AtherosclerosisPhase 2/3NCT04616872
Treatment of Patients With Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles
A Phase 2/3 study testing Methotrexate-LDE in people with Atherosclerosis and Coronary Artery Disease, run by University of Sao Paulo General Hospital at 2 sites in Brazil.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Atherosclerosis, Coronary Artery Disease, Inflammation
- What is being tested?
- Methotrexate-LDE
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 2 sitesBrazil
- Study dates
- 10 Oct 2020to 12 Oct 2023
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 23Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
Brazil2 sites, 2 recruiting
- Recruiting
Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
São Paulo, São Paulo, 05403900
Lucas Marinho, MD, +5511948045001, lucaslage@hotmail.com
- Not yet recruiting
Institute Prevent Senior
São Paulo, São Paulo
Rodrigo Esper, MD;PhD
About this study
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
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.
Read the 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.
- Conditions
- Atherosclerosis, Coronary Artery Disease, Inflammation
- Being tested
- Methotrexate-LDE, Placebo-LDE
- Keywords
- Atherosclerosis, coronary artery disease, inflammation, methotrexate, nanoparticles, nanotechnology, drug delivery system
- Medical subject headings
- Atherosclerosis, Coronary Artery Disease, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methotrexate-LDEDrug
MTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks
Placebo-LDEDrug
Placebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| Methotrexate-LDE | Experimental | Methotrexate carried by a lipid nanoparticle (MTX-LDE) Receives: Drug: Methotrexate-LDE |
| Placebo-LDE | Placebo comparator | Lipid nanoparticle (LDE) Receives: Drug: Placebo-LDE |
What is being measured
The primary outcome is the main question the study is designed to answer.
Low Attenuation Plaque Volume (LAPV) coronary
Compare Low attenuation Plaque Volume( LAPV) measured by coronary CT angiography between groups.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and change from baseline to 12 months
Secondary outcomes (9)
Noncalcified plaque volume (NCPV)
Compare Noncalcified plaque volume (NCPV) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline to 4 months
Dense calcified plaque volume (DCPV)
Compare Dense calcified plaque volume (DCPV) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline to 12 months
Total lumen value (TLV)
Compare Total lumen value (TLV) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline, 4 months and 12 months
Remodeling index (RI)
Compare Remodeling index (RI) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline, 4 months and 12 months
Perivascular fat attenuation index (FAI)
Compare Perivascular fat attenuation index (FAI) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline, 4 months and 12 months
Total atheroma volume (TAV)
Compare Total atheroma volume (TAV) measured by coronary CT angiography between groups.
Measured: Baseline and change from baseline, 4 months and 12 months
Total atheroma volume (TAV) aortic
Compare Total atheroma volume (TAV) measured by aortic CT angiography between groups.
Measured: Baseline and change from baseline, 4 months and 12 months
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.
Measured: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Other adverse events
Compare the incidence of other adverse events (not expected) reported in each visit between groups.
Measured: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2020
- Study start10 Oct 2020
- Primary completion12 Oct 2022 (estimated)
- Study completion12 Oct 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for AtherosclerosisStudies of the same condition, open and under way.
- More trials run by University of Sao Paulo General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, Double-blind, Placebo-control Trial.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Raul Cavalcante Maranhão, University of Sao Paulo General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04616872
- Sponsor's protocol ID
- 4786/19/005
- Status last verified
- Nov 2020
- First submitted
- 24 Oct 2020
- Last updated
- 10 Nov 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 12628952Maranhao 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.
PubMed 28042707Bulgarelli 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.
PubMed 24065615Shapiro 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.
PubMed 26892970van 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.
PubMed 23518178Ridker 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.
PubMed 18997196Ridker 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.
PubMed 26908943Khan 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.
PubMed 25917947Prodanovich 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.
PubMed 15692471Barnabe 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.
PubMed 20957658Vaidya 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.
PubMed 29055633Ridker 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.
PubMed 28845751Ridker 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.
PubMed 30415610Tardif 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.
PubMed 31733140Nidorf 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.
PubMed 32865380
Study at a glance
From the registry record, last updated by the sponsor on 10 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04616872
- Acronym / sponsor ID
- 4786/19/005
- Conditions
- Atherosclerosis, Coronary Artery Disease, Inflammation
- Keywords
- Atherosclerosis, coronary artery disease, inflammation, methotrexate, nanoparticles, nanotechnology, drug delivery system
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Study start
- 10 Oct 2020 (actual)
- Primary completion
- 12 Oct 2022 (estimated)
- Study completion
- 12 Oct 2023 (estimated)
- First posted
- 5 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomized, Double-blind, Placebo-control Trial.
| Arm | Type | Receives |
|---|---|---|
| Methotrexate-LDE | Experimental | Drug: Methotrexate-LDEMethotrexate carried by a lipid nanoparticle (MTX-LDE) |
| Placebo-LDE | Placebo comparator | Drug: Placebo-LDELipid nanoparticle (LDE) |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methotrexate-LDEMTX-LDE 40mg/m2 (250mL total volume) IV and Folic acid 5mg by mouth (the day after MTX-LDE) weekly for 12 weeks | Drug | Methotrexate-LDE |
| Placebo-LDEPlacebo-LDE (250mL total volume) IV and Folic acid 5mg by mouth (the day after Placebo-LDE) weekly for 12 weeks | Drug | Placebo-LDE |
Primary outcome
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.
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.
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.
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.
9 secondary outcomes
Noncalcified plaque volume (NCPV)
Time frame: Baseline and change from baseline to 4 months
Dense calcified plaque volume (DCPV)
Time frame: Baseline and change from baseline to 12 months
Total lumen value (TLV)
Time frame: 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
Perivascular fat attenuation index (FAI)
Time frame: 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
Total atheroma volume (TAV) aortic
Time frame: 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
Other adverse events
Time frame: 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 16 and 52 weeks after randomization
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Nov 2020.
- Background: PubMed 12628952Solomon 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.
- Background: PubMed 28042707Maranhao 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.
- Background: PubMed 24065615Bulgarelli 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.
- Background: PubMed 26892970Shapiro 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.
- Background: PubMed 23518178van 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.
- Background: PubMed 18997196Ridker 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.
- Background: PubMed 26908943Ridker 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.
- Background: PubMed 25917947Khan 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.
- Background: PubMed 15692471Prodanovich 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.
- Background: PubMed 20957658Barnabe 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.
- Background: PubMed 29055633Vaidya 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.
- Background: PubMed 28845751Ridker 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.
- World Health Organization (WHO)Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Methotrexate-LDE in people with Atherosclerosis and Coronary Artery Disease, run by University of Sao Paulo General Hospital at 2 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Raul Maranhão, MD;PhD (+551126615951, raul.maranhao@incor.usp.br), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Low Attenuation Plaque Volume (LAPV) coronary (time frame: Baseline and change from baseline to 4 months.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04616872, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2020.