Treatment of Patients With Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles
NCT ID: NCT04616872
Last Updated: 2020-11-10
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE2/PHASE3
40 participants
INTERVENTIONAL
2020-10-10
2023-10-12
Brief Summary
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Patients with multi-vessels stable coronary disease will be randomized to receive MTX-LDE IV or placebo-LDE IV each 7 days for 12 weeks. The primary and main secondary endpoints will be analyzed by coronary and aortic CT angiography, that will be performed before the first treatment cycle, four weeks after the last drug infusion and 12 months after randomization. Patients will undergo clinical and laboratory safety evaluations before each treatment cycle, four weeks after the last cycle and 12 months after randomization.
An algorithm for drug suspension based on clinical and laboratory finding will be followed.
Detailed Description
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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 (rheumatoid arthritis, psoriasis). The use of methotrexate has been associated with a reduction in cardiovascular events in these patients.
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 systemic use of methotrexate 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, was 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-methotrexate treatment of rabbits induced to exhibit atherosclerosis via high cholesterol intake resulted in a 65% reduction in lesion size.
The aim of this study is to investigate whether patients with aortic and coronary atherosclerotic disease showed good tolerability to LDE-methotrexate treatment and whether this formulation could achieve reduction in plaque volume and characteristics by coronary and aortic CT angiography.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Methotrexate-LDE
Methotrexate carried by a lipid nanoparticle (MTX-LDE)
Methotrexate-LDE
MTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks
Placebo-LDE
Lipid nanoparticle (LDE)
Placebo-LDE
Placebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks
Interventions
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Methotrexate-LDE
MTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks
Placebo-LDE
Placebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks
Eligibility Criteria
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Inclusion Criteria
* Aortic atherosclerosis diagnosis by multidetector computed tomography (MDCT) angiography.
* High-sensitivity C reactive protein (hs-CRP) levels \> 2mg/L
* Signing the study informed consent.
Exclusion Criteria
* 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 Canadian Cardiovascular Society (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
* Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
* Current indication for methotrexate therapy.
* Patient with a history of an allergic reaction or significant sensitivity to methotrexate.
* Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazole) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible.
18 Years
80 Years
ALL
No
Sponsors
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University of Sao Paulo General Hospital
OTHER
Responsible Party
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Raul Cavalcante Maranhão
MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute
Locations
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Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
São Paulo, São Paulo, Brazil
Institute Prevent Senior
São Paulo, São Paulo, Brazil
Countries
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Central Contacts
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Facility Contacts
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Lucas Marinho, MD
Role: primary
Rodrigo Esper, MD;PhD
Role: primary
References
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Bulgarelli A, Leite AC Jr, Dias AA, Maranhao RC. Anti-atherogenic effects of methotrexate carried by a lipid nanoemulsion that binds to LDL receptors in cholesterol-fed rabbits. Cardiovasc Drugs Ther. 2013 Dec;27(6):531-9. doi: 10.1007/s10557-013-6488-3.
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.
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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, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10.
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Related Links
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World Health Organization (WHO)
Other Identifiers
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4786/19/005
Identifier Type: -
Identifier Source: org_study_id