CIRT: Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Completed
• CT.gov ID: NCT02576067
• Collaborator: Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), Unity Health Toronto (Other), National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 123
• Locations: 3
• Arms: 2
• Actual Duration (Months): 39.3
• Patients Per Site: 41
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Vascular Inflammation; Atherosclerotic Cardiovascular Disease	Drug: Low dose methotrexate; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Cardiovascular Inflammation Reduction Trial (CIRT) - Inflammation Imaging Study
• Actual Study Start Date: Dec 18, 2015
• Actual Primary Completion Date: Mar 29, 2019
• Actual Study Completion Date: Mar 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low dose methotrexate average dose of 15-20 mg po/weekly	Drug: Low dose methotrexate; Study participants will additionally receive 1 mg daily oral folate.
Placebo Comparator: Placebo matching placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Arterial Inflammation [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)

Secondary Outcome Measures

1. Change in Max Target-to-background (TBR) [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.

2. Change in Max TBR Within the Carotid Arteries [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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02199
2	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
3	St. Michael's Hospital	Toronto	Ontario	Canada

Sponsors and Collaborators

• Icahn School of Medicine at Mount Sinai
• 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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 7, 2019

More Information

Publications

None provided.

• Responsible Party: Zahi Fayad, Director Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT02576067
• Other Study ID Numbers: GCO 14-1382; 1R01HL128056-01A1
• First Posted: Oct 15, 2015
• Last Update Posted: Apr 20, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Zahi Fayad, Director Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai: Atherosclerotic cardiovascular disease; Inflammation reduction
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Inflammation; Methotrexate

Study Results

Participant Flow

Recruitment Details	Participants enrolled period from Dec 2015 to April 2018

Arm/Group Title	Low Dose Methotrexate	Placebo
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.	matching placebo
Period Title: Overall Study
STARTED	60	63
COMPLETED	26	27
NOT COMPLETED	34	36

Baseline Characteristics

Arm/Group Title	Low Dose Methotrexate	Placebo	Total
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.	matching placebo	Total of all reporting groups
Overall Participants	26	27	53
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	63	65	64
Sex: Female, Male (Count of Participants)
Female	4 15.4%	3 11.1%	7 13.2%
Male	22 84.6%	24 88.9%	46 86.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 11.5%	4 14.8%	7 13.2%
Not Hispanic or Latino	23 88.5%	23 85.2%	46 86.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	5 19.2%	3 11.1%	8 15.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 7.7%	4 14.8%	6 11.3%
White	18 69.2%	20 74.1%	38 71.7%
More than one race	1 3.8%	0 0%	1 1.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
hs-CRP (mg/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/L]	1.4	1.1	1.3
Total Cholesterol (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	138.1	131	134
LDL cholesterol (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]	63	66	64
HDL cholesterol (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]	42.5	40	41.5
MDS TBR Index Vessel (ratio) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ratio]	2.46	2.41	2.44
TMNMX MDS (ratio) [Median (Full Range) ]
LCC - left common carotid	2.04	2.12	2.08
RCC - right common carotid	2.12	2.13	2.12
ATA - ascending thoracic aorta	2.45	2.22	2.34
TMNMX (ratio) [Median (Inter-Quartile Range) ]
Combined Carotid	1.93	1.93	1.93
ATA	2.34	2.12	2.23
SMNMX (ratio) [Median (Full Range) ]
Combined Carotid	1.82	1.78	1.80
ATA	2.26	2.24	2.25

Outcome Measures

1. Primary Outcome

Title	Change in Arterial Inflammation
Description	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)
Time Frame	baseline and 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose Methotrexate	Placebo
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.	matching placebo
Measure Participants	26	27
Median (Inter-Quartile Range) [percent change]	0.03	0.20

2. Secondary Outcome

Title	Change in Max Target-to-background (TBR)
Description	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.
Time Frame	baseline and 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose Methotrexate	Placebo
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.	matching placebo
Measure Participants	26	27
Median (Inter-Quartile Range) [ratio]	0.06	0.02

3. Secondary Outcome

Title	Change in Max TBR Within the Carotid Arteries
Description	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)
Time Frame	baseline and 8 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose Methotrexate	Placebo
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.	matching placebo
Measure Participants	26	27
Median (Inter-Quartile Range) [ratio]	-0.04	0.06

Adverse Events

Time Frame	8 months
Arm/Group Title	Low Dose Methotrexate		Placebo
Arm/Group Description	Low dose methotrexate - average dose of 15-20 mg po/weekly. will additionally receive 1 mg daily oral folate.		matching placebo
All Cause Mortality
	Low Dose Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)		1/63 (1.6%)
Serious Adverse Events
	Low Dose Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/63 (0%)
Other (Not Including Serious) Adverse Events
	Low Dose Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)		1/63 (1.6%)
Investigations
Missinjected dose (isotope)	1/60 (1.7%)		1/63 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.