Please select the eligibility criteria that correspond to the clinical trial below.
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).


Options:
A: Inclusion Criteria:

* Men or women equal or elder 40 years of age
* Either acute ischaemic stroke or high-risk TIA as defined here and randomisation occurring within 24 hours after onset of symptoms

Key Exclusion Criteria:

* Planned use of antithrombotic therapy in addition to study medication including antiplatelets (eg, open label ASA, GPIIb/IIIa inhibitors, clopidogrel, ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol) and anticoagulants (eg, warfarin, oral thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and low molecular weight heparins). - Any history of atrial fibrillation, ventricular aneurysm or suspicion of cardioembolic pathology for TIA or stroke. - Planned carotid, cerebrovascular, or coronary revascularisation that requires halting study medication within 7 days of randomisation. - Receipt of any intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation - History of previous symptomatic non-traumatic intracerebral bleed at any time (asymptomatic microbleeds do not qualify), gastrointestinal (GI) bleed within the past 6 months, or major surgery within 30 days.
B: Main Study Inclusion Criteria:

* Written informed consent
* Male, or Female of non-child-bearing potential
* Age ≥ 18 years.
* Spontaneous MI at least 30 days before randomization. hsCRP ≥ 2 mg/L

Substudy 1 Inclusion:

* All Inclusion from Main Study
* Acquisition of evaluable baseline MRI images of bilateral carotid arteries by the imaging core laboratory

Substudy 2 Inclusion:

* All inclusion from Main Study
* T2D at baseline per Main protocol criteria and be on a stable anti-hyperglycemic medication for at least 4 weeks prior to the baseline OGTT test
* Willing to have the OGTT assessment started before 10 am

Main Study Exclusion Criteria:

* Pregnant or nursing (lactating) women
* Women of child-bearing potential
* Any of the following concomitant diseases
* Planned coronary revascularization (PCI or CABG)
* Major non-cardiac surgical or endoscopic procedure within past 6 months
* Multi-vessel CABG surgery within the past 3 years
* Symptomatic patients with Class IV heart failure (HF) (New York Heart Association \[NYHA\].
* Uncontrolled hypertension
* Uncontrolled diabetes
* History or evidence of active tuberculosis (TB) infection Substudy 1 Exclusion
* All Main exclusion
* Patients with prior history of carotid angioplasty, stenting, or carotid atherectomy
* Patients with contraindications to MRI examination (brain aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker, pacemaker wires or defibrillator, prosthetic heart valves, cochlear implant, ocular foreign body or other implanted body, tattoos, implanted insulin pump, metal shrapnel or bullet)
* Patients prone to claustrophobia or known anxiety disorders
* BMI \> 40 kg/m2 Substudy 2 Exclusion
* This sub-study does not have any additional exclusion criteria.
C: 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.
D: Inclusion criteria:

* Adult subjects (male or female≥40 years)
* Acute non-disabling ischemic stroke (NIHSS≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle
* TIA (Neurological deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with study drug within 24 hours of symptoms onset and with moderate-to-high risk of stroke recurrence (ABCD2 score≥4 at the time of randomization).Symptom onset is defined by the "last see normal" principle
* Informed consent signed

Exclusion Criteria:

* Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major non-ischemic brain disease (e.g., multiple sclerosis) on baseline head CT or MRI
* Isolated or pure sensory symptoms (e.g., numbness), isolated visual changes, or isolated dizziness/vertigo without evidence of acute infarction on baseline head CT or MRI
* Modified Rankin Scale Score\>2 at randomization (pre-morbid historical assessment)
* NIH Stroke Score≥4 at randomization
* Clear indication for anticoagulation(presumed cardiac source of embolus, e.g., atrial fibrillation, prosthetic cardiac valves known or suspected endocarditis)
* Contraindication to clopidogrel or ASA
* Known allergy
* Severe renal or hepatic insufficiency
* Severe cardiac failure, asthma
* Hemostatic disorder or systemic bleeding
* History of hemostatic disorder or systemic bleeding
* History of thrombocytopenia or neutropenia
* History of drug-induced hematologic or hepatic abnormalities
* Low white blood cell (\<2 x109/l) or platelet count (\<100 x109/l)
* Use of thrombolysis within 24 hours prior to randomization
* History of intracranial hemorrhage
* Anticipated requirement for long-term non-study antiplatelet drugs, or NSAIDs affecting platelet function
* Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anti coagulation
* Gastrointestinal bleed or major surgery within 3 months
* Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months (if clinically indicated, vascular imaging should be performed prior to randomization whenever possible)
* Scheduled for surgery or interventional treatment requiring study drug cessation
* Qualifying TIA or minor stroke induced by angiography or surgery
* Severe non-cardiovascular comorbidity with life expectancy \< 3 months
* Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test
* Currently receiving an investigational drug or device

Answer: C