Ignite Creation Date:
2024-05-06 @ 9:34 AM
Last Modification Date:
2024-10-26 @ 12:16 PM
Study NCT ID:
NCT03017963
Status:
COMPLETED
Last Update Posted:
2018-04-17
First Post:
2016-12-24
Brief Title:
Safety and Tolerability of Sodium Thiosulfate in Patients With an ACS Undergoing CAG Via Trans-radial Approach
Sponsor:
University Medical Center Groningen
Organization:
University Medical Center Groningen
Study Overview
Official Title:
Safety and Tolerability of Sodium Thiosulfate in Patients Presenting With an Acute Coronary Syndrome Undergoing Coronary Angiography Via Trans-radial Approach a Dose-escalation Study
Status:
COMPLETED
Status Verified Date:
2018-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SAFE-ACS
Brief Summary:
The purpose of this trial is to evaluate the safety and maximum tolerable dose MTD of sodium thiosulfate in patients presenting with an acute coronary syndrome and treated with primary percutaneous coronary intervention PPCI via trans-radial approach in adjunction to standard treatment
Detailed Description:
Despite the recent advances in treatment acute myocardial infarction AMI frequently results in permanent myocardial injury imposing an increased risk for adverse cardiac remodelling diminished cardiac function and the development of heart failure Decreased cardiac function after PPCI is associated with impaired prognosis
Although PPCI has a tremendous benefit in AMI not only ischemia but also reperfusion itself is considered to cause myocardial injury and cardiomyocyte deathThis phenomena is referred to as ischemia reperfusion injury in literature and is caused by the sudden restoration of blood flow and its accompanying intracellular pH change calcium overload cardiomyocyte hypercontracture myocardial inflammation oxidative stress generation and mitochondrial permeability transition pore opening Reducing ischemia reperfusion injury is expected to further decrease infarct size decrease adverse cardiac remodelling and improve cardiac function as well as clinical outcome
Hydrogen sulfide H2S is the third endogenous gaseous transmitter next to carbon monoxide CO and nitric oxide NO and is involved as a physiological mediator in several body organ and tissue processes H2S is synthesized endogenously by enzymatic and non-enzymatic pathways A non-enzymatic pathway is by the reductive reaction with thiosulfate with pyruvate acting as a hydrogen donor Thiosulfate itself acts as an intermediate in the sulfur metabolism of cysteine and is known as a metabolite of H2S and in that way is also able to produce H2S especially under hypoxic conditions
H2S has been shown to protect myocardium from ischemia reperfusion injury in various experimental animal models of ischemic heart disease eg it reduces infarct size and apoptosis and attenuates cardiac function Inhibition of leukocyte endothelial cell interactions neutralization of reactive oxygen species ROS and the reduction of apoptotic signalling are the suggested as additional mechanisms underlying the cardioprotective effect of H2S in this setting
STS an H2S donor is used in humans since 1933 for the treatment of cyanide intoxication and is used since the eighties for treatment of vascular calcifications in end-stage renal disease It is also used to prevent toxicity of cisplatin treatment More recently studies have shown STS can delay the progression of coronary artery calcification in haemodialysis patients The mechanism of action in these diseases is thought to be based on potential antioxidant properties of STS In all these cases intravenous STS was used in different doses from 5 to 75 g per day Side effects of STS include hypotension nausea and vomiting gastrointestinal disturbances hypernatraemia and in 5 of hemodialysis patients metabolic acidosis occurred Most side effects were mild and manageable
STS administration has never been tested in the clinical setting of ACS Cardiac catheterization via trans-radial approach has been increasingly used instead of trans-femoral approach resulting in fewer vascular complications minimal risk of nerve injury and virtually no postprocedural bed rest However during radial approach a combination of vasodilating blood pressure lowering and anticoagulant drugs are given to the patient verapamil nitroglycerin heparin the radialis-cocktail These drugs could potentially interact with STS and data regarding the safety of STS in patients with ACS treated with PCI via radial approach is lacking
The SAFE ACS is a phase 12 open-label dose-escalation study to test the hypothesis that STS on top of standard medical treatment can be safely administered in patients presenting with an ACS and is well-tolerated We will use a 33 design with a fixed dosing endpoint of 30 gram of STS in 2 gifts of 15 gram based on the standard dose of 25 gram used for other indications Additionally we will test the effect of STS treatment on oxidative stress during and after STS infusion by laboratory analysis of various oxidative stress markers
Although PPCI has a tremendous benefit in AMI not only ischemia but also reperfusion itself is considered to cause myocardial injury and cardiomyocyte deathThis phenomena is referred to as ischemia reperfusion injury in literature and is caused by the sudden restoration of blood flow and its accompanying intracellular pH change calcium overload cardiomyocyte hypercontracture myocardial inflammation oxidative stress generation and mitochondrial permeability transition pore opening Reducing ischemia reperfusion injury is expected to further decrease infarct size decrease adverse cardiac remodelling and improve cardiac function as well as clinical outcome
Hydrogen sulfide H2S is the third endogenous gaseous transmitter next to carbon monoxide CO and nitric oxide NO and is involved as a physiological mediator in several body organ and tissue processes H2S is synthesized endogenously by enzymatic and non-enzymatic pathways A non-enzymatic pathway is by the reductive reaction with thiosulfate with pyruvate acting as a hydrogen donor Thiosulfate itself acts as an intermediate in the sulfur metabolism of cysteine and is known as a metabolite of H2S and in that way is also able to produce H2S especially under hypoxic conditions
H2S has been shown to protect myocardium from ischemia reperfusion injury in various experimental animal models of ischemic heart disease eg it reduces infarct size and apoptosis and attenuates cardiac function Inhibition of leukocyte endothelial cell interactions neutralization of reactive oxygen species ROS and the reduction of apoptotic signalling are the suggested as additional mechanisms underlying the cardioprotective effect of H2S in this setting
STS an H2S donor is used in humans since 1933 for the treatment of cyanide intoxication and is used since the eighties for treatment of vascular calcifications in end-stage renal disease It is also used to prevent toxicity of cisplatin treatment More recently studies have shown STS can delay the progression of coronary artery calcification in haemodialysis patients The mechanism of action in these diseases is thought to be based on potential antioxidant properties of STS In all these cases intravenous STS was used in different doses from 5 to 75 g per day Side effects of STS include hypotension nausea and vomiting gastrointestinal disturbances hypernatraemia and in 5 of hemodialysis patients metabolic acidosis occurred Most side effects were mild and manageable
STS administration has never been tested in the clinical setting of ACS Cardiac catheterization via trans-radial approach has been increasingly used instead of trans-femoral approach resulting in fewer vascular complications minimal risk of nerve injury and virtually no postprocedural bed rest However during radial approach a combination of vasodilating blood pressure lowering and anticoagulant drugs are given to the patient verapamil nitroglycerin heparin the radialis-cocktail These drugs could potentially interact with STS and data regarding the safety of STS in patients with ACS treated with PCI via radial approach is lacking
The SAFE ACS is a phase 12 open-label dose-escalation study to test the hypothesis that STS on top of standard medical treatment can be safely administered in patients presenting with an ACS and is well-tolerated We will use a 33 design with a fixed dosing endpoint of 30 gram of STS in 2 gifts of 15 gram based on the standard dose of 25 gram used for other indications Additionally we will test the effect of STS treatment on oxidative stress during and after STS infusion by laboratory analysis of various oxidative stress markers
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None