This test has been used in several studies 
including MESA. 
 
6. STUDY SUBJECTS 
 
(this section includes references) 
 
Subjects fulﬁlling the 2010 ACR-EULAR diagnostic criteria for RA (1) but without any history of previous self 
reported or physician diagnosed cardiovascular events will be eligible for participation in the study. The goal is to 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 16 of 23 
 
 
enroll 150 patients for the purposes of this protocol. Subjects will be recruited from the arthritis clinics at the 
Columbia University. 
 
Among the subjects above, patients with RA who have moderate to high disease activity as deﬁned by a CDAI higher 
than 10 will be given the opportunity to consent for randomization in treatment with either a TNF inhibitor or 
alternative treatment and return for follow up visits as indicated in earlier sections. 50 patients will be randomized to 
this aspect of the study. 
 
15 subjects without RA and without prior cardiovascular disease will also be recruited. These subjects will be recruited 
among patients in the internal medicine clinics at the Columbia University or from friends of the recruited patients. 
 
Inclusion Criteria 
For patient participation in Study Visit I (150 participants): 
 
Diagnosis of RA 
Age>18 years old 
For patient participation in the randomized treatment and subsequent visits (50 of the initially recruited 150 
participants): 
 
Moderate to high RA disease activity deﬁned by a CDAI of >10 
 
Stable dose of Methotrexate for 6 weeks prior to enrollment; 
 
Stable doses of NSAID and prednisone (if already taking these medications) for 2 weeks prior to study 
 
For control participation (15 controls): 
Age>18 years old 
Absence of diagnosis of RA. 
Major Exclusion Criteria 
For patient participation in Visit I (150 participants): 
Prior self-reported physician diagnosed CV event (MI; angina; stroke or TIA; HF; prior CV procedure (e.g., coronary 
artery bypass graft, angioplasty, valve replacement, pacemaker); 
Contraindications to having a PET-CT scan or receive adenosine or FDG. 
Active treatment for Cancer 
 
For patient participation in the randomized treatment and follow up visits (50 of the 150 initially enrolled 
participants): 
 
Uncontrolled hypertension 
Diabetes 
Smoking 
Treatment with a TNF inhibitor or other biologic currently or within the last 6 months 
Treatment with any non-biologic DMARD other than MTX in the past two months; 
Untreated positive PPD or active tuberculosis 
History of Lymphoma and Melanoma 
Ejection Fraction (EF) < 40% (if not known in advance then the Study Visit I Echocardiogram results will be used to 
exclude the patient in this part of the study) 
Change with NSAID/Prednisone dosage in last 2 weeks 
Participation in other research studies involving imaging/radiation exposure 
 
A copy of the Patient Screening Form is attached to the protocol as Appendix XXV. 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 17 of 23 
 
 
 
 
For controls : 
 
Prior self-reported or physician diagnosed CV event (MI; angina; stroke or TIA; HF; prior CV procedure (e.g., 
coronary artery bypass graft, angioplasty, valve replacement, pacemaker); 
Contraindications to having a PET-CT scan or receive adenosine or FDG. 
Uncontrolled hypertension. 
Participation in other research studies involving imaging/radiation exposure 
 
A copy of the Control Screening Form is attached to the protocol as Appendix XXVI and a copy of the Radiation 
Screening Form is attached as Appendix XXVII. 
 
RA subjects and controls who do not consent to any aspect of the study such as to the blood draws or to evaluation 
with PET-CT will be excluded from this study. 
 
In addition patient and controls who are receiving treatment for cancer, with cognitive inability will be excluded from 
the study. 
 
Patients and controls on statin treatment for hyperlipidemia should ideally stay on a stable dose and the same statin 
agent for the duration of the study. We will encourage but not require the participants and their treating physicians to do 
so. The reason is that statins are known to have an anti-inflammatory effect and may interfere with analysis/ 
interpretation of the amount of myocardial inflammation as measured during PET-CT imaging. Recognizing however, 
that some patients will be newly diagnosed with hypercholesterolemia during the clinical trial portion of the study and 
require treatment with a statin, we will allow for this medication initiation, anticipating that the number of new statin 
starts will be balanced between the two groups due to randomization. 
 
References: 
 
1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, 
Luthra HS, et al: The American Rheumatism Association 1987 revised criteria for the classiﬁcation of rheumatoid 
arthritis. Arthritis Rheum 1988, 31:315-324 
 
7. RECRUITMENT 
 
Rheumatology colleagues in the CUMC Division of rheumatology will be informed about the current study during 
regular divisional research meetings where ongoing research projects in the division is reviewed and also during day to 
day discussions among faculty and fellows. 
 
150 adult patients with RA will be recruited from the patient population seen in the rheumatology private practices and 
clinics at New York Presbyterian Hospital and Columbia University Medical Center. A letter (attached to the protcol as 
Appendix XXIX) will be sent on behalf of the Columbia rheumatology physicians to all the patients with Rheumatoid 
Arthritis followed by the above rheumatologists inviting them to participate in the study. A follow-up phone call by the 
study coordinator may also take place within a week of mailing out the letters to answer any questions the patients 
may have. 
 
Flyers (see Appendix XIX) will be available in the waiting area of the rheumatology clinics informing the patients 
about the ongoing study. 
For the enrollment of the controls the following process will be followed: Every RA patient enrolled in the study will 
be asked whether they could notify and refer friends without RA who may be willing to participate in the study. 
Referred friends will be asked to communicate by telephone with our research coordinator in order to review eligibility 
and then arrange the ﬁrst visit if eligible and willing to consent. 
 
In addition flyers describing the study and tailored for recruitment of non-RA controls will be available in the waiting 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 18 of 23 
 
 
rooms of the internal medicine clinics of the New York Presbyterian Hospital (see Appendix XX). Non-RA subjects 
who are interested in participating will use the contact information provided on the flyers to contact our research 
coordinator and undergo review of eligibility before proceeding to the consent process. 
 
 
 
8. INFORMED CONSENT PROCESS 
 
As noted above, patients will be informed of this study by their treating physician and, if the patient expresses an 
interest in participating, the Principal Investigator or Co-Investigator or the Study Coordinator will explain the study 
and review the IRB approved consent form in detail. Each potential subject will have the opportunity to ask questions. 
Each potential subject will reiterate in his or her own words the purpose of the study, the risks, the beneﬁts, and the 
alternatives to participating. Individuals who decide to participate in the study will provide written consent. The 
investigator will also sign and date the consent form. One copy of the consent form will be given to the subject and the 
original will be ﬁled in the study's research ﬁle. Those who want to sign the consent form immediately will be allowed 
to do so, but will be encouraged to take the consent form home and discuss the study with their family and/or signiﬁcant 
other before deciding whether or not to participate. 
 
Patients who are not fluent in English will be provided with an appropriate IRB approved translation of the IRB 
approved English consent form. The consent form discussion will take place with the assistance of a translator or 
bilingual member of the study team. Due to the demographics of our local population, we anticipate the need for a 
Spanish translation and will obtain a certiﬁed Spanish translation of the consent form as soon as the English version is 
approved by the IRB. We have accessibility to Spanish translators to assist with consent form discussions and other 
study visits and at least two member of our study team are bilingual. Translators are also available through the hospital 
should the need arise. 
 
9. CONFIDENTIALITY OF STUDY DATA 
 
All data and specimens collected during this study will be assigned a unique code number and will be separated from 
the patient's name and any other information that could identify the patient. The data ﬁle and the ﬁle that links the 
unique code number to patient identity will be maintained in separate password protected ﬁles on password protected 
computers in a locked ofﬁce in the Division of Rheumatology. Only the Principal Investigator and key study personnel 
designated by the Principal Investigator will have access to these ﬁles. Those with access are held to the strictest 
standards of conﬁdentiality. The results of this research may be published in scientiﬁc journals or presented at medical 
meetings, but patient identity will not be disclosed. 
 
 
 
10. PRIVACY PROTECTIONS 
 
The consent form discloses to potential participants the individuals and/or agencies that are able to look at and copy 
research records, namely: 
 
- The investigator, study staff and other medical professionals who may be evaluating the study 
- Authorities from Columbia University and New York Presbyterian Hospital, including the Institutional Review Board 
('IRB') 
- The Ofﬁce of Human Research Protections ('OHRP') 
- The Food and Drug Administration ('FDA') 
- The sponsor of this study, the National Institutes of Health, including persons or organizations working with or 
owned by the sponsor 
 
Information made available for inspection will be handled in strictest conﬁdence and in accordance with local data 
protection laws. 
 
In addition to conﬁdentiality disclosures described in the consent form, potential participants will also sign the 

NCT01548768 
05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 19 of 23 
 
 
attached study speciﬁc HIPAA Form before participating in this study. 
 
 
 
11. POTENTIAL RISKS 
 
A risk exists that despite all provisions to maintain participants conﬁdentiality, conﬁdentiality nonetheless may be 
compromised. As mentioned above every effort will be made to secure the data collected and separate identifying from 
deidentiﬁed information. 
 
Phlebotomy is associated with minor discomfort and occasional patients may experience a more severe vaso-vagal 
reaction and light-headedness. A minor risk of a skin infection at the site of phlebotomy also exists but may be treated 
with a short course of antibiotics should it occur. 
 
The mortality of the PET-CT imaging is low and associated mainly with the stress phase and administration of 
adenosine. In patients with established coronary artery disease, mortality is reported to be 2/10000 patients. The risk 
for an acute myocardial infarction is also reported to be 2/10000. These numbers will not be applicable to our 
participants as candidates with prior cardiovascular events will be screened out. 
 
In addition the mortality at the Columbia university PET center has been 0% for PET-CT stress tests for the last 11 
years with over 11000 PET-CT stress tests performed. Research participants with contraindications or risk factors for 
complications to PET-CT imaging and its stress phase (i.e., patients with cardiac blocks, or severe bronchospastic 
disease) will be excluded from the study. 
 
The radiation exposure/dosimetry with PET-CT imaging is within FDA guidelines for research of this type. The 
radiation obtained during each PET examination in our protocol would be equivalent to few months of natural and 
cosmic radiation. 
 
The additional 3 CT transverse images described above, the cardiac CT for CAC evaluation, and the DEXA are also 
associated with a small radiation exposure but no other signiﬁcant risks. Female patients will be tested with a 
pregnancy test the morning of the day of each test associated with radiation exposure. 
 
In addition the patients will have to be fasting overnight when they present for their study visits and this may cause 
mild discomfort. 
 
In every study visit participants will be asked if they received radiation from imaging procedures outside the current 
protocol (for their clinical care). If other imaging studies have taken place the cumulative radiation exposure will be 
calculated and if it exceeds the level of 50 mSv which is considered to be the maximum acceptable radiation exposure 
per year then the subject will not continue with further participation in the study. 
 
The testing performed in this study may unmask conditions that have been silent (asymptomatic). If a signiﬁcant 
medical ﬁnding is noted during participation in this study, the P.I. will be notiﬁed immediately by study personnel, 
PET-CT or Echocardiography centers. Findings will be handled as "alerts" , need for "urgent" or "immediate" referral. 
An "alert" refers to a medical ﬁnding that may have adverse health consequences if untreated. An "urgent referral" is 
made for abnormalities that require medical attention but not on an emergency basis. An "immediate referral" is a 
medical emergency that requires immediate notiﬁcation of both the participant and his/her primary care physician. 
Examples of "immediate referrals" for PET-CT scans or echocardiography will include, pericardial effusions or 
pulmonary tumors. 
 
If cause for an "immediate referral" is identiﬁed by clinical personnel or PET-CT or echocardiography personnel, the 
cardiologist or technicians will notify Dr Bathon immediately. Dr. Bathon will then take appropriate medical action 
which will include informing the patient's primary care provider immediately. The less urgent "alerts" will be 
transmitted back to the PI from the Reading Centers within two weeks after receiving the scan. Dr. Bathon will take 
appropriate action, which again will include notiﬁcation of the patient's primary care physician. A record of all this 

05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 20 of 23 
NCT01548768 
events will be maintained. 
 
 
 
 
 
12. DATA AND SAFETY MONITORING 
 
This study is a single site study employing FDA approved medications for an FDA approved indication. Furthermore, 
the study is of short duration and does not involve vulnerable populations. Therefore, it is considered low risk and in 
discussions with the NAIMS program ofﬁcer requires a safety monitoring committee but not an external DSMB. Our 
proposed safety monitoring plan for this study consists of: 
 
i. Continuous, close monitoring by the Principal Investigator in conjunction with a named Safety Ofﬁcer during the 
ﬁrst meetings of a Safety Monitoring Committee (see below);  and 
 
ii. Twice yearly meetings of a Safety Monitoring Committee (SMC). 
 
There will be prompt reporting of all adverse events to the Safety Ofﬁcer as well as prompt reporting of unanticipated 
problems, serious adverse events as well as other risk-related events to the Columbia University Medical Center IRB, 
in accordance with their reporting policy. This plan is deemed appropriate because study drugs are FDA approved and 
are used for FDA approved indications; it does not involve high risk or vulnerable populations; and it is a single site 
study of short duration. 
 
The Safety Ofﬁcer and Safety Monitoring Committee (SMC) will act in an advisory capacity to monitor patient safety 
and evaluate the efﬁcacy of the interventions described in this study. 
 
Safety assessments 
Toxicity monitoring, joint examination, general clinical examination vital signs (including blood pressure) will be 
assessed at every visit. In between Study Visits I and II patients will return every 6 to 8 weeks for safety visits per 
standard of care and which will be focused on toxicity monitoring. Interim safety visits will include the following 
laboratory assessments: CBC with differential, comprehensive metabolic panel, CRP, and ESR. An exit safety visit 
will take place approximately 8 weeks after the completion of study visit II and the evaluations mentioned above will 
take place as well. Study visits including radiation exposure (PET-CT, DEXA, x-rays) will include a urine pregnancy 
test for all female participants of childbearing potential. Disease activity will be evaluated using the CDAI score at the 
time of every safety and study visit and treatment will be escalated according to standard of care until they reach the 
state of low disease activity or remission as deﬁned by a CDAI score of less than or equal to 10. 
 
A copy of the Safety Visit Check Off Sheet is attached as Appendix XXVIII. 
Deﬁnitions of Adverse Events 
An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug (or 
therapy). Medical conditions/diseases present before starting study treatment are only considered adverse events if 
they worsen after starting study treatment. 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: (1) is fatal or life-threatening, (2) 
required or prolonged hospitalization, (3) results in persistent or signiﬁcant disability/incapacity, (4) constitutes a 
congenital anomaly or a birth defect, (5) is medically signiﬁcant, in that it may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
In this study, we will utilize a mild, moderate, and severe scale to grade adverse events. 
 
- Mild adverse events will include common side effects with these and other medications, transient laboratory test 
alterations; discomforts noted but no disruption of daily activities; no therapy, or only symptomatic therapy required. 
- Moderate adverse events will include persistent mild events that cause signiﬁcant impairment in quality of life, 
laboratory test alterations indicating injury without long-term risk; discomfort sufﬁcient to modify normal daily 
activity; speciﬁc therapy required (i.e. more than symptomatic). 

05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 21 of 23 
NCT01548768 
 
 
- Severe adverse events prompting immediate withdrawal from the study include laboratory test indicating a serious 
health threat or permanent injury; incapacity, inability to work, inability to perform normal daily activity; 
hospitalization required or prolonged; emergency treatment required; life-threatening events; death. 
 
An "unanticipated problem" is any incident, experience or outcome during the study that: 
- is serious adverse event or suggests that the study may be placing subjects at a greater risk of harm than was 
previously known or recognized, and 
- is related or possibly related to participation in the research and 
- is unexpected given the study procedures and the characteristics or the subject population being studied 
 
All unanticipated problems will be reported promptly to the IRB. All unanticipated problems will also be reported to 
the safety ofﬁcer, the SMC, and the funding source for this study (NIH/NIAMS). 
 
In addition all adverse events regardless of whether they constitute unanticipated problems as well as adverse events 
thought to be related or possibly related to study procedures will also be reported to IRB and to the safety ofﬁcer, the 
SMC, and the funding source for this study (NIH/NIAMS). 
 
 
 
SMC Responsibilities 
The SMC will evaluate the progress of this study, including periodic assessments of data quality and timeliness, 
participant recruitment, accrual and retention, participant risk versus beneﬁt, performance of trial site, and other factors 
that can affect study outcome. They will also consider factors external to the study when interpreting the data, such as 
scientiﬁc or therapeutic developments that may have an impact on the safety of the participants or the ethics of the 
study. 
 
The SMC will make recommendations to the investigators concerning continuation or conclusion of the study. 
The SMC will protect the conﬁdentiality of the trial data and the results of monitoring. 
Membership 
The SMC will consist of three voting members who are not investigators in the study 
- A Cardiologist at Mt. Sinai Hospital NY, NY, (Roxana Mehran, MD) 
- A Rheumatologist at Cornell University/Hospital for Special Surgery  (Steven A. Paget, MD) 
- A Columbia University Rheumatologist (Laura Geraldino, MD) 
 
The members will have no ﬁnancial or scientiﬁc conflict of interest with this study. Written documentation attesting to 
absence of conflict of interest will be available upon request. 
 
The Chairperson for the SMC will be decided during the ﬁrst meeting and will be responsible for overseeing the 
meetings and developing the agenda. He/She is the contact person for the SMC. 
 
A Safety Ofﬁcer will be identiﬁed by the PI and committee members at the ﬁrst meeting. This person will be the 
contact person for severe adverse event reporting. Procedures for notifying the Chair of the SMC will be discussed at 
the ﬁrst meeting. 
 
Committee Process 
The ﬁrst meeting will take place before the study is initiated to discuss the protocol, any modiﬁcations, and to establish 
guidelines to monitor the study. The SMC Chairperson and the PI will prepare the agenda to address the review of 
modiﬁcation of the study design, initiation of the trial, identiﬁcation of a Safety Ofﬁcer, reporting of adverse events, 
stopping rules, interim analysis plan, etc. 
 
Meetings of the SMC will be held twice yearly at the call of the Chairperson but additional meetings will be held if 
the need arises. In addition to committee members, the meetings are attended by the principal investigator and 

05/03/2012 
Printed On: 01/19/2012 at 13:20 
page 22 of 23 
NCT01548768 
 
 
members of the study team, when appropriate. Meetings may be convened as conference calls as well as in person, 
although the initial meeting and meetings to discuss interim analysis will be face-to-face. An emergency meeting of 
the SMC may be called at any time by the Chairperson should questions of patient safety arise - such as at the time of 
any adverse events or unanticipated problems. 
 
Meeting Format 
SMC meetings will consist of an open and a closed session. The open session may be attended by the principal 
investigator and/or members of the study team. Issues discussed at open sessions will include conduct and progress of 
the study, including patient accrual, compliance with protocol, and problems encountered. Patient­speciﬁc data and 
treatment group data may not be presented in the open session. 
 
The closed session will be attended only by voting SMC members. The SMC may request others to attend by part or all 
of the closed session as appropriate. All safety and efﬁcacy data will be presented at this session. The discussion at the 
closed session is completely conﬁdential. 
 
Should the SMC decide to issue a termination recommendation, full vote of the SMC will be required. In the event of a 
split vote, majority vote will rule and a minority report will be appended. 
 
Reports 
i. Interim Reports: Interim reports will be prepared and distributed by the principal investigator to the SMC during the 
week preceding the meeting. Additions and other modiﬁcations to these reports may be directed by the DSMC on a 
one-time or continuing basis. Interim data reports generally consist of two parts: 
- Part 1 (Open Session Report) provides information on study aspects such as accrual, baseline characteristics, and 
other general information on study status. 
- Part 2 (Closed Session Report) may contain data on study outcomes, including safety data, and depending on the 
study, perhaps efﬁcacy data. The Closed Session Report is considered conﬁdential and should be destroyed at the 
conclusion of the meeting. 
ii. Reports from the SMC: A written report containing the recommendations for continuation or modiﬁcations of the 
study, signed by the SMC Chairperson, will be sent to the Principal Investigator within one week following the 
meeting. 
 
It is the responsibility of the PI to distribute the SMC recommendation report to all co-investigators and to assure that 
copies are submitted to the IRB associated with the study. 
 
Conﬁdentiality 
All materials, discussions and proceedings of the SMC are completely conﬁdential. Members and other participants in 
SMC meetings are expected to maintain conﬁdentiality. 
 
13. POTENTIAL BENEFITS 
 
No direct beneﬁt to study subjects should be expected from this study. Treatment is the same as is provided in 
standard of care. Rheumatoid arthritis may improve, remain the same, or worsen. Although subjects may not 
personally beneﬁt from participating in this study, by taking part they may contribute new information that may beneﬁt 
RA patients in the future. 
In addition incidental abnormalities in any of the tests performed in this study will be communicated to the patient 
with the advice to follow up with the primary care physician as appropriate and as described earlier. 
 
14. ALTERNATIVES 
 
Subjects do not have to take part in this study to receive treatment for Rheumatoid Arthritis. Alternatives to 
participating in this study include continuing on their current treatment or other standard of care treatment from their 
primary Rheumatologist, which may or may not be the same as the treatment received during participation in this 
study. Prospective participants should discuss treatment options with the study doctor to obtain enough information to 

NCT01548768 
Columbia University IRB,_l_..,. 
\:ti:tl
Approved for 
use until: 05/0 3 /2012 
Printed On: 01/19/2012 at 13:20 
page 23 of 23 
 
 
decide if they want to join the study. 
 
15. RESEARCH AT EXTERNAL SITES: Not applicable. 
 
16. COLUMBIAAS LEAD INSTITUTION: Not applicable.