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

November 7, 2020 updated by: Raul Cavalcante Maranhão, University of Sao Paulo General Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Brazil
    • SP
      • São Paulo, SP, Brazil, 05403900
        • Recruiting
        • Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
        • Contact:
      • São Paulo, SP, Brazil
        • Not yet recruiting
        • Institute Prevent Senior
        • Contact:
          • Rodrigo Esper, MD;PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Low Attenuation Plaque Volume (LAPV) coronary
Time Frame: Baseline and change from baseline to 4 months.
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
Time Frame: Baseline and change from baseline to 12 months
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
Time Frame: Baseline and change from baseline to 4 months
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
Time Frame: Baseline and change from baseline to 12 months
Compare Low attenuation Plaque Volume( LAPV) measured by aortic CT angiography between groups.
Baseline and change from baseline to 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Noncalcified plaque volume (NCPV)
Time Frame: Baseline and change from baseline to 4 months
Compare Noncalcified plaque volume (NCPV) measured by coronary CT angiography between groups.
Baseline and change from baseline to 4 months
Dense calcified plaque volume (DCPV)
Time Frame: Baseline and change from baseline to 12 months
Compare Dense calcified plaque volume (DCPV) measured by coronary CT angiography between groups.
Baseline and change from baseline to 12 months
Total lumen value (TLV)
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Total lumen value (TLV) measured by coronary CT angiography between groups.
Baseline and change from baseline, 4 months and 12 months
Remodeling index (RI)
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Remodeling index (RI) measured by coronary CT angiography between groups.
Baseline and change from baseline, 4 months and 12 months
Perivascular fat attenuation index (FAI)
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Perivascular fat attenuation index (FAI) measured by coronary CT angiography between groups.
Baseline and change from baseline, 4 months and 12 months
Total atheroma volume (TAV)
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Total atheroma volume (TAV) measured by coronary CT angiography between groups.
Baseline and change from baseline, 4 months and 12 months
Total atheroma volume (TAV) aortic
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Total atheroma volume (TAV) measured by aortic CT angiography between groups.
Baseline and change from baseline, 4 months and 12 months
Clinical significant symptoms
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other adverse events
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Red blood cell count
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
White blood cell count
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Platelet count
Time Frame: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Compare Platelet levels between groups.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Alanine aminotransferase (ALT)
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Aspartate aminotransferase (AST)
Time Frame: 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.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Creatinine
Time Frame: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Compare Creatinine levels between groups.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Urea
Time Frame: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Compare Urea levels between groups.
1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Inflammatory biomarkers
Time Frame: 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.
Baseline and change from baseline, 4 months and 12 months
Cholesterol
Time Frame: 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.
Baseline and change from baseline, 4 months and 12 months
Cholesterol efflux
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Cholesterol efflux between groups.
Baseline and change from baseline, 4 months and 12 months
Creatine phosphokinase (CPK)
Time Frame: Baseline and change from baseline, 4 months and 12 months
Compare Creatine phosphokinase (CPK) levels between groups.
Baseline and change from baseline, 4 months and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Sao Paulo General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 10, 2020

Primary Completion (Anticipated)

October 12, 2022

Study Completion (Anticipated)

October 12, 2023

Study Registration Dates

First Submitted

October 24, 2020

First Submitted That Met QC Criteria

October 29, 2020

First Posted (Actual)

November 5, 2020

Study Record Updates

Last Update Posted (Actual)

November 10, 2020

Last Update Submitted That Met QC Criteria

November 7, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4786/19/005

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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