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

Acute Myocardial Infarction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05215743
• Other study ID #: FONDECYT 1211850
• Status: Completed
• Phase: Phase 1
• Start date: August 9, 2022
• Est. completion date: December 22, 2022

Study information

• Verified date: January 2024
• Source: University of Chile
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: December 22, 2022
• Est. primary completion date: November 22, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Infarction
• Ischemia
• Ischemia-reperfusion Injury
• Myocardial Infarction
• Myocardial Reperfusion Injury
• Reperfusion Injury
• Reperfusion Injury, Myocardial
• Wounds and Injuries

Intervention

Drug:
• Antioxidant therapy
Active therapy
• NaCl 0.9%
Placebo

Locations

Country	Name	City	State
Chile	University of Chile	Santiago de Chile

Sponsors (2)

Lead Sponsor	Collaborator
University of Chile	Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Country where clinical trial is conducted

Chile, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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.