Safety and Tolerability of Sodium Thiosulfate in Patients With an ACS Undergoing CAG Via Trans-radial Approach. (SAFE-ACS)

April 12, 2018 updated by: Pim van der Harst, University Medical Center Groningen

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.

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 death.This 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; e.g. 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 1/2, 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 "3+3 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
18

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9700RB
        • University Medical Centre Groningen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years;
  • The diagnosis ACS defined by: chest pain suggestive for myocardial ischemia for at least 30 minutes, the time from onset of the symptoms less than 24 hours before hospital admission, with (STEMI) or without (nSTEMI/uAP) an electrocardiogram (ECG) recording with ST- segment elevation of more than 0.1 millivolt (mV) in 2 or more contiguous leads;
  • PCI via trans-radial approach is being considered as treatment;
  • Patient is willing to cooperate with the trial during hospitalization

Exclusion Criteria:

  • Known cardiomyopathy or LVEF<35%;
  • History of a malignancy treated with chemo- and/or radiotherapy < 1 year;
  • Systolic blood pressure under 100 mmHg or over 180 mmHg at presentation;
  • Cardiogenic shock at presentation
  • Sedated and/or intubated patients;
  • Pregnant/breastfeeding at time of presentation
  • The existence of a condition with a life expectancy of less than 1 year;
  • A condition which, according to the clinical judgment of the investigator and/or treating physician, does not allow the patient to successfully participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: dose-escalation cohort
Patients are divided in 6 groups of 3 patients to receive the following intervention: 0 gram (g), 2.5 g, 5 g, 10 g, 12.5 g and 15 g of sodium thiosulfate pentahydrate (STS) intravenous. The first dose is given in 15 min immediately after inclusion at the cath-lab. In the absence of dose-limiting toxicity (DLT), a second gift of STS is given in 30 min, 6 hours later at the coronary care unit (CCU). When no DLT is observed in any of the patients after 2 gifts of the same dose an extra 3 subjects are enrolled into the next higher dose cohort. If 1 out of 3 patient develops DLT at a specific dose, an extra 3 subjects are enrolled into the same dose cohort. When more than 1 out of 6 patients develop DLT the trial will be terminated because the maximum tolerable dose (MTD) has been exceeded.
Drug: Sodium Thiosulfate Pentahydrate
Sodium Thiosulfate Pentahydrate is administered intravenously in 250 centiliters infusion fluid in two doses: first dose with an infusion rate of 16.66 milliliter (ml) per minute (min), second dose with 8.33 ml / min

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Dose limiting toxicity (DLT)
Time Frame: up to 24 hours or discharge from coronary care unit to the ward/home

DLT defined as all-cause mortality or hemodynamic instability of significant clinical impact:

Hemodynamic instability of significant clinical impact is defined as:

  • Systolic blood pressure <90 millimeters mercury (mmHg) for >30 min and/or
  • Catecholamines required to maintain pressure >90 mmHg during systole and
  • Signs of pulmonary congestion or elevated left-ventricular filling pressures and;

  • Signs of impaired organ perfusion with ≥1 of the following criteria:

    • Confusion;
    • Cool, clammy skin;
    • Oliguria (urine output <30 ml/h);
    • Serum-lactate >2.0 mmol/l.
  • Shock of other causes (hypovolemia, sepsis, bradycardia) are ruled out.
up to 24 hours or discharge from coronary care unit to the ward/home

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Severe hypersensitivity/allergic reaction using a binary scale (yes/no)
Time Frame: up to 24 hours or discharge from coronary care unit to the ward/home
Severe hypersensitivity/allergic reaction such as angio-edema, heavy itch/rash. Outcome measurement will assessed using a binary scale: present (yes) or absent (no)
up to 24 hours or discharge from coronary care unit to the ward/home
Nausea/vomiting
Time Frame: up to 24 hours or discharge from coronary care unit to the ward/home
using a 4-point Likert-scale: 0= none, 1= nauseated but able to eat and/or 1 episode of vomiting in 24 hours, 2= food intake significantly decreased and/or 2-5 episodes of vomiting in 24 hours, 3= intravenous fluids required and/or >5 episodes of vomiting in 24 hours
up to 24 hours or discharge from coronary care unit to the ward/home
effect of STS on oxidative stress markers in blood
Time Frame: up to 12 hours
effect of STS on oxidative stress markers in blood by laboratory analysis of free thiols in blood. Unity: µmol/l. Measurement on different timeframes, starting at T=0, to evaluate the effect of STS on free thiol levels in blood.
up to 12 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Medical Center Groningen

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Pim van der Harst, Professor, University Medical Center Groningen

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 6, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 23, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 23, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 24, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 9, 2017

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 11, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 17, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 12, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • SAFE ACS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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