Treatment of Patients With Atherosclerotic Disease With Paclitaxel-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-proliferative agent paclitaxel in a cholesterol-rich non-protein nanoparticle (Paclitaxel -LDE) in patients with stable coronary disease. Patients with multi-vessels stable coronary disease will be randomized to receive Paclitaxel-LDE IV or placebo-LDE IV each 21 days for 6 weeks. The primary and main secondary endpoints will be analyzed by coronary and aortic CTA, that will be performed 1-4 weeks after randomization and at 3-8 weeks after the last treatment cycle. Patients will undergo clinical and laboratory safety evaluations before each treatment cycle and 3-8 weeks after the last cycle. 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 31% 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, such as rheumatoid arthritis (AR); in systemic lupus erythematosus; in psoriasis and inflammatory bowel disease, in this patients the spread of the inflammatory cascade results in premature atherosclerotic plaque formation. Cardiovascular mortality is the cause of death in 40-50% of AR patients. The treatment of systemic diseases with TNF-a inhibitors has been associated with a reduction in cardiovascular events in patients with AR and psoriasis. 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 most potent anti-proliferative drugs currently available are chemotherapeutic agents used for cancer treatment. However, the systemic use of these drugs 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, Maranhão et al. 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-paclitaxel treatment of rabbits induced to exhibit atherosclerosis via high cholesterol intake resulted in a 65% reduction in lesion size. In rabbits that underwent heterotopic heart transplantation, LDE-paclitaxel treatment markedly reduced heart graft damage by preventing coronary vessel destruction and macrophage invasion into the myocardium. In a pilot study Maranhão et al showed that treatment with high-dose LDE-paclitaxel had low enough toxicity to permits the use in patients with cardiovascular disease, and an average 18% reduction in aortic plaque volume in four out of the eight participants, which is a promising finding. This result was especially noteworthy in view of the short 18-week treatment period and when considering that plaque reduction did not occur in any of the control group patients. In contrast, statistically significant disease progression was observed in the non-treated control patients. The aim of this study is to investigate whether patients with aortic and coronary atherosclerotic disease showed good tolerability to LDE-paclitaxel 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 Paclitaxel-associated to LDL Like Nanoparticles. A Randomized, Double-blind, Placebo-control Trial.

Conditions
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Coronary Artery Disease, Atherosclerosis, Inflammation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multi-vessels coronary artery disease diagnosis by coronary CTA scan or invasive angiography Aortic atherosclerosis diagnosis by multidetector computed tomography (MDCT) angiography. Signing the study informed consent. Exclusion Criteria: History of AMI 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 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

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDE-Paclitaxel<br>Paclitaxel carried by a lipid nanoparticle (LDE-Paclitaxel) | Drug: LDE-Paclitaxel<br>* LDE-Paclitaxel at the dose of 175 mg/m2 IV each 21 days for 6 weeks<br>|
| Placebo Comparator: LDE-Placebo<br>Lipid nanoparticle (LDE) | Drug: LDE-Placebo<br>* LDE-Placebo at the dose of 175 mg/m2 IV each 21 days for 6 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 CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Low Attenuation Plaque Volume (LAPV) aortic | Compare Low attenuation Plaque Volume( LAPV) measured by aortic CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Noncalcified plaque volume (NCPV) | Compare Noncalcified plaque volume (NCPV) measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Dense calcified plaque volume (DCPV) | Compare Dense calcified plaque volume (DCPV) measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Total lumen value (TLV) | Compare Total lumen value (TLV) measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Remodeling index (RI) | Compare Remodeling index (RI)measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Perivascular fat attenuation index (FAI) | Compare Perivascular fat attenuation index (FAI)measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Total atheroma volume (TAV) | Compare Total atheroma volume (TAV) measured by coronary CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 months | 
| Total atheroma volume (TAV) aortic | Compare Total atheroma volume (TAV) measured by aortic CTA between Paclitaxel-LDE and Placebo-LDE groups. | Baseline and change from baseline to 6-8 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 Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Other adverse events | Compare the incidence of other adverse events (not expected) reported in each visit between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Red blood cell count | Compare hemoglobin and hematocrits levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| White blood cell count | Compare leucocyte and neutrophil levels levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Platelet count | Compare total Platelet levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Alanine aminotransferase (ALT) | Compare Alanine aminotransferase (ALT) levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Aspartate aminotransferase (AST) | Compare Aspartate aminotransferase (AST) levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Creatinine | Compare Creatinine levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 
| Urea | Compare Urea levels between Paclitaxel-LDE and Placebo-LDE groups. | 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATHEROSCLEROSIS, CORONARY ARTERY DISEASE, INFLAMATION, NANOPARTICLES, PACLITAXEL, DRUG TARGETING, DRUG DELIVERY SYSTEM