Ignite Creation Date:
2025-12-25 @ 3:00 AM
Ignite Modification Date:
2026-01-27 @ 3:32 PM
Study NCT ID:
NCT04148833
Status:
UNKNOWN
Last Update Posted:
2020-10-27
First Post:
2019-10-30
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Treatment of Patients With Atherosclerotic Disease With Paclitaxel-associated to LDL Like Nanoparticles
Sponsor:
University of Sao Paulo General Hospital
Organization:
Study Overview
Official Title:
Treatment of Patients With Coronary and Aortic Atherosclerotic Disease With Paclitaxel-associated to LDL Like Nanoparticles. A Randomized, Double-blind, Placebo-control Trial.
Status:
UNKNOWN
Status Verified Date:
2020-10
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PAC-MAN
Brief Summary:
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.
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:
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.
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.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: