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

NCT03516903 | Terminated Phase 2 DMC

• 2 other identifiers: CAAE 68743417.5.0000.0068SCOC SDC: 4508/17/008
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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.

Conditions

Myocardial Infarction, Anterior Wall; Myocardial Remodeling, Ventricular

Keywords

Anterior myocardial infarction; Methotrexate; Myocardial remodeling

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Left ventricular end-systolic volume (LVESV)

  90±7 days

• Left ventricular ejection fraction (LVEF)

  90±7 days

• Left ventricular mass (LVM)

  90±7 days

• Infarct size

  90±7 days

• Positive remodelling

  90±7 days

Other Outcomes (31)

• High-sensitivity C reactive protein (hs-CRP)

  90±7 days

• Interleukin 6 (IL-6)

  90±7 days

• Platelet agregability - ADP

  Baseline, 3±1, 35±1 and 90±7 days

Study Arms (2)

Methotrexate & Folic acid

ACTIVE COMPARATOR

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; Drug: Folic Acid

Placebo & folic acid

PLACEBO COMPARATOR

Placebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks

Drug: Placebo; Drug: Folic Acid

Interventions

Methotrexate DRUG

ddMTX-LDE (Methotrexate carried by a lipid nanoemulsion)

Also known as: Methotrexate carried by a lipid nanoemulsion (ddMTX-LDE)

Methotrexate & Folic acid

Placebo DRUG

Placebo-LDE (Lipid nanoemulsion)

Also known as: Placebo-LDE

Placebo & folic acid

Folic Acid DRUG

Folic acid pill

Also known as: FoliFolin (EMS)

Methotrexate & Folic acid; Placebo & folic acid

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Sao Paulo: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (1)

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

São Paulo, Brazil

Location

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MeSH Terms

Conditions

Anterior Wall Myocardial Infarction; Ventricular Remodeling

Interventions

Methotrexate; Folic Acid

Condition Hierarchy (Ancestors)

Myocardial Infarction; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Pathological Conditions, Anatomical

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• José C. Nicolau, MD, PhD

  InCor Heart Institute

  STUDY CHAIR

• Aline G. Ferrari, MD

  InCor Heart Institute

  PRINCIPAL INVESTIGATOR

• Rocío Salsoso, PhD

  InCor Heart Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, PhD

Study Record Dates

• First Submitted: April 10, 2018
• First Posted: May 7, 2018
• Study Start: April 17, 2018
• Primary Completion: December 17, 2020
• Study Completion: December 17, 2020
• Last Updated: January 11, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

BR (1)