Clinical trial NCT05215743: Combined Antioxidant Therapy Against Myocardial Reperfusion Injury. Phase I Study.
Official title: Cardioprotection of Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Angioplasty Through a Combined Antioxidant Therapy. A Phase I, Randomized Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myocardial Infarction
Ischemia-reperfusion Injury
Reperfusion Injury, Myocardial
Reperfusion Arrhythmias
Reperfusion Injury
Keywords: antioxidants
acute myocardial infarction
reperfusion injury
randomized clinical trial
multi-target interventions
Lead sponsor: University of Chile
Sponsor class: OTHER
Collaborators: name: Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
First posted: 2022-01-31
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Combined antioxidant therapy (CAT) and placebo
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Peak plasma concentration (Cmax) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Half-life time (T1/2) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Area under the plasma concentration versus time curve (AUC) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Volume of distribution (Vd) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Clearence (CL) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Elimination rate constant (Ke) of each CAT component
timeFrame: 180 minutes (just before the infusion onset up to 90 minutes after infusion ending)
measure: Incidence of serious adverse events during combined antioxidant therapy infusion or along the 30-day follow-up
timeFrame: From day 0 to day 30 after the intervention
Secondary outcomes:
measure: Incidence of any adverse event (serious and non-serious) up to thirty days after infusion ending
timeFrame: From day 0 to day 30 after the intervention
measure: Number of patients with any adverse event (severe and non-severe) up to thirty days after infusion ending
timeFrame: From day 0 to day 30 after the intervention
measure: Plasma levels of oxidative stress biomarkers over the time
timeFrame: 0 (just before infusion onset) and 30, 90 and120 minutes after infusion onset.
measure: Plasma concentrations over the time of each CAT component
timeFrame: 0 (just before infusion onset) and 30, 60, 90, 120 and 180 minutes after infusion onset.
Other outcomes:
Locations:
city: Santiago de Chile
country: Chile
facility: University of Chile
Study officials:
affiliation: Program of Pharmacology, ICBM, Faculty of Medicine, University of Chile
name: Ramón Rodrigo, Prof.
role: STUDY_DIRECTOR
affiliation: Intensive Care Unit, Hospital Clínico Universidad de Chile
name: Abraham IJ Gajardo, MD, PhD
role: STUDY_CHAIR
References: