Treatment of Patients With Atherosclerotic Disease With Paclitaxel-associated to LDL Like Nanoparticles (PAC-MAN)

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

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.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease; Inflammation; Atherosclerosis
• Intervention / Treatment: Drug: LDE-Paclitaxel; Drug: LDE-Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • SP
    • São Paulo, SP, Brazil, 05403900
      • Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LDE-Paclitaxel; Paclitaxel carried by a lipid nanoparticle (LDE-Paclitaxel)	Drug: LDE-Paclitaxel; LDE-Paclitaxel at the dose of 175 mg/m2 IV each 21 days for 6 weeks
Placebo Comparator: LDE-Placebo; Lipid nanoparticle (LDE)	Drug: LDE-Placebo; LDE-Placebo at the dose of 175 mg/m2 IV each 21 days for 6 weeks

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
High-sensitivity C reactive protein (hs-CRP)	Compare High-sensitivity C reactive protein (hs-CRP) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Interleukin 6 (IL-6)	Compare Interleukin 6 (IL-6) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Interleukin 1b (IL-1b)	Compare Interleukin 1b (IL-1b) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Interleukin 10 (IL-10)	Compare Interleukin 10 (IL-10) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Interleukin 8 (IL-8)	Compare Interleukin 8 (IL-8) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Interferon gamma (IFN-y)	Compare Interferon gamma (IFN-y) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Tumor necrosis factor-alpha (TNF-a)	Compare Tumor necrosis factor-alpha (TNF-a) between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Total Cholesterol	Compare Total Cholesterol levels between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
High-density lipoprotein cholesterol (HDL)	Compare High-density lipoprotein cholesterol (HDL) levels between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Low-density lipoprotein cholesterol (LDL)	Compare Low-density lipoprotein cholesterol (LDL) levels between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Triglyceride	Compare Triglyceride levels between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Creatine phosphokinase (CPK)	Compare Creatine phosphokinase (CPK) levels between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months
Cholesterol efflux	Compare Cholesterol efflux between Paclitaxel-LDE and Placebo-LDE groups.	Baseline and change from baseline to 6-8 months

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Investigators: Study Chair: Raul C Maranhão, MD;PhD, Director Lipid Metabolism Laboratory, Heart Institute

Publications and helpful links

General Publications

• Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.
• Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. doi: 10.1056/NEJMoa0807646. Epub 2008 Nov 9.
• Vaidya K, Arnott C, Martinez GJ, Ng B, McCormack S, Sullivan DR, Celermajer DS, Patel S. Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study. JACC Cardiovasc Imaging. 2018 Feb;11(2 Pt 2):305-316. doi: 10.1016/j.jcmg.2017.08.013. Epub 2017 Oct 18.
• Shapiro MD, Fazio S. From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk. Circ Res. 2016 Feb 19;118(4):732-49. doi: 10.1161/CIRCRESAHA.115.306471.
• van Diepen JA, Berbee JF, Havekes LM, Rensen PC. Interactions between inflammation and lipid metabolism: relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis. Atherosclerosis. 2013 Jun;228(2):306-15. doi: 10.1016/j.atherosclerosis.2013.02.028. Epub 2013 Mar 1.
• Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J. 2016 Jun 7;37(22):1720-2. doi: 10.1093/eurheartj/ehw024. Epub 2016 Feb 22. No abstract available.
• Khan R, Spagnoli V, Tardif JC, L'Allier PL. Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis. 2015 Jun;240(2):497-509. doi: 10.1016/j.atherosclerosis.2015.04.783. Epub 2015 Apr 18.
• Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005 Feb;52(2):262-7. doi: 10.1016/j.jaad.2004.06.017. Erratum In: J Am Acad Dermatol. 2005 Apr;52(4):670. Prodanowich, Srdjan [corrected to Prodanovich, Srdjan].
• Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011 Apr;63(4):522-9. doi: 10.1002/acr.20371.
• Dias ML, Carvalho JP, Rodrigues DG, Graziani SR, Maranhao RC. Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers. Cancer Chemother Pharmacol. 2007 Jan;59(1):105-11. doi: 10.1007/s00280-006-0252-3. Epub 2006 May 13.
• Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003 Mar 11;107(9):1303-7. doi: 10.1161/01.cir.0000054612.26458.b2.
• Maranhao RC, Vital CG, Tavoni TM, Graziani SR. Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents. Expert Opin Drug Deliv. 2017 Oct;14(10):1217-1226. doi: 10.1080/17425247.2017.1276560. Epub 2017 Jan 1.
• Maranhao RC, Tavares ER, Padoveze AF, Valduga CJ, Rodrigues DG, Pereira MD. Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerosis regression in the rabbit. Atherosclerosis. 2008 Apr;197(2):959-66. doi: 10.1016/j.atherosclerosis.2007.12.051. Epub 2008 Mar 4.
• Shiozaki AA, Senra T, Morikawa AT, Deus DF, Paladino-Filho AT, Pinto IM, Maranhao RC. Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles. Clinics (Sao Paulo). 2016 Aug;71(8):435-9. doi: 10.6061/clinics/2016(08)05.
• Maranhao RC, Garicochea B, Silva EL, Llacer PD, Pileggi FJ, Chamone DA. Increased plasma removal of microemulsions resembling the lipid phase of low-density lipoproteins (LDL) in patients with acute myeloid leukemia: a possible new strategy for the treatment of the disease. Braz J Med Biol Res. 1992;25(10):1003-7.
• Lourenco-Filho DD, Maranhao RC, Mendez-Contreras CA, Tavares ER, Freitas FR, Stolf NA. An artificial nanoemulsion carrying paclitaxel decreases the transplant heart vascular disease: a study in a rabbit graft model. J Thorac Cardiovasc Surg. 2011 Jun;141(6):1522-8. doi: 10.1016/j.jtcvs.2010.08.032. Epub 2011 Mar 31.

Helpful Links

• WHO

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2019
• Primary Completion (Actual): August 12, 2020
• Study Completion (Anticipated): August 23, 2021

Study Registration Dates

• First Submitted: October 30, 2019
• First Submitted That Met QC Criteria: October 30, 2019
• First Posted (Actual): November 4, 2019

Study Record Updates

• Last Update Posted (Actual): October 27, 2020
• Last Update Submitted That Met QC Criteria: October 24, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: PACLITAXEL; ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; INFLAMATION; NANOPARTICLES; DRUG TARGETING; DRUG DELIVERY SYSTEM
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Inflammation; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: 02090118.7.0000.0068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No