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

NCT04616872 | Unknown Phase 2

• 1 other identifier: 4786/19/005
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

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-inflammatory agent methotrexate in a cholesterol-rich non-protein nanoparticle (MTX-LDE) in patients with stable coronary disease. 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.

Conditions

Atherosclerosis; Coronary Artery Disease; Inflammation

Keywords

Atherosclerosis; coronary artery disease; inflammation; methotrexate; nanoparticles; nanotechnology; drug delivery system

Outcome Measures

Primary Outcomes (4)

• Low Attenuation Plaque Volume (LAPV) coronary

  Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups.

  Baseline and change from baseline to 4 months.

• Low Attenuation Plaque Volume (LAPV) coronary

  Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups.

  Baseline and change from baseline to 12 months

• Low Attenuation Plaque Volume (LAPV) aortic

  Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups.

  Baseline and change from baseline to 4 months

• Low Attenuation Plaque Volume (LAPV) aortic

  Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups.

  Baseline and change from baseline to 12 months

Secondary Outcomes (9)

• Noncalcified plaque volume (NCPV)

  Baseline and change from baseline to 4 months

• Dense calcified plaque volume (DCPV)

  Baseline and change from baseline to 12 months

• Total lumen value (TLV)

  Baseline and change from baseline, 4 months and 12 months

• Remodeling index (RI)

  Baseline and change from baseline, 4 months and 12 months

• Perivascular fat attenuation index (FAI)

  Baseline and change from baseline, 4 months and 12 months

Other Outcomes (11)

• Red blood cell count

  1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization

• White blood cell count

  1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization

• Platelet count

  1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization

Study Arms (2)

Methotrexate-LDE

EXPERIMENTAL

Methotrexate carried by a lipid nanoparticle (MTX-LDE)

Drug: Methotrexate-LDE

Placebo-LDE

PLACEBO COMPARATOR

Lipid nanoparticle (LDE)

Drug: Placebo-LDE

Interventions

Methotrexate-LDE DRUG

MTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks

Methotrexate-LDE

Placebo-LDE DRUG

Placebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks

Placebo-LDE

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 CT or invasive angiography
• Aortic atherosclerosis diagnosis by multidetector computed tomography (MDCT) angiography.
• High-sensitivity C reactive protein (hs-CRP) levels \> 2mg/L
• Signing the study informed consent.

You may not qualify if:

• History of Acute myocardial infarction 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 Canadian Cardiovascular Society (CCS) III-IV

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead

Study Sites (2)

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

São Paulo, São Paulo, 05403900, Brazil

RECRUITING

Institute Prevent Senior

São Paulo, São Paulo, Brazil

NOT YET RECRUITING

Related Publications (19)

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

  PMID: 24065615 BACKGROUND

• 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.

  PMID: 26892970 BACKGROUND

• 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.

  PMID: 23518178 BACKGROUND

• 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.

  PMID: 18997196 BACKGROUND

• 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

• 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.

  PMID: 30415610 BACKGROUND

• Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L'Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16.

  PMID: 31733140 BACKGROUND

• Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL; LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847. doi: 10.1056/NEJMoa2021372. Epub 2020 Aug 31.

  PMID: 32865380 BACKGROUND

• Moura JA, Valduga CJ, Tavares ER, Kretzer IF, Maria DA, Maranhao RC. Novel formulation of a methotrexate derivative with a lipid nanoemulsion. Int J Nanomedicine. 2011;6:2285-95. doi: 10.2147/IJN.S18039. Epub 2011 Oct 12.

  PMID: 22072866 BACKGROUND

• Bulgarelli A, Martins Dias AA, Caramelli B, Maranhao RC. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol. 2012 Apr;59(4):308-14. doi: 10.1097/FJC.0b013e318241c385.

  PMID: 22113347 BACKGROUND

• Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006 Jul;6(7):508-19. doi: 10.1038/nri1882. Epub 2006 Jun 16.

  PMID: 16778830 BACKGROUND

• Hansson GK. Inflammation and Atherosclerosis: The End of a Controversy. Circulation. 2017 Nov 14;136(20):1875-1877. doi: 10.1161/CIRCULATIONAHA.117.030484. Epub 2017 Sep 15. No abstract available.

  PMID: 28916641 BACKGROUND

Related Links

• World Health Organization (WHO)

MeSH Terms

Conditions

Atherosclerosis; Coronary Artery Disease; Inflammation

Condition Hierarchy (Ancestors)

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

Central Study Contacts

Raul Maranhão, MD;PhD

CONTACT

+551126615951; raul.maranhao@incor.usp.br

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: MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute

Model Details: Randomized, Double-blind, Placebo-control Trial.

Study Record Dates

• First Submitted: October 24, 2020
• First Posted: November 5, 2020
• Study Start: October 10, 2020
• Primary Completion: October 12, 2022
• Study Completion: October 12, 2023
• Last Updated: November 10, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

BR (2)