Combined Antioxidant Therapy Against Myocardial Reperfusion Injury. Phase I Study.
Condition: Acute Myocardial Infarction; Ischemia-reperfusion Injury; Reperfusion Injury, Myocardial; Reperfusion Arrhythmias; Reperfusion Injury
MeSH terms: Myocardial Infarction; Reperfusion Injury; Myocardial Reperfusion Injury; Infarction; Ischemia; Wounds and Injuries
Study type: Interventional
Phase: Phase 1

Summary: 
      Background: Acute myocardial infarction (AMI) has remained a leading cause of mortality and
      disability worldwide. Although percutaneous coronary angioplasty (PCA) is the best treatment
      for these patients, paradoxically this procedure causes reperfusion injury. Considerable
      efforts aimed to reduce this damage have been made, but the results are disappointing and
      there is still no effective therapy for preventing the damage. Previously, the investigators
      have achieved a reduction of infarct size in an experimental model of an isolated rat heart,
      through a synergistic effect of three compounds in a "combined antioxidant therapy" (CAT).

      In this study, the investigators aim to describe the pharmacokinetics and safety of CAT
      intravenously administered to healthy subjects. This is the first step to a later clinical
      application of CAT in AMI patients.

      Methodology: The safety and pharmacokinetics of the CAT (deferoxamine, N-acetylcysteine, and
      ascorbate) will be assessed in healthy volunteers in a "phase I clinical trial". Two
      different formulations (mass of CAT components by bag) with different infusion rates each one
      will be tested (CAT1 and CAT2). Subjects (18-35 years old, n=18) will be randomized 1:2 to
      receive a placebo or CAT for 90 minutes. Blood concentrations of each CAT component will be
      measured in plasma at 0, 15, 30, 60, 90, 120, and 180 minutes after the infusion onset.
      Adverse events will be registered from the onset of infusion until day 30.
    

Detailed description: 
      In this single-blind trial, healthy subjects from 18-35 years old will be allocated to a
      placebo or an intravenous combined antioxidant therapy (CAT) following a fixed-dose scalation
      approach. Before the study onset, blood samples will be drawn from eligible subjects to
      measure a general health profile, and also a physician evaluation and medical exams will be
      scheduled to further confirm the healthy status two weeks after the CAT/placebo infusion.

      Two different CAT formulations (named CAT1 and CAT2) will be tested, each one with a
      different dose of deferoxamine, N-acetylcysteine, and ascorbate. The infusions (CAT or
      placebo) will be administered at the "CREA" - Hospital Clínico Universidad de Chile. The
      first nine subjects will be randomized 1:2 to placebo (NaCl 0.9%) or CAT1, infused at two
      different rates (one in the first 30 min, and another one in the following 60 minutes). If
      the stopping rules are not observed (see below), then the next nine subjects will be
      randomized 1:2 to placebo or CAT2 to be infused I.V over 90 min at a constant rate. The
      protocol will be stopped at any time if more than 33% of the subjects in a group (2
      volunteers) suffer a serious adverse event, following the international definitions (death,
      disability, life-threatening, medical admission).

      Vital signs will be continuously assessed during the IV infusion and for the following 90
      minutes after the infusion ends, together with adverse events assessment in this 180-minute
      observation period. Blood samples will be collected at 0, 15, 30, 60, 90, 120, and 180
      minutes. Concentrations of ascorbate, deferoxamine, and N-acetylcysteine will be measured, as
      well as oxidative stress biomarkers. Subjects will be contacted by phone asking for health
      status and adverse events at 14 and 30 days after the IV infusion.
    

Intervention name(s): Antioxidant therapy; NaCl 0.9%
Intervention type(s): Drug; Drug
Intervention description(s): Active therapy; Placebo
Other intervention name(s): ascorbate; n-acetylcysteine; deferoxamine; saline solution
Intervention MeSH terms: Acetylcysteine; Antioxidants; Deferoxamine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Combined antioxidant therapy (CAT) and placebo
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: antioxidants; acute myocardial infarction; reperfusion injury; randomized clinical trial; multi-target interventions