Clinical trial NCT04148833: Treatment of Patients With Atherosclerotic Disease With Paclitaxel-associated to LDL Like Nanoparticles
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Coronary Artery Disease
Atherosclerosis
Inflammation
Keywords: ATHEROSCLEROSIS
CORONARY ARTERY DISEASE
INFLAMATION
NANOPARTICLES
PACLITAXEL
DRUG TARGETING
DRUG DELIVERY SYSTEM
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
First posted: 2019-11-04
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Low Attenuation Plaque Volume (LAPV) coronary
timeFrame: Baseline and change from baseline to 6-8 months
measure: Low Attenuation Plaque Volume (LAPV) aortic
timeFrame: Baseline and change from baseline to 6-8 months
Secondary outcomes:
measure: Noncalcified plaque volume (NCPV)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Dense calcified plaque volume (DCPV)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Total lumen value (TLV)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Remodeling index (RI)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Perivascular fat attenuation index (FAI)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Total atheroma volume (TAV)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Total atheroma volume (TAV) aortic
timeFrame: Baseline and change from baseline to 6-8 months
measure: Clinical significant symptoms
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Other adverse events
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Red blood cell count
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: White blood cell count
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Platelet count
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Alanine aminotransferase (ALT)
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Aspartate aminotransferase (AST)
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Creatinine
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
measure: Urea
timeFrame: 3±1, 6±1, 9±1, 12±1, 15±1 and 18±1 weeks
Other outcomes:
measure: High-sensitivity C reactive protein (hs-CRP)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Interleukin 6 (IL-6)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Interleukin 1b (IL-1b)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Interleukin 10 (IL-10)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Interleukin 8 (IL-8)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Interferon gamma (IFN-y)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Tumor necrosis factor-alpha (TNF-a)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Total Cholesterol
timeFrame: Baseline and change from baseline to 6-8 months
measure: High-density lipoprotein cholesterol (HDL)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Low-density lipoprotein cholesterol (LDL)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Triglyceride
timeFrame: Baseline and change from baseline to 6-8 months
measure: Creatine phosphokinase (CPK)
timeFrame: Baseline and change from baseline to 6-8 months
measure: Cholesterol efflux
timeFrame: Baseline and change from baseline to 6-8 months
Locations:
city: São Paulo
country: Brazil
facility: Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
state: SP
Study officials:
affiliation: Director Lipid Metabolism Laboratory, Heart Institute
name: Raul C Maranhão, MD;PhD
role: STUDY_CHAIR
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