Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study

NCT02576067 | Completed Phase 3 Results DMC

• 2 other identifiers: GCO 14-13821R01HL128056-01A1
• Study Type: interventional
• Target: 123
• Locations: 2 countries
• Sites: 3

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.

Conditions

Vascular Inflammation; Atherosclerotic Cardiovascular Disease

Keywords

Atherosclerotic cardiovascular disease; Inflammation reduction

Outcome Measures

Primary Outcomes (1)

• Change in Arterial Inflammation

  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)

  baseline and 8 months

Secondary Outcomes (2)

• Change in Max Target-to-background (TBR)

  baseline and 8 months

• Change in Max TBR Within the Carotid Arteries

  baseline and 8 months

Study Arms (2)

Low dose methotrexate

EXPERIMENTAL

average dose of 15-20 mg po/weekly

Drug: Low dose methotrexate

Placebo

PLACEBO COMPARATOR

matching placebo

Drug: Placebo

Interventions

Low dose methotrexate DRUG

Study participants will additionally receive 1 mg daily oral folate.

Low dose methotrexate

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive
• Chronic hepatitis B or C infection
• Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. Chest x-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
• Prior history of non basal cell malignancy or myeloproliferative or lymphoproliferative disease within the past 5 years
• White blood cell count \<3,500/mm3, hematocrit \<32%, or platelet count \<75000/mm3
• Liver transaminase levels (AST/ALT) greater than the upper limit of normal or albumin less than the lower limit of normal
• Creatinine clearance (CrCl) \<40 mL/min as estimated by the Cockcroft-Gault equation
• History of alcohol abuse or unwillingness to limit alcohol consumption to \<4 drinks per week
• Women of child bearing potential, even if currently using contraception, and women intending to breastfeed
• Men who plan to father children during the study period or who are unwilling to use contraception
• 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
• Current indication for methotrexate therapy
• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers
• Known chronic pericardial effusion, pleural effusion, or ascites
• New York Heart Association class IV congestive heart failure

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Unity Health Toronto: collaborator
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (3)

Massachusetts General Hospital

Boston, Massachusetts, 02199, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

St. Michael's Hospital

Toronto, Ontario, Canada

Location

MeSH Terms

Conditions

Atherosclerosis

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Zahi Fayad, PhD
• Organization: Icahn School of Medicine at Mount Sinai

zahi.fayad@mssm.edu

212-824-8471

Study Officials

• Zahi Fayad, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Translational and Molecular Imaging Institute

Study Record Dates

• First Submitted: October 13, 2015
• First Posted: October 15, 2015
• Study Start: December 18, 2015
• Primary Completion: March 29, 2019
• Study Completion: March 29, 2019
• Last Updated: April 20, 2020
• Results First Posted: April 20, 2020

Record last verified: 2020-04

Locations

CA (1); US (2)