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

• ClinicalTrials.gov Identifier: NCT03516903
• Recruitment Status: Terminated
• First Posted: May 7, 2018
• Last Update Posted: January 11, 2021
• Sponsor: University of Sao Paulo
• Collaborator: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Information provided by (Responsible Party): Jose Carlos Nicolau, University of Sao Paulo

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Myocardial Infarction, Anterior Wall; Myocardial Remodeling, Ventricular	Drug: Methotrexate; Drug: Placebo; Drug: Folic Acid	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After ST-elevation Myocardial Infarction
• Actual Study Start Date: April 17, 2018
• Actual Primary Completion Date: December 17, 2020
• Actual Study Completion Date: December 17, 2020

Arms and Interventions

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 Name: Methotrexate carried by a lipid nanoemulsion (ddMTX-LDE); Drug: Folic Acid; Folic acid pill; Other Name: 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: Placebo; Placebo-LDE (Lipid nanoemulsion); Other Name: Placebo-LDE; Drug: Folic Acid; Folic acid pill; Other Name: FoliFolin (EMS)

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Left ventricular end-systolic volume (LVESV) [ Time Frame: 90±7 days ]
   Compare LVESV measured by CMR between ddMTX-LDE and Placebo-LDE groups.
2. Left ventricular ejection fraction (LVEF) [ Time Frame: 90±7 days ]
   Compare LVEF measured by CMR between ddMTX-LDE and Placebo-LDE groups.
3. Left ventricular mass (LVM) [ Time Frame: 90±7 days ]
   Compare LVM measured by CMR between ddMTX-LDE and Placebo-LDE groups.
4. Infarct size [ Time Frame: 90±7 days ]
   Compare infarct size measured by CMR between ddMTX-LDE and Placebo-LDE groups.
5. Positive remodelling [ Time Frame: 90±7 days ]
   Compare the percentual of patients with positive (≥20% increase on LVEDV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.
6. Negative remodelling [ Time Frame: 90±7 days ]
   Compare the percentual of patients with negative (≥ 10% decrease on LVESV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.
7. Clinical significant symptoms [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
   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.
8. Other adverse events [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
   Compare the incidence of other adverse events (not expected) between ddMTX-LDE and Placebo-LDE groups.
9. Mean red blood cell count [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
   Compare haemoglobin and hematocrits levels between ddMTX-LDE and Placebo-LDE groups.
10. Mean white blood cell count [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare leucocyte and neutrophil levels between ddMTX-LDE and Placebo-LDE groups.
11. Platelet count [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare total platelet count between ddMTX-LDE and Placebo-LDE groups.
12. Alanine aminotransferase (ALT) [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare ALT levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.
13. Aspartate aminotransferase (AST) [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare AST levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.
14. Bilirubin [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare bilirubin levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.
15. Creatinine clearance [ Time Frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days ]
    Compare creatinine clearance measured by MDRD-4 variable equation between ddMTX-LDE and Placebo-LDE groups.

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Brazil

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

São Paulo, Brazil

Sponsors and Collaborators

University of Sao Paulo

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

  Study Documents (Full-Text)

Documents provided by Jose Carlos Nicolau, University of Sao Paulo:

Statistical Analysis Plan  [PDF] October 13, 2020

More Information

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• Responsible Party: Jose Carlos Nicolau, Professor, PhD, University of Sao Paulo
• ClinicalTrials.gov Identifier: NCT03516903
• Other Study ID Numbers: CAAE 68743417.5.0000.0068; SCOC SDC: 4508/17/008 ( Other Identifier: Heart Institute (InCor) )
• First Posted: May 7, 2018
• Last Update Posted: January 11, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD can be shared after reasonable request approved by the study coordination.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)

• 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

Keywords provided by Jose Carlos Nicolau, University of Sao Paulo:

Anterior myocardial infarction; Methotrexate; Myocardial remodeling

Additional relevant MeSH terms:

Myocardial Infarction; Anterior Wall Myocardial Infarction; Infarction; Ventricular Remodeling; Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pathological Conditions, Anatomical; Folic Acid; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors; Hematinics