Conditions: Vascular Inflammation Atherosclerotic Cardiovascular Disease
Keywords: Atherosclerotic cardiovascular disease Inflammation reduction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 123
Healthy volunteers: yes

Brief summary:
Vascular inflammation, a central feature of atherosclerosis, participates in the initiation, perpetuation and instability of plaques. Multiple clinical trials of cholesterol lowering therapy with statins have demonstrated that reductions in atherosclerotic cardiovascular disease (CVD) events are associated with reductions in both LDL cholesterol (LDL-C) and the systemic inflammatory mediator C-reactive protein (CRP). The Cardiovascular Inflammation Reduction Trial (CIRT) investigates if an anti-inflammatory agent commonly used in rheumatoid arthritis (low dose methotrexate (LDM)) can reduce CV morbidity and mortality among patients with a prior myocardial infarction or angiographically demonstrated multivessel coronary artery disease (GCO#13-1467).

In this ancillary CIRT imaging study, the investigators propose to use this well validated approach by non-invasive serial FDG-PET/CT imaging in a subset of patients enrolled in the main CIRT trial to directly visualize vascular inflammation. Once the subjects are enrolled in the main CIRT trial, baseline imaging will be done and follow up imaging will be done approximately 8 months after the baseline imaging.

18FDG-PET imaging data will be acquired, analyzed centrally and results incorporated into the main CIRT database. The investigators hypothesize that LDM treatment will result in a significant decrease in plaque inflammation as measured by 18-FDG-PET/CT after 8 months as compared to placebo.

Detailed description:
The NHLBI funded (Ridker 5U01HL101422) Cardiovascular Inflammation Reduction Trial (CIRT) provides a unique opportunity to investigate whether a commonly used anti-inflammatory agent used in rheumatoid arthritis (low dose methotrexate (LDM)) can reduce CVD morbidity and mortality among patients with stable coronary artery disease. CIRT, is a randomized, double-blind, placebo-controlled, multi-center trial among 7,000 men and women with prior myocardial infarction or angiographically demonstrated multivessel coronary artery disease. Eligible participants will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM (average dose of 15-20 mg po/weekly. CIRT proposes that the reduction in CVD events with methotrexate derives from its effect on vascular inflammation, thus it is crucial to incorporate a measure of vascular inflammation imaging for confirmation of the primary mechanism of action underlying CIRT. As such, the direct evaluation of arterial inflammation would enhance the scientific value of the CIRT trial.

The inclusion of the proposed vascular inflammation imaging substudy has widespread implications that will allow this imaging modality to serve as a surrogate measure of disease, and thereby provide an opportunity for stratification in individuals at risk for CVD and evaluation of other interventions with presumed anti-inflammatory effects.

Arms:
arm 1: average dose of 15-20 mg po/weekly arm 2: matching placebo

Interventions: intervention 1: Low dose methotrexate intervention 2: Placebo
Intervention descriptions: intervention 1: Study participants will additionally receive 1 mg daily oral folate. intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Cardiovascular Inflammation Reduction Trial (CIRT) Inflammation Imaging 
Dr. Zahi A. Fayad
NCT02576067
Document Date: March 7, 2019


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: 
; Renata Pyzik: ext. 
 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
1 
Revised  9/2/14 
MSSM Protocol Template HRP-503a 
Instructions: 
1. Prepare a document with the following sections. Note that, depending on the nature of your research, 
certain sections below may not be applicable. Indicate N/A as appropriate, explaining where possible. 
2. For any items described in the sponsor’s protocol, grant application or other source documents 
submitted with the application, you may reference the title and page numbers of these documents rather 
than cutting and pasting into this document. Do NOT refer to any derived documents, such as the 
Sample Consent document, or other internal documents required with the submission. 
3.  If you reference page numbers, attach those pages to this protocol. 
4. When you write a protocol, keep an electronic copy. You will need to modify this copy when making 
changes. 
 
Brief Summary of Research (250-400 words): 
Vascular inflammation, a central feature of atherosclerosis, participates in the initiation, 
perpetuation and instability of plaques. Multiple clinical trials of cholesterol lowering 
therapy with statins have demonstrated that reductions in atherosclerotic cardiovascular 
disease (CVD) events are associated with reductions in both LDL cholesterol (LDL-C) 
and the systemic inflammatory mediator C-reactive protein (CRP). The Cardiovascular 
Inflammation Reduction Trial (CIRT) investigates if an anti-inflammatory agent 
commonly used in rheumatoid arthritis (low dose methotrexate (LDM)) can reduce CV 
morbidity and mortality among patients with a prior myocardial infarction or 
angiographically demonstrated multivessel coronary artery disease (GCO#13-1467).  
 
In this ancillary CIRT imaging study, we propose to use this well validated approach by non-
invasive serial FDG-PET/CT imaging in a subset of patients enrolled in the main CIRT trial to 
directly visualize vascular inflammation. Once the subjects are enrolled in the main CIRT trial, 
baseline imaging will be done and follow up imaging will be done approximately 8 months after 
the baseline imaging. To clarify, we anticipate on having the randomization visit to follow closely 
after the baseline imaging visit, which means that subjects will be coming approximately 8 
months after the randomization visit in the main CIRT Trial. 
18FDG-PET imaging data will be acquired, analyzed centrally and results incorporated 
into the main CIRT database. We hypothesize that LDM treatment will result in a 
significant decrease in plaque inflammation as measured by 18-FDG-PET/CT after 8 
months as compared to placebo. 
1) Objectives: 
Research Question: 
To determine the impact of anti-inflammatory treatment with LDM on arterial 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
2 
Revised  9/2/14 
inflammation, as assessed by FDG-PET/CT imaging in patients with stable  coronary 
artery disease who are at increased risk. We will determine the effect of LDM on the 
change from baseline in the target (plaque) to background (blood) ratio (TBR) based on 
18-FDG uptake measured with PET/CT after 8 months of weekly dosing with LDM 
(primary endpoint). 
 
To evaluate changes in imaging endpoints in relation to changes in systemic 
inflammatory biomarkers (especially high sensitivity C-reactive protein (hs-CRP). 
2) Background 
The NHLBI funded (Ridker 5U01HL101422) Cardiovascular Inflammation Reduction 
Trial (CIRT) provides a unique opportunity to investigate whether a commonly used anti-
inflammatory agent used in rheumatoid arthritis (low dose methotrexate (LDM)) can 
reduce CVD morbidity and mortality among patients with stable coronary artery disease. 
CIRT, is a randomized, double-blind, placebo-controlled, multi-center trial among 7,000 
men and women with prior myocardial infarction or angiographically demonstrated 
multivessel coronary artery disease. Eligible participants will be randomly allocated over 
a three to four year period to usual care plus placebo or usual care plus LDM (average 
dose of 15-20 mg po/weekly. CIRT proposes that the reduction in CVD events with 
methotrexate derives from its effect on vascular inflammation, thus it is crucial to 
incorporate a measure of vascular inflammation imaging for confirmation of the primary 
mechanism of action underlying CIRT. As such, the direct evaluation of arterial 
inflammation would enhance the scientific value of the CIRT trial. 
 
The inclusion of the proposed vascular inflammation imaging substudy has widespread 
implications that will allow this imaging modality to serve as a surrogate measure of 
disease, and thereby provide an opportunity for stratification in individuals at risk for 
CVD and evaluation of other interventions with presumed anti-inflammatory effects. 
( Please see Protocol NIH CIRT imaging for more details -pages 104). 
Current protocol for the Main CIRT trial as well as CIRT imaging sub study are 
provided as an Appendix 
3) Setting of the Human Research 
The total study duration is 38-40 weeks which includes a pre-randomization phase (up to 
8 weeks), and a double-blind treatment phase (approximately 32 weeks). There will be 
four imaging  centers (Mount Sinai Medical Center, New York, NY, University Health 
Network, Ontario,  Canada, Massachusetts General Hospital, Boston, MA, and University 
of California San Francisco (UCSF), San Francisco, CA), which will perform all the 
imaging for the surrounding referring centers. There will be recruiting centers in each 
region (New York, Toronto, and Boston) for 17 centers in total. For the NY region, the 7 
recruiting centers where the subjects will be identified and recruited will be Montefiore 
Medical Center (Dr. Bortnick-PI), Winthrop University Hospital (Dr. DeLeon - PI), 
NewYork-Presbyterian Queens (Dr. Ramnauth-PI), Weill Cornell Medical Center (Dr. 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
3 
Revised  9/2/14 
Pena-PI), Mount Sinai (Dr. R. Rosenson-PI), University of California San Francisco 
Medical Center (UCSF) (Dr. P. Hsue-PI), and Clinton, Maryland (Dr. Hakim-PI). For the 
Boston region, the 5 recruiting centers are Massachusetts General Hospital (Dr. Tawakol-
PI), Lahey Clinic (Dr. Draper-PI), South Shore Internal Medicine (Dr. Cronin-PI), MGH-
Chelsea Health Care (Dr. Benzaquen-PI) and Southern New Hampshire Medical Center 
(Dr. Schwartz-PI).  For the Toronto region, the 5 recruiting centers are UHN/Toronto 
General Hospital (Dr. Farkouh-PI), Scarborough General Hospital Cardiology Research 
Associates (Dr. Roth-PI), Brampton Research Hospital (Dr. Gupta-PI), Humber River 
Regional Hospital (Dr. Singal-PI) and Sewa Ram Singal Professional Corp.-Finch site 
(Dr. Singal-PI). . Additional recruitment centers may be added in the future. 
 
 
The Imaging Center at Mount Sinai will also act as the Imaging Data Coordinating 
Center for all 3 Imaging Centers. (Protocol NIH CIRT imaging -page 111). All imaging 
scans will be sent to Mount Sinai for Data Analysis. UCSF will also be an imaging center 
for their own site and will send all data to Mount Sinai. 
(Please see Protocol NIH CIRT imaging for more details -pages 107-108). 
Current protocol for the Main CIRT trial as well as CIRT imaging sub study are 
provided as an Appendix 
4) Resources Available to Conduct the Human Research 
The Mount Sinai research group has had excellent success in recruiting this type of 
patients in the New York area. There will be four major recruiting centers in the New 
York region. The Imaging Center at Mount Sinai has collaborated with all the recruiting 
centers in the past on both NIH and pharmaceutical funded studies.  All personnel 
involved in the study are PPHS accredited and composed of experienced researchers.  
5) Study Design 
a) Recruitment Methods 
The recruiting centers will be responsible for identifying suitable subjects for the study, 
recruiting the subjects into the study, informed consent, blood work and arranging for 
transportation of the subjects to the imaging centers as part of the CIRT imaging 
substudy. This is a sub study of the parent NHLBI funded CIRT trial (Ridker 
5U01HL101422). Only subjects that are part of the main CIRT study and have consented 
to being approached for ancillary studies will be approached for recruitment into this 
CIRT imaging substudy.  In the main CIRT trial, patients are recruited from 300 to 400 
clinical sites (average of 20 randomized participants per site) in the US and Canada, 
all of whom have demonstrated experience in the identification, randomization, and 
long-term follow-up of patients with cardiovascular disease. In CIRT, as of August 
14th, 2015, 4,559 subjects  have answered the question regarding being contacted for 
ancillary study participation in the ICF. Taking out those who have withdrawn, 2,662 
subjects have answered the question. Of these 2,662 subjects, 2,192 have consented to 
be contacted and 470 have not consented to be contacted. 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
4 
Revised  9/2/14 
The total subjects to be recruited for the CIRT Imaging substudy will be 170 (56 to 57 
subjects are planned to be imaged in each of the three Imaging Centers). Only subjects 
recruited to the main trial will be recruited to the imaging substudy. The imaging study 
team will support main CIRT recruitment by using study flyers and postcard distributed 
at the Cardiac units, inpatients and outpatients clinics inside the Mount Sinai Health 
System, within the New York metropolitan area.   
(Please see Protocol NIH CIRT imaging for more details -pages 111-112, 121). 
Subjects will be consented for the imaging substudy by the clinical PI at the main CIRT 
trial centers during their initial study visit for the main CIRT trial. Subjects will also sign 
a consent form for the imaging sub study at the imaging center unless the PI obtaining 
consent is affiliated with the institution where the imaging center is located; in which 
case, the subjects will only sign one consent form for the imaging substudy. More details 
are provided in the “consent process” section. 
b) Inclusion and Exclusion Criteria 
The FDG-PET/CT imaging study will be performed as a substudy of CIRT, the 
inclusion/exclusion criteria for this imaging sub-study will include all of those of the 
main trial.   
 
(Please see protocol NIH CIRT Imaging for more details -pages 117-118) 
 
Inclusion Criteria include the following: 
a.   Age > 18 years at screening 
b.   Documented MI in the past or past evidence of multivessel coronary artery 
disease by angiographymust have completed any planned coronary 
revascularization procedures associated with the qualifying event, and must be 
clinically stable for at least 60 d before screening; the qualifying prior MI must be 
documented either by hospital records or by evidence on current electrocardiogram 
of Q waves in 2 contiguous leads and/or an imaging test demonstrating wall motion 
abnormality or scar; the qualifying documentation of multivessel coronary disease 
must include angiographic evidence of atherosclerosis in at least 2 major epicardial 
vessels defined either as the presence of a stent, a coronary bypass graft, or an 
angiographic lesion of 60% or greater.  Left main coronary artery disease that has 
been revascularized with a stent or bypass graft will qualify as multivessel disease, as 
will the presence of a 50% or greater isolated left main stenosis. 
c.   History of type 2 diabetes or metabolic syndrome at the time of study enrollment 
d.   Willing to participate as evidence by signing the study informed consent 
 
Exclusion Criteria include the following: 
1.   Prior history of chronic infectious disease, including tuberculosis, severe fungal 
disease, or known HIV positive 
2.   Chronic hepatitis B or C infection 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
5 
Revised  9/2/14 
3.   Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. Chest x-ray 
evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or 
pulmonary fibrosis. 
4.   Prior history of non basal cell malignancy or myeloproliferative or   
lymphoproliferative disease within the past 5 years 
5.   White blood cell count <3,500/mm3, hematocrit <32%, or platelet count 
<75000/mm3 
6.   Liver transaminase levels (AST/ALT) greater than the upper limit of normal or 
albumin less than the lower limit of normal 
7.   Creatinine clearance (CrCl) <40 mL/min as estimated by the Cockcroft-Gault 
equation 
8.   History of alcohol abuse or unwillingness to limit alcohol consumption to <4 
drinks per week 
9.   Women of child bearing potential, even if currently using contraception, and 
women intending to breastfeed 
10. Men who plan to father children during the study period or who are unwilling to 
use contraception 
11. Requirement for use of drugs that alter folate metabolism 
(trimethoprim/sulfamethoxazol)  or reduce tubular excretion (probenecid) or 
known allergies to antibiotics making avoidance of trimethoprim impossible 
12. Current indication for methotrexate therapy 
13. Chronic use of oral steroid therapy or other immunosuppressive or biologic 
response modifiers 
14. Known chronic pericardial effusion, pleural effusion, or ascites 
15. New York Heart Association class IV congestive heart failure 
16. Life expectancy of <3 years 
 
The study population for the ancillary study will be the same as the main trial with the 
following additional exclusion criteria 
 
a.   Subjects with a history of multiple imaging studies associated with 
radiation exposure 
 
b.  If subject is Type 2 diabetic, hemoglobin A1c greater than 8% as 
determined by patient medical record review in the one year prior to the date of 
consent to this study.  
c.   BMI greater than 37 kg/m2 or weight greater than 350 pounds 
 
c) Number of Subjects 
The total subjects to be recruited for the CIRT Imaging will be 170 (56 to 57 in 
each of the three Imaging Centers). 
(Please see Protocol NIH CIRT  imaging for more details -pages 111-112). 




 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
7 
Revised  9/2/14 
 
( Please see Protocol NIH CIRT imaging  for more details-page 114). 
Current protocol for the Main CIRT trial as well as CIRT imaging sub study are provided 
as an Appendix. 
f) Procedures Involved in the Human Research 
(Please see Protocol NIH CIRT imaging for more details -pages 112 - 113 (Table 
1), 116) 
Timing of imaging visits as part of the CIRT imaging substudy: The first (baseline) 
imaging will take place prior to the open label run in of Low Dose Methotrexate in  the 
CIRT main trial ( between V1 and V2 of main CIRT). The second (follow up) imaging 
visit will take place 8 months after randomization into the main CIRT trial (close to V6 of 
main trial). 
Table 1: Workflow for each imaging visit 
Time (minutes) 
Action 
Before imaging visit 
Subject is consented for CIRT imaging trial at main CIRT clinical site 
-360 
Subjects begins fast (only oral hydration permitted) 
0 
Subject arrives at imaging facility 
5 
Subject changes into hospital clothing(gown) and prepared for study 
10 
IV inserted for injection of FDG and for drawing blood 
12 
10 ml of blood is drawn for biomarker assessments 
13 
Blood glucose measurements for determining eligibility for FDG injection 
15 
10milli Curie of FDG injected into subject 
105 
Subject rests in a relaxed position to allow FDG circulation 
120 
Aorta PET/CT scans acquired 
135 
Carotid PET/CT scans acquired 
140 
Subject prepped for leaving (miscellaneous,  instructions for future visits) 
150 
Imaging visit completed, subject leaves imaging center 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
8 
Revised  9/2/14 
Due to early closure of the main CIRT Trial, subjects who have not reached the 8 months 
final imaging timepoint will be asked to go to their Imaging Center by the end of May 
2018 and/or till all final imaging visits are completed, as advised by NHLBI.  Subjects 
who have been on the Imaging substudy for 5 months or less after their baseline scan will 
need to be seen within this new time period.  
Subject will be asked to verify with a physician insulin regiment for fasting and dieting 
needed prior to each imaging visit and provide study team with physician’s 
recommendations whether to continue with our imaging study. On the day of the visit, the 
subject will be able to proceed with the imaging only when fasting glucose is equal or 
less than 170 mg/dL and equal or greater than 80 mg/dL. This will be verified at our site 
prior to the scan by finger stick or i.v. If the fasting blood glucose is less than 80 mg/dL 
each subject will be instructed to eat a snack or we will provide sugar cubes. Once fasting 
blood glucose is above 80 mg/dL, we will proceed with the imaging. 
g) Specimen Banking 
Ancillary Study Data Collection. This ancillary proposal will additionally collect the 
following data from each study subject participating in the imaging ancillary study 
1) PET/CT Imaging data in the form of DICOM images.  
2) Blood draw for evaluation of inflammatory biomarkers. These samples will also be 
stored in a coded fashion. The blood will only be stored for the purpose of the trial. 
3) Blood draw for evaluation of pre scan glucose. This is an instant test and the data are 
not stored. This information is used only to determine if the subject is eligible for FDG 
injection at the time of imaging or if the imaging test needs to be postponed. Patients with 
a fasting glucose of >170 mg/dl will need to be rescheduled for an on-trial FDG-PET 
scan at a later date (p. 112 of other protocol) 
4) Only the PIs of the imaging sub study and the main CIRT trial and their authorized 
representatives will have access to the code that links the imaging and blood data back to 
each individual subject. The linking files will be stored securely on a hard disk in Co-
investigator’s office.  
 
(Please see Protocol NIH CIRT imaging for more details-page 119). 
h) Data Management and Confidentiality 
Image identifiers (blinded data) will be removed by the imaging site investigators and 
prepared for transfer to the Mount Sinai PET/CT Core Laboratory using either secure 
FTP or by mailing CDs with DICOM data. All Images will be coded and be identified 
only by a study ID number. All coded image data will also be stored at the central 
laboratory for imaging (Mount Sinai) on encrypted hard disks specific to this trial (CIRT 
image data repository). Only study personnel authorized to evaluate images, the imaging 
data manager and the PI will have access to imaging data. All imaging data and meta-
analysis files are also stored on the same encrypted hard disk (image data repository). 
The image data repository has access controls and an audit trail feature built in using Mac 
Hg version control. This system is 21 CFR Part 11 compliant. 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
9 
Revised  9/2/14 
(Please see Protocol NIH CIRT imaging for more details -page 113). 
i) Provisions to Monitor the Data to Ensure the Safety of subjects 
Data for the substudy will be linked to the parent database by subject identification 
number only. The Mount Sinai imaging data coordinating center has programs, policies 
and procedures in use at all times to ensure the security and confidentiality of the data. 
Direct identifiable variables such as name, address, DOB, MRN, SSN, that can link the 
data to a person's identity will not be sent to us from the imaging sites. Only coded data is 
received at the core laboratory and is identifiable only by the subject ID). Research data 
files will be stored using this ID as the unique identifier. The linking code file which 
contains the linking information between the unique identifier and the direct identifiable 
variables will be stored in a different location than the de-identified and identifiable 
information and is available only to the PI and select individuals. 
Part I: Elements of a Data and Safety Monitoring Plan 
 
MSSM Principal Monitor: 
Last Name: Rosenson 
First Name: Robert 
Academic Title: Professor 
Department: CVI 
Mailing Address: 
 
Phone: 
 
Email: robert.rosenson@mssm.edu 
MSSM Additional Monitor: 
Last Name: Heiba 
First Name: Sherif 
Academic Title: Associate Professsor 
Department: Radiology 
Mailing Address: 
. 
Phone: 
1 
Email: sherif.heiba@mountsinai.org 
2. Justify your choice of principal monitor in terms of the assessed risk to the research 
subject‘s health and wellbeing. In high risk studies when the principal monitor is 
independent of the study staff, indicate the individual’s credentials, relationship to the PI, 
and the rationale for selection.  


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
10 
Revised  9/2/14 
The investigators and research team are experienced in conducting clinical trials, trained 
(having met the IRB’s educational requirements) and knowledgeable about the protocol, 
and are therefore qualified to review safety updates, monitor subjects for adverse events 
and assess their health and well-being during the trial. The additional monitor is also an 
expert in imaging and will be responsible for the safety of the subjects during their 
imaging visits. The co-investigators and the research team are responsible for the safety 
and welfare of the subjects and for conducting the trial as outlined in the protocol.  
3. List the specific items that will be monitored for safety (e.g., adverse events, 
subject compliance with the protocol, drop outs, etc.).  
Additional items that will be monitored during their imaging visit will be a chance of 
swelling, pain, bruising, infection or redness during blood draw; subject compliance 
which will also be monitored by the subject's main site and subjects will also be 
monitored for reactions during the injection of the 18-FDG radiotracer although there are 
no known side effects with the use of the agent. 
4. Indicate the frequency at which ACCUMULATED safety and data information (items 
listed in number 3 above and interim analysis of efficacy outcomes) will be reviewed by 
the monitor(s) or the Data Monitoring Committee (DMC). Although this information 
must be reviewed at least annually, the higher the study risks, the more frequently 
reviews must be scheduled.  
Subjects with IDDM should consult with their physician prior enrolling in our 
imaging sub-study. The visit preparation form called “Getting ready for your 
visit” includes all details as to fasting, low carbohydrate diet restriction as well 
medication and insulin requirements.   
Subjects will have regularly scheduled visits with their main site during which the 
research staff will carefully assess subjects for any signs or symptoms of drug toxicity, in 
addition to the occurrence of any trial endpoints. A questionnaire designed to capture 
information about drug toxicity (including symptoms of a pulmonary, infectious, 
gastrointestinal, 
hematologic, 
dermatologic, 
and 
other 
toxicities), 
intercurrent 
hospitalizations, and elective or planned surgical procedures will be administered to all 
subjects. 
Study algorithms will combine data from recent laboratory safety evaluations with 
subject's reported symptoms to determine study drug dosing and/or cessation, including 
sham placebo dose adjustments. Responsible physicians will be informed of any changes 
in the study medication dosing. Adverse events, patient symptoms, laboratory 
abnormalities, or other reasons for discontinuation of or reduction in dose of study drug 
will be collected through electronic case report forms and monitored centrally by the 
DCC. A Medical Monitoring program will be developed and will help identify potential 
adverse drug reactions to the study medication. Study coordinators will be given 
instructions to contact the Medical Monitor for symptoms or signs that raise the 
possibility of drug toxicity. The Medical Monitor will be on call 24 hours a day 7 days 
each week.  


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
11 
Revised  9/2/14 
5. Where applicable, describe rules which will guide interruption or alteration of the 
study design.  
The principal features of the study design and of the plan for statistical analysis of the 
data are outlined in the protocol. Any changes in these principal features will require a 
protocol amendment. 
6. Where applicable, indicate dose selection procedures that will be used to 
minimize toxicity. 
Risks associated with 18-FDG-PET/CT: 
There are no known side effects with the use of the 18-FDG radiotracer. The procedure 
involves a single vein puncture for FDG administration. PET/CT scanning is widely used 
in oncology and cardiology. The metabolic tracer FDG is very safe with no potential for 
allergy. The radiation dose for the PET/CT scan would be the same as the background 
exposure of living in New York City for 1 year. The total effective whole body dose 
(TEDE) from a single PET study is 700 mRem. The whole body CT portion of the PET 
scan adds another 70 mRem to the TEDE. The resulting effective total body dose is 770 
mRem, which compares with a 100 mRem yearly recommended limit for exposure for 
the general public and 5,000 mRem yearly limit for persons who work with radiation, 
established by the Nuclear Regulatory Commission (NRC). The critical organ, which is 
the organ which will receive the maximum dose and exceed the TEDE for FDG is the 
urinary bladder, which will receive 5900 mRem. This dose is well within the 50,000 
mRem limit for a single organ, established by the NRC. While at this level, this kind of 
radiation exposure has not been shown to cause malignancies, this possibility can never 
be excluded. There are no other known side effects with the use of FDG as a PET agent. 
7. List any specialized grading system that will be used to evaluate adverse 
events (e.g., National Cancer Institute Common Toxicity Criteria).  
To ensure safe and effective use of nuclide imaging, a rigorous quality assurance (QA) 
protocol of the imaging tools and integration of the imaging data is currently in place 
under the guidance of the respective radiation safety offices of the participating 
institutions. Overall, the goal of this QA program is to identify and minimize the sources 
of uncertainties and errors, taking into consideration the economic, medical, legal, and 
regulatory implications. The PET-CT scanners will comply with all The National 
Electrical Measurement Association (NEMA) standards and will be tested on a routine 
basis for compliance. The minimum dose of 18-FDG for adequate image quality will be 
used in all subjects. 
8. Describe procedures that will be used to assure data accuracy and 
completeness. 
A Data and Safety Monitoring Plan (described below), including pre-specified stopping 
rules has been defined by an NIH appointed, independent, Data Safety Monitoring Board 
(DSMB) for CIRT. This DSMB will ensure conduct of the parent study in a manner 
suited to optimal research subject safety. In addition, the DSMB will review and approve 
ancillary study proposals and will on an ongoing basis review summary data pertaining to 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
12 
Revised  9/2/14 
subject participation and information collected in ancillary studies in order to ensure 
subject safety and to ensure that subject and site burden is minimized. 
9. Should a temporary or permanent suspension of your study occur, in addition 
to the PPHS, indicate to whom (NIH, FDA, sponsor, IRB) will you report the 
occurrence. 
Temporary or permanent suspension would be reported to the NHLBI and to all the sites. 
Data Safety Monitoring 
For the Imaging substudy, communication with the collaborating Mount Sinai co-
investigators will be conducted via bi-weekly teleconferences and quarterly meetings. 
Confidentiality of subject data will be protected as previously described. 
Unanticipated problems from the other study sites will be discussed at the 
teleconferences. Urgent problems will be immediately addressed by direct 
communication between the research teams. Plan for reporting unanticipated events that 
cause risk of harm to subjects or others will be reported to the PPHS in accordance with 
PPHS policies on reportable information. 
The DSMB was constituted by the NHLBI and will be composed of members from the 
following areas: 1) physicians with specific expertise in the clinical management of 
cardiovascular disease 2) a biostatistician with specific expertise in the design, analysis, 
and safety monitoring of multi-center clinical trials 3) a medical ethicist, and 4) a 
physician with specific expertise in rheumatologic disease. The DSMB will oversee the 
main CIRT trial as well as the CIRT Imaging Study and the physician with expertise on 
rheumatologic disease will be from the Brigham and Women's Hospital site which will 
also provide the overall programmatic and statistical support for the CIRT Imaging 
Study. Dr. Fayad who is the PI of the CIRT Imaging Study and Dr. Rosenson who is the 
co-investigator of the CIRT Imaging Study will take part in the semiannual review.  
The Committee members will collect and review the safety data every 6 months and be 
responsible for review of: 
a) 
study recruitment goals and tracking of enrollment;  
b) 
presentation of spreadsheets for data analysis; 
c) 
adverse and reportable events as defined by the investigators; 
As of 4/2/18, enrollment has ended due to early termination of the main CIRT Trial.  
There will  no longer be any DSMB meetings. 
(Please see Protocol NIH CIRT – imaging  for more details: pages 120-122). 
 
j) Withdrawal of Subjects 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
13 
Revised  9/2/14 
Participation in this imaging study is voluntary. The subjects can withdraw at any time by 
informing the PI and/or the study coordinators. Although the subjects can withdraw from 
the imaging study, they can still continue to participate in the CIRT main trial. 
6) Risks to Subjects 
Risks associated with 18-FDG-PET/CT: 
 
There are no known side effects with the use of the 18-FDG radiotracer. The procedure 
involves a single vein puncture for FDG administration. PET/CT scanning is widely used 
in oncology and cardiology. The metabolic tracer FDG is very safe with no potential for 
allergy. The radiation dose for the PET/CT scan would be the same as the background 
exposure of living in New York City for 1 year. The total effective whole body dose 
(TEDE) from a single PET study is 700 mRem. The whole body CT portion of the PET 
scan adds another 70 mRem to the TEDE. The resulting effective total body dose is 770 
mRem, which compares with a 100 mRem yearly recommended limit for exposure for 
the general public and 5,000 mRem yearly limit for persons who work with radiation, 
established by the Nuclear Regulatory Commission (NRC). The critical organ, which is 
the organ which will receive the maximum dose and exceed the TEDE for FDG is the 
urinary bladder, which will receive 5900 mRem. This dose is well within the 50,000 
mRem limit for a single organ, established by the NRC. While at this level, this kind of 
radiation exposure has not been shown to cause malignancies, this possibility can never 
be excluded. There are no other known side effects with the use of FDG as a PET agent. 
 
Risks associated with venipuncture and blood draw: During the collection of the blood 
samples, there is a chance of swelling, pain, bruising, infection, or redness at the site 
where the blood is drawn. Also, there is chance that the subject may feel faint.  
 
(Please see Protocol NIH CIRT imaging for more details-page 120-121). 
 
Risks of Fasting:  If the subjects feel disoriented or dizzy, the coordinator will ask the 
subject to lie down until they regain their composure and will be given water. Their vital 
signs will be monitored until they have stabilized. If no improvement is seen, the subjects 
will be referred to the Co-PI, Dr. Rosenson who is the MD in this study for further 
management and the scan will be rescheduled. 
 
To prevent such occurrences from happening, the coordinator will make sure of the 
following: 1) Remind subjects to come on time or enough time for the preparations 
before the scan; 2) That there is no delay in the scheduled imaging scan and that the dose 
is available and ready; 3) A coordinator be present with the subject to monitor the overall 
condition of the subject to undergo the scan. Once injected with the FDG and before the 
scan, the coordinator will periodically check on the subject to check his overall status. 
7) Provisions for Research Related Injury 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
14 
Revised  9/2/14 
If subjects are injured or made sick from taking part in this research study, medical care 
will be provided. Generally, this care will be billed to their insurance and will be 
responsible for all treatment costs not covered by insurance.  In the event of injury, the 
subjects can contact the Co-Investigator, Dr. Rosenson who is an MD in this study. 
8) Potential Benefits to Subjects 
This CIRT imaging sub study has the potential to provide valuable information with 
regard to the inflammatory status of the vessel walls of the subjects participating in this 
trial. This may provide mechanistic insights into the role of methotrexate in reducing 
cardiovascular inflammation and thereby provide additional data on future CV risk. There 
may however not be any direct benefit to the subject. 
(Please see Protocol NIH CIRT imaging for more details -page 122-123). 
 
9) Provisions to Protect the Privacy Interests of Subjects 
The subjects will be recruited at several different hospitals.  After the recruitment, they 
will be referred to the Imaging center in their geographic area for their imaging.  The 
imaging centers will not be directly involved in recruiting the subjects. When patient 
consents to the study, his/her name, address, phone numbers, date of birth, medical record 
number will be collected and kept with the informed consent form in their respective 
recruiting centers. The subject will also sign a consent form at the imaging centers for the 
imaging and other study related procedures.  Once the subjects are recruited and referred 
to the imaging center for imaging, the following measures will be taken to ensure subject 
privacy.  The study treatment and procedures will be thoroughly explained to them in a 
private office/area, at a time of mutual convenience to both subject and investigator, by 
appointment. All their questions will be addressed in a simple language so that the 
interested subjects can adequately understand the rationale for the study as well as 
potential risks and benefits prior to consenting. Once the subject has agreed to participate 
in the study, they will be asked their preferences regarding mode of contact and 
limitations if any to contact by phone.  Their wishes will be respected by study 
coordinators and investigators.  All conversations will be held in a professional manner 
and in a manner that maintains subject privacy. 
If subject requests the research images, they could be provided.  However, these images 
will contain their private information and they will be responsible for protecting them and 
any future use of them. 
10) 
Economic Impact on Subjects 
Subjects will also receive 
 per imaging visit for a total of 
for two visits for their 
time. In the case that subjects do not complete their scan, but do have blood drawn, they 
will still be compensated the 
. Subjects’ travel will be arranged by coordinator.  If 
subjects use their own form of transportation, they will be reimbursed for the 
transportation cost for the imaging visit upon providing receipts, either by cash or check. 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
15 
Revised  9/2/14 
11) 
Payment to Subjects 
Subjects will receive 
 for Baseline visit, and 
 for follow-up visit by cash 
or check. 
12) 
Consent Process 
Once the subject has agreed to participate in the main study and signed the main consent 
form, and has agreed to be approached for ancillary studies, the PI or the designated 
research staff of their respective main study site will introduce the imaging substudy to 
the subjects. If the subjects agree to participate in imaging substudy, the research staff of 
the main clinical site will consent the subject for the imaging substudy at their center. 
This will be done prior to reviewing the subjects’ medical records to ensure eligibility for 
the imaging substudy.  If the subject meets the eligibility criteria for the imaging 
substudy, staff at the recruiting center will contact the research staff of the Imaging center 
and inform of the new subject recruited. The research staff of the imaging center will then 
contact the subject and in conjunction with the staff at the recruitment center schedule the 
subject for their imaging visits. The consent form from the imaging center may be sent to 
the subject either by email or regular mail if the subjects requests for it so the subject can 
review it thoroughly. The imaging center research staff will also over the phone go over 
any questions on the consent form and verify that the subject would be willing to 
participate in the imaging substudy. Consent at the imaging center will be obtained by the 
co-Investigator and/or designated research staff in a private office on a date or time prior 
to baseline scanning being performed. A consent form from the imaging center for this 
study will be given to the subject if it has not been given previously. Subjects can read 
the form on the day of the scan. All questions will be answered and the consent form will 
be signed if the subject wishes to participate.  To ensure participant understanding, the 
consent form will be thoroughly discussed with the subject, section by section.  If any 
questions arise, the coordinator or principal/ coinvestigator will answer their questions 
until they have a clear understanding of what is expected of them if they participate.  
Subjects will be asked to provide in their own words a statement of their understanding of 
the risks and procedures of the study, and the general concept of the study.  Subjects must 
clearly understand the potential risks and benefits before signing the consent. 
Prior to collecting study data, the following details will be explained to the participant: 
(1) that the study represents a research effort, (2) that participation is voluntary, and there 
is no penalty for withdrawal, (3) there are no costs to the patient for participation, (4) 
potential risks and benefits for participation and (5) contact information for additional 
concerns. Patients will be informed of the purpose of the study, the need to be available 
for questionnaires and medical tests, and of their options to accept or refuse entry into the 
study without affecting their clinical care. All sources of research materials will be in the 
form of medical records, blood work, and imaging studies.  The consent form at the 
recruitment center and the imaging center describe the same procedures and are 
essentially similar but will be approved by the respective institutional review boards. 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
16 
Revised  9/2/14 
Non-English speaking subjects may also be enrolled since there is a large population of 
Spanish-speaking patients as well as some other non-English speaking patients in the 
area.  During the consent process, an approved Spanish consent will be provided to those 
subjects. A short form of the consent is available, in English and in Arabic for a single 
use.  
13) 
Process to Document Consent in Writing 
The standard PPHS consent template will be used to document consent. 
14) 
Vulnerable Populations 
Include 
Exclude 
Vulnerable Population Type 
 
x 
Adults unable to consent 
 
x 
Individuals who are not yet adults (e.g. infants, children, 
teenagers) 
 
x 
Wards of the State (e.g. foster children) 
 
x 
Pregnant women 
 
x 
Prisoners 
 
15) 
Multi-Site Human Research (Coordinating Center) 
The Imaging Center at Mount Sinai will also act as the Imaging Data Coordinating 
Center for all 4 Imaging Centers in the CIRT imaging substudy. All imaging scans will 
be sent to Mount Sinai Imaging Center for Data Analysis via secure FTP or in CD rom 
in DICOM format. 
16) 
Community-Based Participatory Research 
N/A 
17) 
Sharing of Results with Subjects 
The research results of the study will not be shared with the subject and the 
subject's physician. However, any incidental findings or gross abnormalities read 
by the radiologist will be shared with the subject's physician involved in research. 
The research team will notify the primary care physician of the subject or the PI 
of the recruitment center of the subject for any incidental findings. 
18) 
IRB Review History 


 
Protocol Title: 
Cardiovascular Inflammation Reduction Trial (CIRT) 
Inflammation Imaging Study 
Principal Investigator 
Name/Contact Info:  
Zahi A. Fayad, PhD/zahi.fayad@mssm.edu 
Primary Contact 
Name/Contact Info 
Catherine Ma: Catherine.ma@mssm.edu; Renata Pyzik: ext. 
5-8484 
Date Revised: 
March 7, 2019 
Study Number: 
GCO# 14-1382; IF2430508; HS# 14-00185 
 
17 
Revised  9/2/14 
5/7/2014, 11/3/2015, 2/2/2016, 4/22/2016 approval, 6/30/2017 – new flyers 
approved; 6/30- 7/27/2016 – insulin amendment; 4/19/17 continuation approval; 
9/9/17 modification approved; 11/17/17 short form (English/Arabic) approved 
 
19) 
Control of Drugs, Biologics, or Devices 
Note: The IDS has its own forms that must be completed and a review process 
that must be followed before the IDS representative will sign off on Appendix B 
for submission to the PPHS.