Treatment of Patients With Coronary and Aortic Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles. A Randomized, Double-blind, Placebo-control Trial
试验速览
- 阶段
- 2 期
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Low Attenuation Plaque Volume (LAPV) coronary
研究概览
简要总结
The investigators propose a prospective, randomized, double-blind, placebo-controlled study. The purpose of the study is to evaluate the safety and efficacy of an anti-inflammatory agent methotrexate in a cholesterol-rich non-protein nanoparticle (MTX-LDE) in patients with stable coronary disease.
Patients with multi-vessels stable coronary disease will be randomized to receive MTX-LDE IV or placebo-LDE IV each 7 days for 12 weeks. The primary and main secondary endpoints will be analyzed by coronary and aortic CT angiography, that will be performed before the first treatment cycle, four weeks after the last drug infusion and 12 months after randomization. Patients will undergo clinical and laboratory safety evaluations before each treatment cycle, four weeks after the last cycle and 12 months after randomization.
An algorithm for drug suspension based on clinical and laboratory finding will be followed.
详细描述
Atherosclerosis is a life-threatening condition, as long as cardiovascular disease is responsible for one-third of all global mortality.
Inflammation is extremely important in atherosclerosis pathophysiology. 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 showed that individuals with lower high sensitive C-reactive protein (hsCRP) have better clinical outcomes than those with higher levels.
The potential benefit of anti-inflammatory therapy in atherosclerosis has been previously demonstrated in studies in patients with chronic inflammatory diseases (rheumatoid arthritis, psoriasis). The use of methotrexate has been associated with a reduction in cardiovascular events in these patients.
In this setting, the use of non-invasive treatments to reduce lesion size and inflammation is essential for the prevention of sub-sequent cardiovascular events.
The systemic use of methotrexate at high doses for the treatment of atherosclerotic cardiovascular diseases is unlikely due to their significant, often life-threatening toxicity. Nonetheless, the toxicity of such agents can be strongly diminished by the use of optimized drug-delivery systems. In a pioneer study performed on patients with acute leukemia, was reported the potential of a cholesterol-rich non-protein nanoparticle (LDE) as a drug targeting agent. LDE particles have lipid compositions and structures that resemble low-density lipoprotein (LDL) and can be injected directly into the bloodstream. When LDE particles come into contact with plasma, the particles acquire exchangeable apolipoproteins from native lipoproteins, such as apolipoprotein (apo) E, which binds the particles to LDL receptors. In neoplastic cells, lipoprotein receptors are overexpressed, such that uptake of native LDL and of LDE particles is increased relative to that in normal tissues. In aortas of cholesterol-fed rabbits the uptake of LDE particles is increased in comparison to normal aortas and in rabbit-grafted hearts take up the nanoemulsion at amounts fourfold greater than native hearts.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Multi-vessels coronary artery disease diagnosis by coronary CT or invasive angiography
- •Aortic atherosclerosis diagnosis by multidetector computed tomography (MDCT) angiography.
- •High-sensitivity C reactive protein (hs-CRP) levels > 2mg/L
- •Signing the study informed consent.
排除标准
- •History of Acute myocardial infarction in the last 30 days
- •Heart failure with ejection fraction <40%
- •Estimated glomerular filtration rate < 40 mL/min/1.73 m
- •Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive.
- •Chronic hepatitis B or C infection.
- •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 3-fold the upper limit of normal.
- •History of actual 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.
- •Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers.
- •Known chronic pericardial effusion, pleural effusion, or ascites.
- •Angina pectoris Canadian Cardiovascular Society (CCS) III-IV
- •New York Heart Association class III-IV congestive heart failure.
- •Contraindication for the use of iodinated contrast
- •Life expectancy of < 1 years.
- •Acute or Chronic aortic dissection
- •Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
- •Current indication for methotrexate therapy.
- •Patient with a history of an allergic reaction or significant sensitivity to methotrexate.
- •Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazole) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible.
研究组 & 干预措施
Methotrexate-LDE
Methotrexate carried by a lipid nanoparticle (MTX-LDE)
干预措施: Methotrexate-LDE (Drug)
Placebo-LDE
Lipid nanoparticle (LDE)
干预措施: Placebo-LDE (Drug)
结局指标
主要结局
Low Attenuation Plaque Volume (LAPV) coronary
时间窗: Baseline and change from baseline to 12 months
Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups.
Low Attenuation Plaque Volume (LAPV) aortic
时间窗: Baseline and change from baseline to 12 months
Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups.
次要结局
- Remodeling index (RI)(Baseline and change from baseline, 4 months and 12 months)
- Noncalcified plaque volume (NCPV)(Baseline and change from baseline to 4 months)
- Dense calcified plaque volume (DCPV)(Baseline and change from baseline to 12 months)
- Total lumen value (TLV)(Baseline and change from baseline, 4 months and 12 months)
- Total atheroma volume (TAV)(Baseline and change from baseline, 4 months and 12 months)
- Total atheroma volume (TAV) aortic(Baseline and change from baseline, 4 months and 12 months)
- Other adverse events(1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization)
- Perivascular fat attenuation index (FAI)(Baseline and change from baseline, 4 months and 12 months)
- Clinical significant symptoms(1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization)
研究者
Raul Cavalcante Maranhão
MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute
University of Sao Paulo General Hospital