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

• Status: Terminated
• Trial end date: 2020-12-17
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Sao Paulo
• Collaborator: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Treatments: Folic Acid; Methotrexate; Vitamin B Complex

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.