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

Sponsor
University of Sao Paulo General Hospital (Other)
Overall Status
Recruiting
CT.gov ID
NCT04616872
Collaborator
(none)
40
Enrollment
2
Locations
2
Arms
36
Anticipated Duration (Months)
20
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed 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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Randomized, Double-blind, Placebo-control Trial.Randomized, Double-blind, Placebo-control Trial.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Oct 10, 2020
Anticipated Primary Completion Date :
Oct 12, 2022
Anticipated Study Completion Date :
Oct 12, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Methotrexate-LDE

Methotrexate carried by a lipid nanoparticle (MTX-LDE)

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 Comparator: Placebo-LDE

Lipid nanoparticle (LDE)

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

Outcome Measures

Primary Outcome Measures

  1. Low Attenuation Plaque Volume (LAPV) coronary [Baseline and change from baseline to 4 months.]

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

  2. Low Attenuation Plaque Volume (LAPV) coronary [Baseline and change from baseline to 12 months]

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

  3. Low Attenuation Plaque Volume (LAPV) aortic [Baseline and change from baseline to 4 months]

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

  4. Low Attenuation Plaque Volume (LAPV) aortic [Baseline and change from baseline to 12 months]

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

Secondary Outcome Measures

  1. Noncalcified plaque volume (NCPV) [Baseline and change from baseline to 4 months]

    Compare Noncalcified plaque volume (NCPV) measured by coronary CT angiography between groups.

  2. Dense calcified plaque volume (DCPV) [Baseline and change from baseline to 12 months]

    Compare Dense calcified plaque volume (DCPV) measured by coronary CT angiography between groups.

  3. Total lumen value (TLV) [Baseline and change from baseline, 4 months and 12 months]

    Compare Total lumen value (TLV) measured by coronary CT angiography between groups.

  4. Remodeling index (RI) [Baseline and change from baseline, 4 months and 12 months]

    Compare Remodeling index (RI) measured by coronary CT angiography between groups.

  5. Perivascular fat attenuation index (FAI) [Baseline and change from baseline, 4 months and 12 months]

    Compare Perivascular fat attenuation index (FAI) measured by coronary CT angiography between groups.

  6. Total atheroma volume (TAV) [Baseline and change from baseline, 4 months and 12 months]

    Compare Total atheroma volume (TAV) measured by coronary CT angiography between groups.

  7. Total atheroma volume (TAV) aortic [Baseline and change from baseline, 4 months and 12 months]

    Compare Total atheroma volume (TAV) measured by aortic CT angiography between groups.

  8. Clinical significant symptoms [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    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.

  9. Other adverse events [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare the incidence of other adverse events (not expected) reported in each visit between groups.

Other Outcome Measures

  1. Red blood cell count [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare hemoglobin and hematocrits levels between groups.

  2. White blood cell count [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare leucocyte and neutrophil levels between groups.

  3. Platelet count [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare Platelet levels between groups.

  4. Alanine aminotransferase (ALT) [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare Alanine aminotransferase (ALT) levels between groups.

  5. Aspartate aminotransferase (AST) [1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization]

    Compare Aspartate aminotransferase (AST) levels between groups.

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

    Compare Creatinine levels between groups.

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

    Compare Urea levels between groups.

  8. Inflammatory biomarkers [Baseline and change from baseline, 4 months and 12 months]

    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.

  9. Cholesterol [Baseline and change from baseline, 4 months and 12 months]

    Compare Total Cholesterol; High-density lipoprotein cholesterol (HDL) ; Low-density lipoprotein cholesterol (LDL); Triglyceride levels between groups.

  10. Cholesterol efflux [Baseline and change from baseline, 4 months and 12 months]

    Compare Cholesterol efflux between groups.

  11. Creatine phosphokinase (CPK) [Baseline and change from baseline, 4 months and 12 months]

    Compare Creatine phosphokinase (CPK) levels between groups.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil São Paulo SP Brazil 05403900
2 Institute Prevent Senior São Paulo SP Brazil

Sponsors and Collaborators

  • University of Sao Paulo General Hospital

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
Raul Cavalcante Maranhão, MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute, University of Sao Paulo General Hospital
ClinicalTrials.gov Identifier:
NCT04616872
Other Study ID Numbers:
  • 4786/19/005
First Posted:
Nov 5, 2020
Last Update Posted:
Nov 10, 2020
Last Verified:
Nov 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Raul Cavalcante Maranhão, MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute, University of Sao Paulo General Hospital
Atherosclerosis
coronary artery disease
inflammation
methotrexate
nanoparticles
nanotechnology
drug delivery system
Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Atherosclerosis
Inflammation
Methotrexate

Study Results

No Results Posted as of Nov 10, 2020