<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03017963</url>
  </required_header>
  <id_info>
    <org_study_id>SAFE ACS</org_study_id>
    <nct_id>NCT03017963</nct_id>
  </id_info>
  <brief_title>Safety and Tolerability of Sodium Thiosulfate in Patients With an ACS Undergoing CAG Via Trans-radial Approach.</brief_title>
  <acronym>SAFE-ACS</acronym>
  <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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Center Groningen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Center Groningen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this trial is to evaluate the safety and maximum tolerable dose (MTD) of&#xD;
      sodium thiosulfate in patients presenting with an acute coronary syndrome and treated with&#xD;
      primary percutaneous coronary intervention (PPCI) via trans-radial approach in adjunction to&#xD;
      standard treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Despite the recent advances in treatment, acute myocardial infarction (AMI) frequently&#xD;
      results in permanent myocardial injury imposing an increased risk for adverse cardiac&#xD;
      remodelling, diminished cardiac function and the development of heart failure. Decreased&#xD;
      cardiac function after PPCI is associated with impaired prognosis.&#xD;
&#xD;
      Although PPCI has a tremendous benefit in AMI, not only ischemia but also reperfusion itself&#xD;
      is considered to cause myocardial injury and cardiomyocyte death.This phenomena is referred&#xD;
      to as &quot;ischemia reperfusion injury&quot; in literature and is caused by the sudden restoration of&#xD;
      blood flow and its accompanying intracellular pH change, calcium overload, cardiomyocyte&#xD;
      hypercontracture, myocardial inflammation, oxidative stress generation and mitochondrial&#xD;
      permeability transition pore opening. Reducing ischemia reperfusion injury is expected to&#xD;
      further decrease infarct size, decrease adverse cardiac remodelling and improve cardiac&#xD;
      function as well as clinical outcome.&#xD;
&#xD;
      Hydrogen sulfide (H2S) is the third endogenous gaseous transmitter next to carbon monoxide&#xD;
      (CO) and nitric oxide (NO) and is involved as a physiological mediator in several body organ&#xD;
      and tissue processes. H2S is synthesized endogenously by enzymatic and non-enzymatic&#xD;
      pathways. A non-enzymatic pathway is by the reductive reaction with thiosulfate, with&#xD;
      pyruvate acting as a hydrogen donor. Thiosulfate itself acts as an intermediate in the sulfur&#xD;
      metabolism of cysteine and is known as a metabolite of H2S and in that way is also able to&#xD;
      produce H2S, especially under hypoxic conditions.&#xD;
&#xD;
      H2S has been shown to protect myocardium from ischemia reperfusion injury in various&#xD;
      experimental animal models of ischemic heart disease; e.g. it reduces infarct size and&#xD;
      apoptosis and attenuates cardiac function. Inhibition of leukocyte endothelial cell&#xD;
      interactions, neutralization of reactive oxygen species (ROS) and the reduction of apoptotic&#xD;
      signalling are the suggested as additional mechanisms underlying the cardioprotective effect&#xD;
      of H2S in this setting.&#xD;
&#xD;
      STS, an H2S donor, is used in humans since 1933 for the treatment of cyanide intoxication and&#xD;
      is used since the eighties for treatment of vascular calcifications in end-stage renal&#xD;
      disease. It is also used to prevent toxicity of cisplatin treatment. More recently, studies&#xD;
      have shown STS can delay the progression of coronary artery calcification in haemodialysis&#xD;
      patients. The mechanism of action in these diseases is thought to be based on potential&#xD;
      antioxidant properties of STS. In all these cases intravenous STS was used in different doses&#xD;
      from 5 to 75 g per day. Side effects of STS include hypotension, nausea and vomiting,&#xD;
      gastrointestinal disturbances, hypernatraemia and in 5% of hemodialysis patients metabolic&#xD;
      acidosis occurred. Most side effects were mild and manageable.&#xD;
&#xD;
      STS administration has never been tested in the clinical setting of ACS. Cardiac&#xD;
      catheterization via trans-radial approach has been increasingly used, instead of&#xD;
      trans-femoral approach, resulting in fewer vascular complications, minimal risk of nerve&#xD;
      injury and virtually no postprocedural bed rest. However, during radial approach a&#xD;
      combination of vasodilating, blood pressure lowering and anticoagulant drugs are given to the&#xD;
      patient (verapamil, nitroglycerin, heparin), the &quot;radialis-cocktail&quot;. These drugs could&#xD;
      potentially interact with STS and data regarding the safety of STS in patients with ACS&#xD;
      treated with PCI via radial approach is lacking.&#xD;
&#xD;
      The SAFE ACS is a phase 1/2, open-label, dose-escalation study to test the hypothesis that&#xD;
      STS, on top of standard medical treatment, can be safely administered in patients presenting&#xD;
      with an ACS and is well-tolerated. We will use a &quot;3+3 design&quot; with a fixed dosing endpoint of&#xD;
      30 gram of STS in 2 gifts of 15 gram, based on the standard dose of 25 gram used for other&#xD;
      indications. Additionally we will test the effect of STS treatment on oxidative stress during&#xD;
      and after STS infusion by laboratory analysis of various oxidative stress markers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 6, 2017</start_date>
  <completion_date type="Actual">March 23, 2018</completion_date>
  <primary_completion_date type="Actual">March 23, 2018</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose limiting toxicity (DLT)</measure>
    <time_frame>up to 24 hours or discharge from coronary care unit to the ward/home</time_frame>
    <description>DLT defined as all-cause mortality or hemodynamic instability of significant clinical impact:&#xD;
Hemodynamic instability of significant clinical impact is defined as:&#xD;
Systolic blood pressure &lt;90 millimeters mercury (mmHg) for &gt;30 min and/or&#xD;
Catecholamines required to maintain pressure &gt;90 mmHg during systole and&#xD;
Signs of pulmonary congestion or elevated left-ventricular filling pressures and;&#xD;
Signs of impaired organ perfusion with ≥1 of the following criteria:&#xD;
Confusion;&#xD;
Cool, clammy skin;&#xD;
Oliguria (urine output &lt;30 ml/h);&#xD;
Serum-lactate &gt;2.0 mmol/l.&#xD;
Shock of other causes (hypovolemia, sepsis, bradycardia) are ruled out.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severe hypersensitivity/allergic reaction using a binary scale (yes/no)</measure>
    <time_frame>up to 24 hours or discharge from coronary care unit to the ward/home</time_frame>
    <description>Severe hypersensitivity/allergic reaction such as angio-edema, heavy itch/rash. Outcome measurement will assessed using a binary scale: present (yes) or absent (no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nausea/vomiting</measure>
    <time_frame>up to 24 hours or discharge from coronary care unit to the ward/home</time_frame>
    <description>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 &gt;5 episodes of vomiting in 24 hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of STS on oxidative stress markers in blood</measure>
    <time_frame>up to 12 hours</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Acute Coronary Syndrome</condition>
  <arm_group>
    <arm_group_label>dose-escalation cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sodium Thiosulfate Pentahydrate</intervention_name>
    <description>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</description>
    <arm_group_label>dose-escalation cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years;&#xD;
&#xD;
          -  The diagnosis ACS defined by: chest pain suggestive for myocardial ischemia for at&#xD;
             least 30 minutes, the time from onset of the symptoms less than 24 hours before&#xD;
             hospital admission, with (STEMI) or without (nSTEMI/uAP) an electrocardiogram (ECG)&#xD;
             recording with ST- segment elevation of more than 0.1 millivolt (mV) in 2 or more&#xD;
             contiguous leads;&#xD;
&#xD;
          -  PCI via trans-radial approach is being considered as treatment;&#xD;
&#xD;
          -  Patient is willing to cooperate with the trial during hospitalization&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known cardiomyopathy or LVEF&lt;35%;&#xD;
&#xD;
          -  History of a malignancy treated with chemo- and/or radiotherapy &lt; 1 year;&#xD;
&#xD;
          -  Systolic blood pressure under 100 mmHg or over 180 mmHg at presentation;&#xD;
&#xD;
          -  Cardiogenic shock at presentation&#xD;
&#xD;
          -  Sedated and/or intubated patients;&#xD;
&#xD;
          -  Pregnant/breastfeeding at time of presentation&#xD;
&#xD;
          -  The existence of a condition with a life expectancy of less than 1 year;&#xD;
&#xD;
          -  A condition which, according to the clinical judgment of the investigator and/or&#xD;
             treating physician, does not allow the patient to successfully participate in the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pim van der Harst, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medical Center Groningen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Medical Centre Groningen</name>
      <address>
        <city>Groningen</city>
        <zip>9700RB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>December 24, 2016</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>April 12, 2018</last_update_submitted>
  <last_update_submitted_qc>April 12, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>Pim van der Harst</investigator_full_name>
    <investigator_title>Prof. dr.</investigator_title>
  </responsible_party>
  <keyword>acute coronary syndrome</keyword>
  <keyword>sodium thiosulfate</keyword>
  <keyword>maximum tolerable dose</keyword>
  <keyword>dose-limiting toxicity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Coronary Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sodium thiosulfate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03017963
org study id: SAFE ACS
nct id: NCT03017963
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose limiting toxicity (DLT)
time frame: up to 24 hours or discharge from coronary care unit to the ward/home
description: 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.
measure: 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
description: Severe hypersensitivity/allergic reaction such as angio-edema, heavy itch/rash. Outcome measurement will assessed using a binary scale: present (yes) or absent (no)
measure: Nausea/vomiting
time frame: up to 24 hours or discharge from coronary care unit to the ward/home
description: 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
measure: effect of STS on oxidative stress markers in blood
time frame: up to 12 hours
description: 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.
arm group label: dose-escalation cohort
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Sodium Thiosulfate Pentahydrate
description: 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
arm group label: dose-escalation cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pim van der Harst, Professor
role: Principal Investigator
affiliation: University Medical Center Groningen
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: Pim van der Harst
investigator title: Prof. dr.
mesh term: Acute Coronary Syndrome
mesh term: Syndrome
mesh term: Sodium thiosulfate
sharing ipd: No