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

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

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.

Study Overview

• Status: Completed
• Conditions: Reperfusion Injury; Acute Myocardial Infarction; Ischemia-reperfusion Injury; Reperfusion Injury, Myocardial; Reperfusion Arrhythmias
• Intervention / Treatment: Drug: Antioxidant therapy; Drug: NaCl 0.9%

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ramón Rodrigo, Prof.; Phone Number: 22978 86126; Email: rrodrigo@med.uchile.cl
• Study Contact Backup: Name: Abraham IJ Gajardo, MD, PhD; Email: aij.gajardo@gmail.com

Study Locations

• Chile
  • Santiago de Chile, Chile
    • University of Chile

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 28 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combined antioxidant therapy (CAT); Intravenous administration of deferoxamine, n-acetylcysteine, and ascorbate over 90 minutes.	Drug: Antioxidant therapy; Active therapy; Other Names: deferoxamine; ascorbate; n-acetylcysteine
Placebo Comparator: Placebo; Intravenous administration of NaCl 0.9% over 90 minutes	Drug: NaCl 0.9%; Placebo; Other Names: saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak plasma concentration (Cmax) of each CAT component	Cmax of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Half-life time (T1/2) of each CAT component	T1/2 of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Area under the plasma concentration versus time curve (AUC) of each CAT component	AUC of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Volume of distribution (Vd) of each CAT component	Vd of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Clearence (CL) of each CAT component	CL of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Elimination rate constant (Ke) of each CAT component	Ke of deferoxamine, n-acetylcysteine and ascorbate	180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
Incidence of serious adverse events during combined antioxidant therapy infusion or along the 30-day follow-up	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	From day 0 to day 30 after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of any adverse event (serious and non-serious) up to thirty days after infusion ending	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	From day 0 to day 30 after the intervention
Number of patients with any adverse event (severe and non-severe) up to thirty days after infusion ending	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	From day 0 to day 30 after the intervention
Plasma levels of oxidative stress biomarkers over the time	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	0 (just before infusion onset) and 30, 90 and120 minutes after infusion onset.
Plasma concentrations over the time of each CAT component	Plasma concentrations of deferoxamine, n-acetylcysteine and ascorbate during the IV infusion and after 90 minutes, assessed by high performance liquid chromatography (HPLC)	0 (just before infusion onset) and 30, 60, 90, 120 and 180 minutes after infusion onset.

Collaborators and Investigators

• Sponsor: University of Chile
• Collaborators: Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
• Investigators: Study Director: Ramón Rodrigo, Prof., Program of Pharmacology, ICBM, Faculty of Medicine, University of Chile; Study Chair: Abraham IJ Gajardo, MD, PhD, Intensive Care Unit, Hospital Clínico Universidad de Chile

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2022
• Primary Completion (Actual): November 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: January 17, 2022
• First Submitted That Met QC Criteria: January 17, 2022
• First Posted (Actual): January 31, 2022

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: antioxidants; acute myocardial infarction; randomized clinical trial; reperfusion injury; multi-target interventions
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Cardiomyopathies; Myocardial Infarction; Infarction; Ischemia; Wounds and Injuries; Reperfusion Injury; Myocardial Reperfusion Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Chelating Agents; Sequestering Agents; Free Radical Scavengers; Expectorants; Iron Chelating Agents; Siderophores; Acetylcysteine; Antioxidants; Deferoxamine
• Other Study ID Numbers: FONDECYT 1211850

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No