Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study (CIRT)

• ClinicalTrials.gov Identifier: NCT02576067
• Recruitment Status: Completed
• First Posted: October 15, 2015
• Results First Posted: April 20, 2020
• Last Update Posted: April 20, 2020
• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: Brigham and Women's Hospital; Massachusetts General Hospital; Unity Health Toronto; National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Zahi Fayad, Icahn School of Medicine at Mount Sinai

Tracking Information

• First Submitted Date: October 13, 2015
• First Posted Date: October 15, 2015
• Results First Submitted Date: March 27, 2020
• Results First Posted Date: April 20, 2020
• Last Update Posted Date: April 20, 2020
• Actual Study Start Date: December 18, 2015
• Actual Primary Completion Date: March 29, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 9, 2020)

Change in Arterial Inflammation [ Time Frame: baseline and 8 months ]

Change in arterial inflammation - The relative change at 8 months as compared to baseline in arterial inflammation as measured by the most diseased segment (MDS) of the index vessel. The MDS is defined as the 1.5 cm segment within the carotid artery (right or left carotid) that demonstrates the highest PET/CT activity, and is calculated as a mean of maximum TBR values derived from 3 contiguous axial segments. The index vessel in turn is defined as the vessel (either aorta, right, or left carotid) with the greatest mean TBR at baseline. (MDS TBR Index Vessel)

Original Primary Outcome Measures (submitted: October 14, 2015)

Change in arterial inflammation [ Time Frame: baseline and 8 months ]

The relative change at 8 months as compared to baseline in arterial inflammation as measured by the most diseased segment (MDS) of the index vessel. The MDS is defined as the 1.5 cm segment within the carotid artery (right or left carotid) that demonstrates the highest PET/CT activity, and is calculated as a mean of maximum TBR values derived from 3 contiguous axial segments. The index vessel in turn is defined as the vessel (either aorta, right, or left carotid) with the greatest mean TBR at baseline.

Current Secondary Outcome Measures (submitted: April 9, 2020)

• Change in Max Target-to-background (TBR) [ Time Frame: baseline and 8 months ]
  Change in max target-to-background (TBR) - The mean of max TBR within the carotid arteries as an average of the slices from the left and right carotid) at follow up imaging as compared to baseline.
• Change in Max TBR Within the Carotid Arteries [ Time Frame: baseline and 8 months ]
  Change in max target-to-background (TBR) - The mean of max TBR within the carotid arteries as an average of the slices from the left and right carotid)

Original Secondary Outcome Measures (submitted: October 14, 2015)

Change in max target-to-background (TBR) [ Time Frame: 8 months ]

The mean of max TBR within the carotid arteries as an average of the slices from the left and right carotid) or ii) as combined (carotid and aorta); iii) the mean of the maximum TBR of all of the slices that compose the index vessel, and iv) Standardized uptake value (SUV) of each vessel analyzed (left carotid, right carotid and ascending aorta)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study
• Official Title: Cardiovascular Inflammation Reduction Trial (CIRT) - Inflammation Imaging Study

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Vascular Inflammation
• Atherosclerotic Cardiovascular Disease

Intervention

• Drug: Low dose methotrexate
  Study participants will additionally receive 1 mg daily oral folate.
• Drug: Placebo

Study Arms

• Experimental: Low dose methotrexate
  average dose of 15-20 mg po/weekly
  Intervention: Drug: Low dose methotrexate
• Placebo Comparator: Placebo
  matching placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 2, 2018): 123
• Original Estimated Enrollment (submitted: October 14, 2015): 216
• Actual Study Completion Date: March 29, 2019
• Actual Primary Completion Date: March 29, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age > 18 years at screening
• Documented MI in the past or past evidence of multivessel coronary artery disease by angiography must 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.
• History of type 2 diabetes or metabolic syndrome at the time of study enrollment
• Willing to participate as evidence by signing the study informed consent

Exclusion Criteria:

1. Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive
2. Chronic hepatitis B or C infection
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/sulfamethoxazoyl) 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

1. Subjects with a history of multiple imaging studies associated with radiation exposure
2. Insulin-dependent diabetics
3. 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.
4. BMI greater than 37 kg/m2 or weight greater than 350 pounds

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT02576067
• Other Study ID Numbers: GCO 14-1382; 1R01HL128056-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Zahi Fayad, Icahn School of Medicine at Mount Sinai
• Original Responsible Party: Same as current
• Current Study Sponsor: Icahn School of Medicine at Mount Sinai
• Original Study Sponsor: Same as current

Collaborators

• Brigham and Women's Hospital
• Massachusetts General Hospital
• Unity Health Toronto
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Zahi Fayad, PhD; Icahn School of Medicine at Mount Sinai

• PRS Account: Icahn School of Medicine at Mount Sinai
• Verification Date: April 2020