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Completed

NCT Number: NCT05215743

Combined Antioxidant Therapy Against Myocardial Reperfusion Injury. Phase I Study.

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.

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Key information

Conditions

Acute Myocardial Infarction Cardiomyopathies Cardiovascular Diseases Heart Diseases Ischemia-Reperfusion Injury Myocardial Ischemia Myocardial Reperfusion Injury Pathologic Processes Pathological Conditions, Signs and Symptoms Postoperative Complications Reperfusion Arrhythmias Reperfusion Injury Reperfusion Injury, Myocardial Vascular Diseases

Age range

18 year–35 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

University of Chile

Santiago, Chile

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Healthy subjects from 18 to 35 years old
  • Not obese (BMI 19-29.9 kg/m2)

Exclusion criteria

  • Impaired renal function (creatinine > 1.5 mg/dL)
  • Liver impairment (liver enzymes more than 3 times over normal values)
  • Glucose 6-phosphate dehydrogenase deficiency
  • Any chronic disease
  • Any acute disease in the last two weeks
  • To be enrolled in another clinical study

Treatment and study plan

Antioxidant therapy

Drug

Active therapy

Other names: ascorbate, n-acetylcysteine, deferoxamine

NaCl 0.9%

Drug

Placebo

Other names: saline solution

Primary outcomes

  1. Peak plasma concentration (Cmax) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    Cmax of deferoxamine, n-acetylcysteine and ascorbate

  2. Half-life time (T1/2) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    T1/2 of deferoxamine, n-acetylcysteine and ascorbate

  3. Area under the plasma concentration versus time curve (AUC) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    AUC of deferoxamine, n-acetylcysteine and ascorbate

  4. Volume of distribution (Vd) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    Vd of deferoxamine, n-acetylcysteine and ascorbate

  5. Clearence (CL) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    CL of deferoxamine, n-acetylcysteine and ascorbate

  6. Elimination rate constant (Ke) of each CAT component

    Time frame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)

    Ke of deferoxamine, n-acetylcysteine and ascorbate

  7. Incidence of serious adverse events during combined antioxidant therapy infusion or along the 30-day follow-up

    Time frame: From day 0 to day 30 after the intervention

    Number of new events that began during I.V infusion, the 90 minutes of observation after the infusion end, or during the 30-day follow-up, and that resulted in death, disability, life-threatening, or medical admission of a patient according to medical records

Secondary outcomes

  1. Incidence of any adverse event (serious and non-serious) up to thirty days after infusion ending

    Time frame: From day 0 to day 30 after the intervention

    Number of serious and non-serious adverse events from day 0 to day 30 after the intervention, assessed by a phone interview on day 14 and day 30 after the infusion, using a standardized report form

  2. Number of patients with any adverse event (severe and non-severe) up to thirty days after infusion ending

    Time frame: From day 0 to day 30 after the intervention

    Number of patients with serious and non-severe adverse events from day 0 to day 30 after the intervention, assessed by a phone interview on day 14 and day 30 after the infusion, using a standardized report form

  3. Plasma levels of oxidative stress biomarkers over the time

    Time frame: 0 (just before infusion onset) and 30, 90 and120 minutes after infusion onset.

    Plasma concentrations of the antioxidant defenses (ferric reducing ability of plasma assay), and lipid peroxidation (F2-isoprostanes) during the IV infusion and after 30 minutes

  4. Plasma concentrations over the time of each CAT component

    Time frame: 0 (just before infusion onset) and 30, 60, 90, 120 and 180 minutes after infusion onset.

    Plasma concentrations of deferoxamine, n-acetylcysteine and ascorbate during the IV infusion and after 90 minutes, assessed by high performance liquid chromatography (HPLC)

Sponsors and collaborators

Lead sponsor

University of Chile

Other

Collaborators

  • Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Registry information

Official study title

Cardioprotection of Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Angioplasty Through a Combined Antioxidant Therapy. A Phase I, Randomized Clinical Trial.

Important dates

Study start
2022
Primary completion
2022
Study completion
2022
First posted
Jan 31, 2022
Registry last updated
Jan 12, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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