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

Coronary Artery Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04616872
• Other study ID #: 4786/19/005
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: October 10, 2020
• Est. completion date: October 12, 2023

Study information

• Verified date: November 2020
• Source: University of Sao Paulo General Hospital
• Contact: Raul Maranhão, MD;PhD
• Phone: +551126615951
• Email: raul.maranhao[@]incor.usp.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Atherosclerosis is a life-threatening condition, as long as cardiovascular disease is responsible for one-third 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 (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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: October 12, 2023
• Est. primary completion date: October 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

• 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.

Related Conditions & MeSH terms

• Atherosclerosis
• Coronary Artery Disease
• Coronary Disease
• Inflammation
• Myocardial Ischemia

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Brazil	Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil	São Paulo	SP
Brazil	Institute Prevent Senior	São Paulo	SP

Sponsors (1)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital

Country where clinical trial is conducted

Brazil, 

References & Publications (19)

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

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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 Aug 31. doi: 10.1056/NEJMoa2021372. [Epub ahead of print] — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, López-Sendón J, Ostadal P, Koenig W, Angoulvant D, Grégoire JC, Lavoie MA, Dubé 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. — View Citation

Vaidya K, Arnott C, Martínez 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. — View Citation

van Diepen JA, Berbée 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. Review. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Red blood cell count	Compare hemoglobin and hematocrits levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	White blood cell count	Compare leucocyte and neutrophil levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Platelet count	Compare Platelet levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Alanine aminotransferase (ALT)	Compare Alanine aminotransferase (ALT) levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Aspartate aminotransferase (AST)	Compare Aspartate aminotransferase (AST) levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Creatinine	Compare Creatinine levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Urea	Compare Urea levels between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other	Inflammatory biomarkers	Compare High-sensitivity C reactive protein (hs-CRP); Interleukin 6 (IL-6); Interleukin 1b (IL-1b); Interleukin 10 (IL-10); Interleukin 8 (IL-8); Interleukin 17 (IL-17); Tumor necrosis factor-alpha (TNF-a); Interferon gamma (IFN-y) levels between groups.	Baseline and change from baseline, 4 months and 12 months
Other	Cholesterol	Compare Total Cholesterol; High-density lipoprotein cholesterol (HDL) ; Low-density lipoprotein cholesterol (LDL); Triglyceride levels between groups.	Baseline and change from baseline, 4 months and 12 months
Other	Cholesterol efflux	Compare Cholesterol efflux between groups.	Baseline and change from baseline, 4 months and 12 months
Other	Creatine phosphokinase (CPK)	Compare Creatine phosphokinase (CPK) levels between groups.	Baseline and change from baseline, 4 months and 12 months
Primary	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.
Primary	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
Primary	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
Primary	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	Noncalcified plaque volume (NCPV)	Compare Noncalcified plaque volume (NCPV) measured by coronary CT angiography between groups.	Baseline and change from baseline to 4 months
Secondary	Dense calcified plaque volume (DCPV)	Compare Dense calcified plaque volume (DCPV) measured by coronary CT angiography between groups.	Baseline and change from baseline to 12 months
Secondary	Total lumen value (TLV)	Compare Total lumen value (TLV) measured by coronary CT angiography between groups.	Baseline and change from baseline, 4 months and 12 months
Secondary	Remodeling index (RI)	Compare Remodeling index (RI) measured by coronary CT angiography between groups.	Baseline and change from baseline, 4 months and 12 months
Secondary	Perivascular fat attenuation index (FAI)	Compare Perivascular fat attenuation index (FAI) measured by coronary CT angiography between groups.	Baseline and change from baseline, 4 months and 12 months
Secondary	Total atheroma volume (TAV)	Compare Total atheroma volume (TAV) measured by coronary CT angiography between groups.	Baseline and change from baseline, 4 months and 12 months
Secondary	Total atheroma volume (TAV) aortic	Compare Total atheroma volume (TAV) measured by aortic CT angiography between groups.	Baseline and change from baseline, 4 months and 12 months
Secondary	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 groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Secondary	Other adverse events	Compare the incidence of other adverse events (not expected) reported in each visit between groups.	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization

External Links

•   World Health Organization (WHO)