Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After STEMI

Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After ST-elevation Myocardial Infarction

Prospective, randomized, double-blind, placebo-controlled, proof of concept study. Patients with first anterior wall STEMI will be randomized with 4±2 days after symptoms beginning to receive ddMTX-LDE at the dose of 40 mg/m2 IV or placebo-LDE weekly for 6 weeks. All study participants will additionally receive folic acid (5 mg po qd) once a week, one day after the study drug. The primary and main secondary endpoints will be analyzed by CMR 3±1 days and at 90±7 days after randomization.

Patients will undergo clinical and laboratory safety evaluations before each study drug administration and 90-day post-randomization. Safety evaluations will include assessment of adherence, side effects, safety laboratory tests, and existing medical conditions or planned procedures that might alter study drug dosing. These visits also include screening for the occurrence of clinical events of interest. An algorithm for drug suspension based on clinical and laboratory finding will be followed.

Pre-specified unblinded interim analyses by an independent investigator will be developed when 20% and 50% of the inclusions are reached.

Study Overview

• Status: Terminated
• Conditions: Myocardial Infarction, Anterior Wall; Myocardial Remodeling, Ventricular
• Intervention / Treatment: Drug: Methotrexate; Drug: Folic Acid; Drug: Placebo

Detailed Description

Inflammation is extremely important in atherosclerosis and atherothrombosis pathophysiology. It is similarly important after acute myocardial infarction (AMI), with a special participation on healing response and, consequently, on left ventricular remodeling (LVR).

Early successful reperfusion is highly effective for limiting tissue necrosis and improving outcomes in AMI, but many of these patients show microcirculation dysfunction, phenomenon related to inflammation, leading to worse LVR. Additionally, inflammation may extend into the noninfarcted remote myocardium, which also contribute to adverse LVR.

As pointed out by Westman et al in a recent review publication, although infarct size correlates with the development of adverse LVR, some patients with relatively small infarcts have adverse LVR, while others with larger infarcts do not. Individual differences in the inflammatory response, perhaps in part genetically, epigenetically, environmentally, or pathogenically modulated, may contribute to this phenomenon.

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 (CVD) showed that individuals with lower high sensitive C-reactive protein (hsCRP) have better clinical outcomes than those with higher levels.

So, anti-inflammatory therapies may be useful in preventing left ventricular dysfunction following AMI despite reperfusion and anti-remodeling treatments.

Among those, methotrexate (MTX) is an anti-inflammatory drug widely used in rheumatology and oncology. It reduces several inflammatory biomarkers including hs-CRP, interleukin 6 (IL-6), and tumor necrosis factor α (TNF α), without affecting negatively lipid, homocysteine or glucose levels, or blood pressure. Besides that, there are reports showing that MTX directly or indirectly releases endogenous anti-inflammatory adenosine, which could be especially useful in AMI patients.

In a systematic review with rheumatologic patients (including rheumatoid arthritis, psoriasis or polyarthritis), methotrexate was associated with 21% lower risk for total cardiovascular disease (CVD) and 18% lower risk for AMI, suggesting that a direct treatment of inflammation with this drug may reduce the risk of CVD in general.

To explore this option of treatment, the CIRT (Cardiovascular Inflammation Reduction Trial) was designed to evaluate the effect of methotrexate for secondary prevention on high risk patients with chronic stable coronary disease; this study is currently ongoing.

Although a potent anti-inflammatory drug, special attention must be given to methotrexate contraindications and numerous potential adverse effects. To overcome this issue, Moura et al developed a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE).

Lipid nanoemulsions (LDE) that bind to low-density lipoprotein receptors was first developed and studied in the cancer scenario by Maranhão et al, who demonstrated that it concentrates the chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression, decreasing the toxicity of the treatment. The lipid nanoemulsion was already tested in patients with acute leukaemia, multiple myeloma and Hodgkin's and non-Hodgkin's lymphoma, suggesting that LDE is taken up by malignant cells with increased LDL receptors and that LDE, as drug-targeting vehicle, is suitable for patient use.

The ddMTX-LDE formulation was shown to be stable and uptake of the formulation by neoplastic cells in vitro was remarkably greater than of commercial methotrexate preparation, with much lower haematological toxicity. A study with intravenous ddMTX-LDE in rabbits showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. These results are conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion. Another study with rabbits fed with high cholesterol diet showed that ddMTX-LDE reduced vessel inflammation and atheromatous lesions.

In Wistar rats with induced AMI treated with LDE without drug, commercial MTX and ddMTX-LDE, we demonstrated significant improvement in LVR along with infarct size reduction in the group ddMTX-LDE, in comparison with the groups commercial MTX and LDE without drug.

The above rational is the basis for the present project, where by the first time the role of LDE methotrexate formulation in humans, regarding LV remodelling post ST-segment elevation myocardial infarction (STEMI), will be tested.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with type 1 STEMI, documented by: ischemic symptoms, new ST-elevation at the J-point in two contiguous leads (0.2 mV in men or 0.15 mV in women in leads V2-V3 and/or 0.1 mV in other leads or new left bundle branch block [LBBB]) and cardiac biomarkers (troponin and/or creatine kinase MB) with at least one value above the 99th percentile of the upper reference limit (URL).
• Submitted to any successful repercussion strategy (thrombolysis or angioplasty).
• Coronary angiography showing successful reperfusion therapy (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 in the infarct-related artery) and residual obstruction in the infarct-related artery < 50%.
• Asymptomatic, without signs of clinical decompensation (heart rate < 100bpm, systolic blood pressure > 90mmHg, without vasoactive dor inotropic drugs, pulse oximetry > 95% with FiO2 21%).
• Signing the study informed consent.

Exclusion Criteria:

• History of AMI.
• Estimated glomerular filtration rate < 40 mL/min/1.73 m2.
• Contraindications for CMR: pacemaker, metallic devices, claustrophobia, obesity over 150 kg total weight.
• Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive.
• Chronic hepatitis B or C infection.
• Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
• Chest x-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
• 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 2-fold the upper limit of normal.
• History of 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.
• Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible.
• Current indication for methotrexate therapy.
• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers.
• Known chronic pericardial effusion, pleural effusion, or ascites.
• New York Heart Association class III-IV congestive heart failure.
• Life expectancy of < 1 years.
• Active infection.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methotrexate & Folic acid; ddMTX-LDE 40mg/m2 (100mL total volume) IV and Folic acid 5mg by mouth (the day after ddMTX-LDE) weekly for 6 weeks	Drug: Methotrexate; ddMTX-LDE (Methotrexate carried by a lipid nanoemulsion); Other Names: Methotrexate carried by a lipid nanoemulsion (ddMTX-LDE); Drug: Folic Acid; Folic acid pill; Other Names: FoliFolin (EMS)
Placebo Comparator: Placebo & folic acid; Placebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks	Drug: Folic Acid; Folic acid pill; Other Names: FoliFolin (EMS); Drug: Placebo; Placebo-LDE (Lipid nanoemulsion); Other Names: Placebo-LDE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventricular Remodelling	Compare left ventricular end-diastolic volume (LVEDV) measured by cardiac magnetic resonance (CMR) between ddMTX-LDE and Placebo-LDE groups.	90±7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular end-systolic volume (LVESV)	Compare LVESV measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Left ventricular ejection fraction (LVEF)	Compare LVEF measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Left ventricular mass (LVM)	Compare LVM measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Infarct size	Compare infarct size measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Positive remodelling	Compare the percentual of patients with positive (≥20% increase on LVEDV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Negative remodelling	Compare the percentual of patients with negative (≥ 10% decrease on LVESV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Clinical significant symptoms	Compare the incidence of clinical significant symptoms (new and persistent stomatitis, vomiting, diarrhea, unexplained cough with fever or shortness of breath) reported in each visit between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Other adverse events	Compare the incidence of other adverse events (not expected) between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean red blood cell count	Compare haemoglobin and hematocrits levels between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean white blood cell count	Compare leucocyte and neutrophil levels between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Platelet count	Compare total platelet count between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Alanine aminotransferase (ALT)	Compare ALT levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Aspartate aminotransferase (AST)	Compare AST levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Bilirubin	Compare bilirubin levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Creatinine clearance	Compare creatinine clearance measured by MDRD-4 variable equation between ddMTX-LDE and Placebo-LDE groups.	7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
High-sensitivity C reactive protein (hs-CRP)	Compare hs-CRP levels (in miligrams per litre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Interleukin 6 (IL-6)	Compare IL-6 levels (in picograms per millilitre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Platelet agregability - ADP	Compare platelet aggregability (measured by Multiplate® ADP [adenosine diphosphate] test) between ddMTX-LDE and Placebo-LDE groups.	Baseline, 3±1, 35±1 and 90±7 days
Platelet agregability - ASPI	Compare platelet aggregability (measured by Multiplate® ASPI [arachidonic acid] test) between ddMTX-LDE and Placebo-LDE groups.	Baseline, 3±1, 35±1 and 90±7 days
Mean platelet volume (MPV)	Compare MPV (in fentoliter) between ddMTX-LDE and Placebo-LDE groups.	Baseline, 3±1, 35±1 and 90±7 days
Immature platelets	Compare immature platelet fraction (in percentage) between ddMTX-LDE and Placebo-LDE groups.	Baseline, 3±1, 35±1 and 90±7 days
Total Colesterol	Compare total colesterol levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
High-density lipoprotein colesterol (HDL)	Compare HDL levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Low-density lipoprotein colesterol (LDL)	Compare LDL levels (in miligrams per decilitre, by Friedewald equation) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Triglyceride	Compare triglyceride levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Glycated haemoglobin (HbA1C)	Compare HbA1C levels (in percentage) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Brain natriuretic peptide (BNP)	Compare BNP levels (in picograms per millilitre) between ddMTX-LDE and Placebo-LDE groups.	90±7 days
Subgroup analysis: sex	Analyse the main endpoint of the study in male and female individuals.	90±7 days
Subgroup analysis: age	Analyse the main endpoint of the study in individuals ≥ or < 65 years.	90±7 days
Subgroup analysis: diabetes mellitus	Analyse the main endpoint of the study in individuals with or without history of diabetes mellitus.	90±7 days
Subgroup analysis: creatinine clearance	Analyse the main endpoint of the study in individuals with creatinine clearance ≥ or < 60mL/kg/min), LVEF < or > 40% (on first CMR), repercussion therapy strategy (thrombolysis or primary angioplasty), time from STEMI symptoms to reperfusion (≥ or < 6 hours), time from STEMI symptoms to first study drug administration (≥ or < 96 hours).	90±7 days
Subgroup analysis: LVEF	Analyse the main endpoint of the study in individuals with LVEF < or > 40% (on first CMR).	90±7 days
Subgroup analysis: repercussion strategy	Analyse the main endpoint of the study in individuals who received different reperfusion therapy strategy (thrombolysis or primary angioplasty).	90±7 days
Subgroup analysis: Time to reperfusion	Analyse the main endpoint of the study in individuals with different time range from STEMI symptoms to reperfusion (≥ or < 6 hours).	90±7 days
Subgroup analysis: Time to study drug administration	Analyse the main endpoint of the study in individuals with different time range from STEMI symptoms to first study drug administration (≥ or < 96 hours).	90±7 days
Correlation of hs-CRP with microcirculation flow.	Evaluate eventual correlation of hs-CRP with microcirculation flow measured by CMR.	Baseline and 90 days
Correlation of IL-6 with microcirculation flow.	Evaluate eventual correlation of IL-6 with microcirculation flow measured by CMR.	Baseline and 90 days
Correlation of platelet aggregation with microcirculation flow.	Evaluate eventual correlation of platelet aggregation with microcirculation flow measured by CMR.	Baseline and 90 days
Correlation of BNP with microcirculation flow.	Evaluate eventual correlation of BNP with microcirculation flow measured by CMR.	Baseline and 90 days
Adenosine	Compare adenosine plasmatic levels between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Interleukin-10	Compare interleukin-10 levels between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Interleukin-6	Compare interleukin-6 levels between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Tumor necrosis factor alpha (TNF-α)	Compare TNF-α levels between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Regulatory T lymphocyte population	Compare regulatory T lymphocyte population between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Expression and activity of ecto-nucleoside triphosphate diphosphohydrolase (CD39)	Compare expression and activity of CD39 between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days
Expression and activity of ecto-5'-nucleotidase (CD73)	Compare expression and activity of CD73 between ddMTX-LDE and placebo-LDE groups.	Baseline, 3±1 and 35±1 days

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Study Chair: José C. Nicolau, MD, PhD, InCor Heart Institute; Principal Investigator: Aline G. Ferrari, MD, InCor Heart Institute; Principal Investigator: Rocío Salsoso, PhD, InCor Heart Institute

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2018
• Primary Completion (Actual): December 17, 2020
• Study Completion (Actual): December 17, 2020

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: April 23, 2018
• First Posted (Actual): May 7, 2018

Study Record Updates

• Last Update Posted (Actual): January 11, 2021
• Last Update Submitted That Met QC Criteria: January 7, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Methotrexate; Myocardial remodeling; Anterior myocardial infarction
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pathological Conditions, Anatomical; Myocardial Infarction; Infarction; Anterior Wall Myocardial Infarction; Ventricular Remodeling; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Vitamin B Complex; Hematinics; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Folic Acid
• Other Study ID Numbers: CAAE 68743417.5.0000.0068; SCOC SDC: 4508/17/008 (Other Identifier: Heart Institute (InCor))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD can be shared after reasonable request approved by the study coordination.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No