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Sodium Thiosulfate to Preserve Cardiac Function in STEMI (GIPS-IV)

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ClinicalTrials.gov Identifier: NCT02899364
Recruitment Status : Recruiting
First Posted : September 14, 2016
Last Update Posted : December 13, 2018
Sponsor:
Information provided by (Responsible Party):
Pim van der Harst, University Medical Center Groningen

Brief Summary:

Rationale: Timely and effective reperfusion by primary percutaneous coronary intervention (PPCI) is currently the most effective treatment of ST-segment elevation myocardial infarction (STEMI). However, permanent myocardial injury related to the ischemia and subsequent reperfusion is observed in the vast majority (88%) of patients and harbours a risk of heart failure development. Administration of hydrogen sulfide (H2S) has been shown to protect the heart from "ischemia reperfusion injury" in various experimental models. Data in humans suggests that the H2S-releasing agent sodium thiosulfate (STS) can be administered safely.

Objective: to evaluate the efficacy and safety of STS compared to placebo treatment on myocardial infarct size in patients presenting with STEMI and treated with PCI

Study design: a single centre, double blind, randomized controlled clinical trial. A total of 380 patients, aged 18 years and above, undergoing primary PCI for a first STEMI and deemed amenable, by the investigator, to be treated with STS 12.5g intravenously (i.v.) or matched placebo immediately after arrival at the catheterization laboratory (cath-lab) and a repeated dose administered 6 hours after the first dose, on top of standard treatment. Primary endpoint is infarct size as measured with cardiac magnetic resonance imaging (CMR-imaging) 4 months after randomization.


Condition or disease Intervention/treatment Phase
Myocardial Infarction Heart Failure Drug: Sodium thiosulfate Drug: Sodium chloride 0.9% Procedure: primary percutaneous coronary intervention Other: cardiac magnetic resonance imaging Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Groningen Intervention Study for the Preservation of Cardiac Function With Sodium Thiosulfate After ST-segment Elevation Myocardial Infarction
Actual Study Start Date : July 20, 2018
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sodium thiosulfate
25 gram sodium thiosulfate is given intravenously in two doses of 12.5 gram (50mL) dissolved in 250 ml sodium chloride 0.9%. Upon arrival at the cath-lab, after confirming in- and exclusion criteria and obtaining verbal informed consent the first dose, will be administered in 20 minutes (infusion rate 15 mL/min). After infusion the patient will receive primary percutaneous coronary intervention. Post-PCI the patient will be admitted to the coronary care unit where he will receive the second dose, 6 hours after start of the first dose. The second dose is administered in 30 minutes (infusion rate 10 mL/min). At 4 months infarct size is assessed by LGE cardiac magnetic resonance imaging.
Drug: Sodium thiosulfate
see description under experimental arm

Procedure: primary percutaneous coronary intervention
Primary treatment of the ischemia-related coronary artery is left to discretion of the operator and might consist of thrombus aspiration, balloon inflation and stent implantation. Additional balloon angioplasty or stenting of the culprit or other lesions will be performed when necessary.
Other Name: PPCI

Other: cardiac magnetic resonance imaging
CMR-imaging will be used for assessment of infarct size, left ventricular function, quantification of myocardial scar and diffuse myocardial fibrosis. CMR-imaging examinations will be performed on a 3 Tesla scanner using a phased array cardiac receiver coil at 4 months after randomization according to standard protocols. The full study protocol lasts approximately 45 minutes and includes anatomy and function, LGE and T1-mapping.
Other Name: CMR-imaging

Placebo Comparator: Sodium chloride 0.9%
50 ml Sodium chloride 0.9%, added to 250ml sodium chloride 0.9% is administered twice. Upon arrival at the cath-lab, after confirming in- and exclusion criteria and obtaining verbal informed consent the first dose, will be administered in 20 minutes (infusion rate 15ml/min). After infusion the patient will receive primary percutaneous coronary intervention. Post-PCI the patient will be admitted to the coronary care unit where he receive the second dose, 6 hours after start of the first dose. The second dose is administered in 30 minutes (infusion rate 10 mL/min). At 4 months infarct size is assessed by LGE cardiac magnetic resonance imaging.
Drug: Sodium chloride 0.9%
see description under placebo comparator arm
Other Name: Placebo

Procedure: primary percutaneous coronary intervention
Primary treatment of the ischemia-related coronary artery is left to discretion of the operator and might consist of thrombus aspiration, balloon inflation and stent implantation. Additional balloon angioplasty or stenting of the culprit or other lesions will be performed when necessary.
Other Name: PPCI

Other: cardiac magnetic resonance imaging
CMR-imaging will be used for assessment of infarct size, left ventricular function, quantification of myocardial scar and diffuse myocardial fibrosis. CMR-imaging examinations will be performed on a 3 Tesla scanner using a phased array cardiac receiver coil at 4 months after randomization according to standard protocols. The full study protocol lasts approximately 45 minutes and includes anatomy and function, LGE and T1-mapping.
Other Name: CMR-imaging




Primary Outcome Measures :
  1. Myocardial infarct size as measured with late gadolinium enhancement cardiac magnetic resonance imaging. [ Time Frame: 4 months after randomization ]
    Primary efficacy parameter


Secondary Outcome Measures :
  1. Left ventricular ejection fraction as assessed by late gadolinium enhancement cardiac magnetic resonance imaging. [ Time Frame: 4 months after randomization ]
    Secondary efficacy parameter

  2. N-terminal prohormone of brain natriuretic peptide (NT pro-BNP) level [ Time Frame: 4 months after randomization ]
    Secondary efficacy parameter

  3. Myocardial haemorrhage as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  4. Microvascular obstruction as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  5. Myocardial salvage index as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  6. Left ventricular ejection fraction as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  7. Left ventricular end-diastolic volume as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  8. Left ventricular end-systolic volume as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  9. Left ventricular mass as assessed by non-mandatory cardiac magnetic resonance imaging. [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Secondary efficacy parameter

  10. All cause mortality [ Time Frame: 4 months after randomization and after 2-year follow-up ]
    Safety parameter

  11. Combined major adverse cardiovascular events [ Time Frame: 4 months after randomization and after 2-year follow-up ]
    Safety parameter. Includes cardiovascular mortality, re-infarction, re-intervention (any revascularization not planned on index CAG), stroke.

  12. Implantable cardioverter defibrillator implantation [ Time Frame: 4 months after randomization and after 2-year follow-up ]
    Safety parameter

  13. Hospitalization for heart failure or chest pain [ Time Frame: 4 months after randomization and after 2-year follow-up ]
    Safety parameter. defined as an overnight stay, with different dates for admission and discharge

  14. Enzymatic infarct size as assessed by peak creatinine kinase myocardial band (CK-MB). [ Time Frame: 0-3 days after randomization (during hospitalization) ]
    Safety parameter


Other Outcome Measures:
  1. Health related quality of life: EuroQol EQ-5D-5L [ Time Frame: 0-5 days after randomization (during hospitalization) and at 4 months follow up ]

    Health related quality of life assessed using the EuroQol EQ-5D-5L.

    The EQ-5D-5L has 2 components:

    There is a descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, unable/extreme problems. The respondent is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.

    The EQ VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'.

    The users guide gives details of the scoring system: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf


  2. General affective status [ Time Frame: 0-5 days after randomization (during hospitalization) and at 4 months follow up ]
    Assessed with PANAS questionnaire (Positive And Negative Affect Schedule), positive affect score can range from 10 to 50, with higher scores representing higher positive affective state; negative affect score ranges from 10 to 50 with lower scores representing lower levels of negative affect

  3. Thrombolysis in myocardial infarction (TIMI) grade flow pre- and post-reperfusion (grade 0-3) [ Time Frame: peri-PCI-procedure ]
    Analysis of primary and secondary endpoints according to important risk factors and known medical history collected during routine clinical care for STEMI.

  4. Changes in electrocardiographic determinants of myocardial reperfusion [ Time Frame: Up to 4 months follow-up visit. ]
    Changes include incidence of new Q waves, ST-segment resolution, persistent ST-deviation.

  5. Creatine Kinase (IU/L) [ Time Frame: 0-3 days after randomization (during hospitalization) ]
    Changes in blood biomarkers

  6. Creatine Kinase myocardial band in international units per litre (IU/L) [ Time Frame: 0-3 days after randomization (during hospitalization) ]
    Changes in blood biomarkers

  7. Troponin T in nanogram per millilitre (ng/mL) [ Time Frame: 0-3 days after randomization (during hospitalization) ]
    Changes in blood biomarkers

  8. N-terminal prohormone of brain natriuretic peptide (NT-ProBNP) in nanogram per litre (ng/L) [ Time Frame: 0-5 days after randomization (during hospitalization) ]
    Changes in blood biomarkers



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years;
  • The diagnosis STEMI defined by (1.) chest pain suggestive for myocardial ischemia for at least 30 minutes, the time from onset of the symptoms less than 12 hours before hospital admission, and (2.) an electrocardiogram (ECG) recording with ST- segment elevation of more than 0.1 millivolt (mV) in 2 or more contiguous leads or presence of new left bundle branch block;
  • Symptoms and/or ST-segment deviation should be present (persisting) at time of arrival in the cath-lab;
  • PPCI is being considered as treatment;
  • Patient is willing to cooperate with follow-up during 2 years.

Exclusion Criteria:

  • Prior MI (STEMI/non-STEMI/acute coronary syndrome (ACS), unless maximum troponin T < 50ng/L.
  • Known permanent atrial fibrillation;
  • Prior CABG;
  • Prior PCI, complicated by periprocedural infarction, unless maximum troponin T < 50 ng/L;
  • Known cardiomyopathy;
  • Previous hospitalization for heart failure;
  • History of a malignancy treated with chemo- and/or radiotherapy;
  • Relieve of symptoms and complete ST-segment resolution prior to arrival at the cath-lab;
  • Presentation with cardiogenic shock (systolic blood pressure <90 mmHg);
  • Severe hypertension (systolic blood pressure >220 mmHg);
  • Sedated and/or intubated patients;
  • The existence of a condition with a life expectancy of less than 1 year;
  • Contraindication for 3 Tesla (T) CMR-imaging (e.g. body weight >250kg; known claustrophobia; 3 T magnetic resonance imaging (MRI) incompatible ferromagnetic objects in the body, end-stage renal disease);
  • Pregnancy or breastfeeding women; women of childbearing potential with clinical suspicion of possible pregnancy;
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02899364


Contacts
Contact: Pim van der Harst, Prof. dr. 0031503616161 p.van.der.harst@umcg.nl
Contact: Marie-Sophie de Koning, M.D. 0031503616161 m.s.l.y.de.koning@umcg.nl

Locations
Netherlands
University Medical Centre Groningen Recruiting
Groningen, Netherlands, 9700RB
Principal Investigator: Pim van der Harst, Professor         
Sub-Investigator: Marie-Sophie de Koning, M.D.         
Sponsors and Collaborators
University Medical Center Groningen
Investigators
Principal Investigator: Pim van der Harst, Prof. dr. University Medical Center Groningen

Responsible Party: Pim van der Harst, MD, PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02899364     History of Changes
Other Study ID Numbers: GIPS-IV
2015-001006-34 ( EudraCT Number )
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: December 13, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pim van der Harst, University Medical Center Groningen:
Sodium thiosulfate
STEMI
Infarct size
Cardiac magnetic resonance imaging
Hydrogen sulfide

Additional relevant MeSH terms:
Heart Failure
Infarction
Myocardial Infarction
ST Elevation Myocardial Infarction
Heart Diseases
Cardiovascular Diseases
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Vascular Diseases
Sodium thiosulfate
Antidotes
Protective Agents
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Chelating Agents
Sequestering Agents