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

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

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

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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 10, 2018
Estimated Primary Completion Date : May 1, 2020
Estimated Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine


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)




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 [ Time Frame: 90±7 days ]
    Compare platelet aggregability (measured by Multiplate® ADP [adenosine diphosphate] test) between ddMTX-LDE and Placebo-LDE groups.

  4. Mean platelet volume (MPV) [ Time Frame: 90±7 days ]
    Compare MPV (in fentoliter) between ddMTX-LDE and Placebo-LDE groups.

  5. Immature platelets [ Time Frame: 90±7 days ]
    Compare immature platelet fraction (in percentage) between ddMTX-LDE and Placebo-LDE groups.

  6. Total Colesterol [ Time Frame: 90±7 days ]
    Compare total colesterol levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.

  7. High-density lipoprotein colesterol (HDL) [ Time Frame: 90±7 days ]
    Compare HDL levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.

  8. 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.

  9. Triglyceride [ Time Frame: 90±7 days ]
    Compare triglyceride levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.

  10. Glycated haemoglobin (HbA1C) [ Time Frame: 90±7 days ]
    Compare HbA1C levels (in percentage) between ddMTX-LDE and Placebo-LDE groups.

  11. Brain natriuretic peptide (BNP) [ Time Frame: 90±7 days ]
    Compare BNP levels (in picograms per millilitre) between ddMTX-LDE and Placebo-LDE groups.

  12. Subgroup analysis: sex [ Time Frame: 90±7 days ]
    Analyse the main endpoint of the study in male and female individuals.

  13. Subgroup analysis: age [ Time Frame: 90±7 days ]
    Analyse the main endpoint of the study in individuals ≥ or < 65 years.

  14. 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.

  15. 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).

  16. Subgroup analysis: LVEF [ Time Frame: 90±7 days ]
    Analyse the main endpoint of the study in individuals with LVEF < or > 40% (on first CMR).

  17. 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).

  18. 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).

  19. 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).

  20. 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.

  21. 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.

  22. 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.

  23. Correlation of BNP with microcirculation flow. [ Time Frame: Baseline and 90 days ]
    Evaluate eventual correlation of BNP with microcirculation flow measured by CMR.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03516903


Contacts
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Contact: Aline G. Ferrari, MD +551126615058 alinegferrari@gmail.com

Locations
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Brazil
Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil Recruiting
São Paulo, Brazil
Contact: Aline G. Ferrari, MD    +551126615058    alinegferrari@gmail.com   
Sponsors and Collaborators
University of Sao Paulo
Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
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Study Chair: José C. Nicolau, MD, PhD InCor Heart Institute
Principal Investigator: Aline G. Ferrari, MD InCor Heart Institute

Publications:
BC Cancer Agency Cancer Drug Manual©. Chapter: Methotrexate. Vancouver, British Columbia: BC Cancer Agency; Limited Revision: 1 February 2016. Pages 1-16.
Ibanez B, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L, Mateos A, Fernández-Ortiz A, García-Ruiz JM, García-Álvarez A, Iñiguez A, Jiménez-Borreguero J, López-Romero P, Fernández-Jiménez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vázquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Pérez de Prado A, Fernández-Campos MJ, Casado I, García-Rubira JC, García-Prieto J, Sanz-Rosa D, Cuellas C, Hernández-Antolín R, Albarrán A, Fernández-Vázquez F, de la Torre-Hernández JM, Pocock S, Sanz G, Fuster V. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation. 2013 Oct 1;128(14):1495-503. doi: 10.1161/CIRCULATIONAHA.113.003653. Epub 2013 Sep 3.
Pizarro G, Fernández-Friera L, Fuster V, Fernández-Jiménez R, García-Ruiz JM, García-Álvarez A, Mateos A, Barreiro MV, Escalera N, Rodriguez MD, de Miguel A, García-Lunar I, Parra-Fuertes JJ, Sánchez-González J, Pardillos L, Nieto B, Jiménez A, Abejón R, Bastante T, Martínez de Vega V, Cabrera JA, López-Melgar B, Guzman G, García-Prieto J, Mirelis JG, Zamorano JL, Albarrán A, Goicolea J, Escaned J, Pocock S, Iñiguez A, Fernández-Ortiz A, Sánchez-Brunete V, Macaya C, Ibanez B. Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction). J Am Coll Cardiol. 2014 Jun 10;63(22):2356-62. doi: 10.1016/j.jacc.2014.03.014. Epub 2014 Mar 30.

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Responsible Party: Jose Carlos Nicolau, Professor, PhD, University of Sao Paulo
ClinicalTrials.gov Identifier: NCT03516903     History of Changes
Other Study ID Numbers: CAAE 68743417.5.0000.0068
SCOC SDC: 4508/17/008 ( Other Identifier: Heart Institute (InCor) )
First Posted: May 7, 2018    Key Record Dates
Last Update Posted: May 7, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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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
Vitamin B Complex
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