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

NCT ID: NCT05215743

Last Updated: 2024-01-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-09
• Study Completion Date: 2022-12-22

Brief 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.

Conditions

Acute Myocardial Infarction; Ischemia-reperfusion Injury; Reperfusion Injury, Myocardial; Reperfusion Arrhythmias; Reperfusion Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Combined antioxidant therapy (CAT)

Intravenous administration of deferoxamine, n-acetylcysteine, and ascorbate over 90 minutes.

Group Type: EXPERIMENTAL

Antioxidant therapy

Intervention Type: DRUG

Active therapy

Placebo

Intravenous administration of NaCl 0.9% over 90 minutes

Group Type: PLACEBO_COMPARATOR

NaCl 0.9%

Intervention Type: DRUG

Placebo

Interventions

Antioxidant therapy

Active therapy

Intervention Type: DRUG

NaCl 0.9%

Placebo

Intervention Type: DRUG

Other Intervention Names

ascorbate; n-acetylcysteine; deferoxamine; saline solution

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

OTHER_GOV

Sponsor Role: collaborator

University of Chile

OTHER

Sponsor Role: lead

Responsible Party

Ramon Rodrigo

Full Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ramón Rodrigo, Prof.

Role: STUDY_DIRECTOR

Program of Pharmacology, ICBM, Faculty of Medicine, University of Chile

Abraham IJ Gajardo, MD, PhD

Role: STUDY_CHAIR

Intensive Care Unit, Hospital Clínico Universidad de Chile

Locations

University of Chile

Santiago, , Chile

Countries

Chile

Other Identifiers

FONDECYT 1211850

Identifier Type: -

Identifier Source: org_study_id