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

Study Overview
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Brief Summary
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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, our team has achieved a reduction of infarct size in an acute myocardial infarction model of isolated rat heart through a synergistic effect of three compounds in a combined antioxidant therapy (CAT). In this study, we 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. Subjects (18-30 years old, n=18) will be randomized 2:1 to receive CAT or placebo over 60 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 reactions will be registered from the onset of infusion until day 7.

Detailed Description
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Healthy subjects from 18-30 years old will be allocated to a placebo or an intravenous combined antioxidant therapy (CAT) following a fixed-dose scalation approach in a single-blind trial. 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. 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 (dextrose 5%) or CAT (deferoxamine, ascorbate, and N-acetylcysteine) to be infused I.V over 90 min at a constant rate. If the stopping rules are not observed (see below), then the next nine subjects will be randomized 1:2 to placebo or CAT with two different rates (one in the first 30 min, and another one in the following 60 minutes). The protocol will be stopped at any time if more than 33% of the subjects in a group (2 volunteers) suffer a severe adverse event, following the international definitions (death, disability, life-threatening, medical admission). Vital signs will be continuously assessed along with the I.Vinfusion, as well as any adverse reaction. Blood samples will be collected at 0, 15, 30, 60, 90, 120, and 180 minutes. Subjects will be daily contacted by phone asking for adverse reactions until day 7. Concentrations of ascorbate, deferoxamine and N-acetylcysteine will be measured by HPLC.

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

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

Intervention / Treatment
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* Drug: Antioxidant formula
* Drug: Dextrose 5% in water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects from 18 to 35 years old Normal BMI (19-24.9 kg/m2) Exclusion Criteria: Impaired renal function (creatinine > 1.5 mg/dL) Liver impairment (liver enzymes over normal values) Glucosa 6-phosphate deshidrogenase deficency Any chronic disease Any acute disease in the last two weeks To be enrolled in other clinical study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Combined antioxidant therapy (CAT) and placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined antioxidant therapy (CAT)<br>Intravenous administration of deferoxamine, n-acetylcysteine, and ascorbate over 90 minutes. | Drug: Antioxidant formula<br>* Active therapy<br>* Other names: deferoxamine;|
| Placebo Comparator: Placebo<br>Intravenous administration of dextrose 5% over 90 minutes | Drug: Dextrose 5% in water<br>* Placebo<br>* Other names: dextrose 5%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic of the combined antioxidant therapy administered by intravenous route during 90 minutes | Pharmacokinetic profile of each antioxidant component (deferoxamine, n-acetylcysteine, and ascorbate) assessed by plasma concentrations during and up to 90 minutes after the I.V infusion onset | 0 (just before infusion onset) and 30, 60, 90 120 and 180 minutes after infusion onset. | 
| Frequency of severe adverse events during combined antioxidant therapy infusion | Frequency of events that resulted in death, disability, life-threatening, or medical admission of a patient | 180 minutes (from infusion onset up to 90 minutes after infusion ending) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of any adverse event up to seven days after infusion ending | Frequency of severe and non-severe adverse events from day 0 to day 7 after the intervention Frequency of severe and non-severe adverse events | From day 0 to day 7 after the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antioxidants, acute myocardial infarction, reperfusion injury, randomized clinical trial, multi-target interventions