Cardiovascular Inflammation Reduction Trial (CIRT)

• ClinicalTrials.gov Identifier: NCT01594333
• Recruitment Status: Completed
• First Posted: May 9, 2012
• Results First Posted: July 24, 2020
• Last Update Posted: July 24, 2020
• Sponsor: Brigham and Women's Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Paul Ridker, Brigham and Women's Hospital

Tracking Information

• First Submitted Date: May 1, 2012
• First Posted Date: May 9, 2012
• Results First Submitted Date: June 20, 2020
• Results First Posted Date: July 24, 2020
• Last Update Posted Date: July 24, 2020
• Study Start Date: April 2013
• Actual Primary Completion Date: April 15, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 23, 2020)

• Number of Subjects With Major Adverse Cardiovascular Events [ Time Frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years ]
  The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke.
• Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization [ Time Frame: From randomization to trial end (April 2, 2018) - up to a maximum of 5 years ]
  The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.

Original Primary Outcome Measures (submitted: May 7, 2012)

Rate of recurrent major cardiovascular events [ Time Frame: Four years ]

Investigate whether low-dose methotrexate (LDM) will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable post-myocardial infarction patients with type 2 diabetes or metabolic syndrome.

Current Secondary Outcome Measures (submitted: July 23, 2020)

• Number of Subjects With All-cause Mortality [ Time Frame: From randomization to the trial end (April 2, 2018) up to a maximum of 5 years ]
  Subjects who died from any cause.
• Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization [ Time Frame: From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years ]
  The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.
• Number of Subjects With Hospitalization for Congestive Heart Failure [ Time Frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years ]
  The first occurrence of Hospitalization for Congestive Heart Failure
• Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality [ Time Frame: From randomization to trial end (April 2, 2018) up to a maximum of 5 years ]
  The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.
• Number of Subjects With New Onset Type 2 Diabetes [ Time Frame: From randomization to the trial end (April 2, 2018) - up to 5 years ]
  New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c >=6.5 or fasting plasma glucose >=126.

Original Secondary Outcome Measures (submitted: May 7, 2012)

• Rate of all-cause mortality [ Time Frame: Four years ]
• Rate of hospitalization for congestive heart failure [ Time Frame: Four years ]
• Rate of incident venous thromboembolism [ Time Frame: Four years ]
• Rate of atrial fibrillation [ Time Frame: Four years ]
• Rate of percutaneous or surgical coronary revascularization [ Time Frame: Four years ]
• Rate of incident diabetes among those without diabetes at randomization [ Time Frame: Four years ]

Current Other Pre-specified Outcome Measures (submitted: July 23, 2020)

• Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization [ Time Frame: From randomization to the trial end (April 2, 2018) up to 5 years ]
  The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization
• Number of Subjects With Coronary Revascularization [ Time Frame: From randomization to trial end (April 2, 2018) up to 5 years ]
  The first occurrence of coronary revascularization
• Number of Subjects With Peripheral Artery Disease [ Time Frame: From randomization to the trial end (April 2, 2018) - up to 5 years ]
  The first occurrence of new or worsening of peripheral artery disease
• Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism [ Time Frame: From randomization to the trial end (April 2, 2018) - up to 5 years ]
  The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism
• Number of Subjects With Aortic Stenosis [ Time Frame: From randomization to the trial end (April 2, 2018) - up to 5 years ]
  The first occurrence of clinically significant aortic stenosis
• Number of Subjects With Atrial Fibrillation [ Time Frame: From randomization to the trial end (April 2, 2018) - up to 5 years ]
  The first occurrence of new or worsening of atrial fibrillation

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cardiovascular Inflammation Reduction Trial
• Official Title: A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Weekly Low-dose Methotrexate (LDM) in the Prevention of Cardiovascular Events Among Stable Coronary Artery Disease Patients With Type 2 Diabetes or Metabolic Syndrome
• Brief Summary: The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack or multiple coronary blockages. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH).
• Detailed Description: While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction in the past or have angiographically demonstrated multivessel coronary artery disease in the past will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is the rate of myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cardiovascular Disease

Intervention

• Drug: Methotrexate
  Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week
  Other Name: Trexall, TEVA Inc (brand of methotrexate)
• Drug: Placebo
  Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

Study Arms

• Experimental: Methotrexate
  Methotrexate: Tablet, Oral, Target dose 15-20mg weekly plus 1.0 mg folic acid 6 days/week
  Intervention: Drug: Methotrexate
• Placebo Comparator: Placebo
  Placebo: Tablet, Oral weekly plus 1.0mg folic acid 6 days/week
  Intervention: Drug: Placebo

Publications *

• Cui J, Chasman DI, Raychaudhuri S, Xu C, Ridker PM, Solomon DH, Karlson EW. Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate. Semin Arthritis Rheum. 2022 Aug;55:152036. doi: 10.1016/j.semarthrit.2022.152036. Epub 2022 May 28.
• Reiss AB, Teboul I, Kasselman L, Ahmed S, Carsons SE, De Leon J. Methotrexate effects on adenosine receptor expression in peripheral monocytes of persons with type 2 diabetes and cardiovascular disease. J Investig Med. 2022 Aug;70(6):1433-1437. doi: 10.1136/jim-2022-002355. Epub 2022 May 23.
• Xu C, Selhub J, Jacques P, Paynter NP, MacFadyen JG, Glynn RJ, Ridker PM, Solomon DH. Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial. Rheumatology (Oxford). 2021 Jun 18;60(6):2963-2968. doi: 10.1093/rheumatology/keaa650.
• Sparks JA, Dellaripa PF, Glynn RJ, Paynter NP, Xu C, Ridker PM, Solomon DH. Pulmonary Adverse Events in Patients Receiving Low-Dose Methotrexate in the Randomized, Double-Blind, Placebo-Controlled Cardiovascular Inflammation Reduction Trial. Arthritis Rheumatol. 2020 Dec;72(12):2065-2071. doi: 10.1002/art.41452. Epub 2020 Oct 7.
• Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Eur Heart J. 2020 Aug 14;41(31):2952-2961. doi: 10.1093/eurheartj/ehaa160.
• Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, Xu C, MacFadyen J, Barbhaiya M, Berliner N, Dellaripa PF, Everett BM, Pradhan AD, Hammond SP, Murray M, Rao DA, Ritter SY, Rutherford A, Sparks JA, Stratton J, Suh DH, Tedeschi SK, Vanni KMM, Paynter NP, Ridker PM. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020 Mar 17;172(6):369-380. doi: 10.7326/M19-3369. Epub 2020 Feb 18.
• Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10.
• Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013 Aug;166(2):199-207.e15. doi: 10.1016/j.ahj.2013.03.018. Epub 2013 May 3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 11, 2019): 4786
• Original Estimated Enrollment (submitted: May 7, 2012): 7000
• Actual Study Completion Date: October 30, 2019
• Actual Primary Completion Date: April 15, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 18 years at screening

• Documented past history of myocardial infarction OR past evidence of multivessel coronary artery disease by angiography.

  • To qualify on the basis of past history of myocardial infarction, the event must be documented either by hospital records or by evidence on current ECG of Q waves in two contiguous leads and/or an imaging test demonstrating wall motion abnormality or scar. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
  • To qualify on the basis of multivessel coronary disease, there must be past 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. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
• History of type 2 diabetes or metabolic syndrome at time of study enrollment
• Willingness to participate as evidenced by signing the study informed consent

Exclusion Criteria:

• Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of < 3 years;
• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease
• White blood cell count < 3,500/ul, hematocrit < 32 percent, or platelet count < 75,000/ul
• Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < the lower limit of normal (LLN);
• Creatinine clearance < 40 ml/min as estimated with the Cockcroft-Gault equation;
• History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks per week
• Women of child bearing potential, even if they are currently using contraception, and women intending to breastfeed.
• Men who plan to father children during the study period or who are unwilling to use effective forms of contraception.
• 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;
• Current indication for methotrexate therapy;
• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers. Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions.
• Chest X-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-ray in the prior 12 months, a chest X-ray will be obtained at baseline as part of the study protocol.
• New York Heart Association Class IV congestive heart failure.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Puerto Rico, United States

Administrative Information

• NCT Number: NCT01594333
• Other Study ID Numbers: 2012P-000857; U01HL101422 ( U.S. NIH Grant/Contract ); U01HL101389 ( 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: Paul Ridker, Brigham and Women's Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Brigham and Women's Hospital
• Original Study Sponsor: Same as current
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Paul Ridker, MD, MPH; Brigham and Women's Hospital

• PRS Account: Brigham and Women's Hospital
• Verification Date: July 2020