Treatment of Patients With Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles

Study Overview
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Brief Summary
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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.

Detailed Description
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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. LDE-methotrexate treatment of rabbits induced to exhibit atherosclerosis via high cholesterol intake resulted in a 65% reduction in lesion size. The aim of this study is to investigate whether patients with aortic and coronary atherosclerotic disease showed good tolerability to LDE-methotrexate treatment and whether this formulation could achieve reduction in plaque volume and characteristics by coronary and aortic CT angiography.

Official Title
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Treatment of Patients With Coronary and Aortic Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles. A Randomized, Double-blind, Placebo-control Trial

Conditions
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Atherosclerosis, Coronary Artery Disease, Inflammation

Intervention / Treatment
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* Drug: Methotrexate-LDE
* Drug: Placebo-LDE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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 m2. 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/mm3. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Double-blind, Placebo-control Trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate-LDE<br>Methotrexate carried by a lipid nanoparticle (MTX-LDE) | Drug: Methotrexate-LDE<br>* MTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks<br>|
| Placebo Comparator: Placebo-LDE<br>Lipid nanoparticle (LDE) | Drug: Placebo-LDE<br>* Placebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Low Attenuation Plaque Volume (LAPV) coronary | Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups. | Baseline and change from baseline to 4 months. | 
| Low Attenuation Plaque Volume (LAPV) coronary | Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups. | Baseline and change from baseline to 12 months | 
| Low Attenuation Plaque Volume (LAPV) aortic | Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups. | Baseline and change from baseline to 4 months | 
| Low Attenuation Plaque Volume (LAPV) aortic | Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups. | Baseline and change from baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Noncalcified plaque volume (NCPV) | Compare Noncalcified plaque volume (NCPV) measured by coronary CT angiography between groups. | Baseline and change from baseline to 4 months | 
| Dense calcified plaque volume (DCPV) | Compare Dense calcified plaque volume (DCPV) measured by coronary CT angiography between groups. | Baseline and change from baseline to 12 months | 
| Total lumen value (TLV) | Compare Total lumen value (TLV) measured by coronary CT angiography between groups. | Baseline and change from baseline, 4 months and 12 months | 
| Remodeling index (RI) | Compare Remodeling index (RI) measured by coronary CT angiography between groups. | Baseline and change from baseline, 4 months and 12 months | 
| Perivascular fat attenuation index (FAI) | Compare Perivascular fat attenuation index (FAI) measured by coronary CT angiography between groups. | Baseline and change from baseline, 4 months and 12 months | 
| Total atheroma volume (TAV) | Compare Total atheroma volume (TAV) measured by coronary CT angiography between groups. | Baseline and change from baseline, 4 months and 12 months | 
| Total atheroma volume (TAV) aortic | Compare Total atheroma volume (TAV) measured by aortic CT angiography between groups. | Baseline and change from baseline, 4 months and 12 months | 
| Clinical significant symptoms | Compare the incidence of clinical significant symptoms (new and persistent stomatitis, vomiting, diarrhea, unexplained cough with fever, shortness of breath, alopecia, neurotoxicity, myalgia, arthralgias, bradycardia, hypotension, local pain) reported in each visit between groups. | 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization | 
| Other adverse events | Compare the incidence of other adverse events (not expected) reported in each visit between groups. | 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atherosclerosis, coronary artery disease, inflammation, methotrexate, nanoparticles, nanotechnology, drug delivery system