Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After ST-elevation Myocardial Infarction
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Ventricular Remodelling
研究概览
简要总结
Prospective, randomized, double-blind, placebo-controlled, proof of concept study. Patients with first anterior wall STEMI will be randomized with 4±2 days after symptoms beginning to receive ddMTX-LDE at the dose of 40 mg/m2 IV or placebo-LDE weekly for 6 weeks. All study participants will additionally receive folic acid (5 mg po qd) once a week, one day after the study drug. The primary and main secondary endpoints will be analyzed by CMR 3±1 days and at 90±7 days after randomization.
Patients will undergo clinical and laboratory safety evaluations before each study drug administration and 90-day post-randomization. Safety evaluations will include assessment of adherence, side effects, safety laboratory tests, and existing medical conditions or planned procedures that might alter study drug dosing. These visits also include screening for the occurrence of clinical events of interest. An algorithm for drug suspension based on clinical and laboratory finding will be followed.
Pre-specified unblinded interim analyses by an independent investigator will be developed when 20% and 50% of the inclusions are reached.
详细描述
Inflammation is extremely important in atherosclerosis and atherothrombosis pathophysiology. It is similarly important after acute myocardial infarction (AMI), with a special participation on healing response and, consequently, on left ventricular remodeling (LVR).
Early successful reperfusion is highly effective for limiting tissue necrosis and improving outcomes in AMI, but many of these patients show microcirculation dysfunction, phenomenon related to inflammation, leading to worse LVR. Additionally, inflammation may extend into the noninfarcted remote myocardium, which also contribute to adverse LVR.
As pointed out by Westman et al in a recent review publication, although infarct size correlates with the development of adverse LVR, some patients with relatively small infarcts have adverse LVR, while others with larger infarcts do not. Individual differences in the inflammatory response, perhaps in part genetically, epigenetically, environmentally, or pathogenically modulated, may contribute to this phenomenon.
The use of inflammatory biomarkers to predict risk, monitor treatments and guide therapy, has shown substantial potential for clinical applicability. Many studies in primary and secondary prevention of cardiovascular disease (CVD) showed that individuals with lower high sensitive C-reactive protein (hsCRP) have better clinical outcomes than those with higher levels.
So, anti-inflammatory therapies may be useful in preventing left ventricular dysfunction following AMI despite reperfusion and anti-remodeling treatments.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with type 1 STEMI, documented by: ischemic symptoms, new ST-elevation at the J-point in two contiguous leads (0.2 mV in men or 0.15 mV in women in leads V2-V3 and/or 0.1 mV in other leads or new left bundle branch block [LBBB]) and cardiac biomarkers (troponin and/or creatine kinase MB) with at least one value above the 99th percentile of the upper reference limit (URL).
- •Submitted to any successful repercussion strategy (thrombolysis or angioplasty).
- •Coronary angiography showing successful reperfusion therapy (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 in the infarct-related artery) and residual obstruction in the infarct-related artery < 50%.
- •Asymptomatic, without signs of clinical decompensation (heart rate < 100bpm, systolic blood pressure > 90mmHg, without vasoactive dor inotropic drugs, pulse oximetry > 95% with FiO2 21%).
- •Signing the study informed consent.
排除标准
- •History of AMI.
- •Estimated glomerular filtration rate < 40 mL/min/1.73 m
- •Contraindications for CMR: pacemaker, metallic devices, claustrophobia, obesity over 150 kg total weight.
- •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 nonbasal cell malignancy or myeloproliferative or lymphoproliferative disease within the past 5 years.
- •White blood cell count <4000/mm3, hematocrit <32%, or platelet count <75000/mm
- •Alanine aminotransferase levels (ALT) greater than 2-fold the upper limit of normal.
- •History of alcohol abuse or unwillingness to limit alcohol consumption to < 4 drinks per week.
- •Pregnancy or breastfeeding.
- •Women of child bearing potential, even if currently using contraception.
- •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/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.
- •Known chronic pericardial effusion, pleural effusion, or ascites.
- •New York Heart Association class III-IV congestive heart failure.
- •Life expectancy of < 1 years.
- •Active infection.
研究组 & 干预措施
Methotrexate & Folic acid
ddMTX-LDE 40mg/m2 (100mL total volume) IV and Folic acid 5mg by mouth (the day after ddMTX-LDE) weekly for 6 weeks
干预措施: Methotrexate (Drug)
Methotrexate & Folic acid
ddMTX-LDE 40mg/m2 (100mL total volume) IV and Folic acid 5mg by mouth (the day after ddMTX-LDE) weekly for 6 weeks
干预措施: Folic Acid (Drug)
Placebo & folic acid
Placebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks
干预措施: Placebo (Drug)
Placebo & folic acid
Placebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks
干预措施: Folic Acid (Drug)
结局指标
主要结局
Ventricular Remodelling
时间窗: 90±7 days
Compare left ventricular end-diastolic volume (LVEDV) measured by cardiac magnetic resonance (CMR) between ddMTX-LDE and Placebo-LDE groups.
次要结局
- Left ventricular ejection fraction (LVEF)(90±7 days)
- Left ventricular mass (LVM)(90±7 days)
- Negative remodelling(90±7 days)
- Mean white blood cell count(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Platelet count(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Aspartate aminotransferase (AST)(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Clinical significant symptoms(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Positive remodelling(90±7 days)
- Alanine aminotransferase (ALT)(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Left ventricular end-systolic volume (LVESV)(90±7 days)
- Infarct size(90±7 days)
- Other adverse events(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Mean red blood cell count(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Bilirubin(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
- Creatinine clearance(7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days)
研究者
Jose Carlos Nicolau
Professor, PhD
University of Sao Paulo