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

NCT04148833 | Unknown Phase 2

• 1 other identifier: 02090118.7.0000.0068
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Coronary Artery Disease; Atherosclerosis; Inflammation

Keywords

ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; INFLAMATION; NANOPARTICLES; PACLITAXEL; DRUG TARGETING; DRUG DELIVERY SYSTEM

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (16)

• Noncalcified plaque volume (NCPV)

  Baseline and change from baseline to 6-8 months

• Dense calcified plaque volume (DCPV)

  Baseline and change from baseline to 6-8 months

• Total lumen value (TLV)

  Baseline and change from baseline to 6-8 months

• Remodeling index (RI)

  Baseline and change from baseline to 6-8 months

• Perivascular fat attenuation index (FAI)

  Baseline and change from baseline to 6-8 months

Other Outcomes (13)

• High-sensitivity C reactive protein (hs-CRP)

  Baseline and change from baseline to 6-8 months

• Interleukin 6 (IL-6)

  Baseline and change from baseline to 6-8 months

• Interleukin 1b (IL-1b)

  Baseline and change from baseline to 6-8 months

Study Arms (2)

LDE-Paclitaxel

EXPERIMENTAL

Paclitaxel carried by a lipid nanoparticle (LDE-Paclitaxel)

Drug: LDE-Paclitaxel

LDE-Placebo

PLACEBO COMPARATOR

Lipid nanoparticle (LDE)

Drug: LDE-Placebo

Interventions

LDE-Paclitaxel DRUG

LDE-Paclitaxel at the dose of 175 mg/m2 IV each 21 days for 6 weeks

LDE-Paclitaxel

LDE-Placebo DRUG

LDE-Placebo at the dose of 175 mg/m2 IV each 21 days for 6 weeks

LDE-Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead

Study Sites (1)

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

São Paulo, São Paulo, 05403900, Brazil

Location

Related Publications (17)

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  PMID: 23518178 BACKGROUND

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• 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.

  PMID: 26908943 BACKGROUND

• 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.

  PMID: 25917947 BACKGROUND

• 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.

  PMID: 15692471 BACKGROUND

• 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.

  PMID: 20957658 BACKGROUND

• 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.

  PMID: 29055633 BACKGROUND

• 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.

  PMID: 28845751 BACKGROUND

• 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.

  PMID: 16699792 BACKGROUND

• 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.

  PMID: 12628952 RESULT

• 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.

  PMID: 28042707 RESULT

• 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.

  PMID: 18289548 RESULT

• 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.

  PMID: 27626473 RESULT

• 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.

  PMID: 1342820 RESULT

• 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.

  PMID: 21458008 RESULT

• Marinho LL, Rached FH, Morikawa AT, Tavoni TM, Cardoso APT, Torres RVA, Assuncao AN Jr, Serrano CV Jr, Nomura CH, Maranhao RC. Safety and possible anti-inflammatory effect of paclitaxel associated with LDL-like nanoparticles (LDE) in patients with chronic coronary artery disease: a double-blind, placebo-controlled pilot study. Front Cardiovasc Med. 2024 Feb 21;11:1342832. doi: 10.3389/fcvm.2024.1342832. eCollection 2024.

  PMID: 38450375 DERIVED

Related Links

• WHO

MeSH Terms

Conditions

Coronary Artery Disease; Atherosclerosis; Inflammation

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Raul C Maranhão, MD;PhD

  Director Lipid Metabolism Laboratory, Heart Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head Professor of Clinical Biochemistry, Faculty of Pharmaceutical Sciences; Director, Lipid Metabolism Laboratory, Heart Institute of the Medical School, University of São Paulo, São Paulo, Brazil. MD, PHD

Study Record Dates

• First Submitted: October 30, 2019
• First Posted: November 4, 2019
• Study Start: June 23, 2019
• Primary Completion: August 12, 2020
• Study Completion: August 23, 2021
• Last Updated: October 27, 2020

Record last verified: 2020-10

Locations

BR (1)