Low-Dose Dobutamine and Single-Dose Tocilizumab in Acute Myocardial Infarction With High Risk of Cardiogenic Shock

Study Overview
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Brief Summary
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In the present study, we aim to investigate the effects of dobutamine infusion and/or a single intravenous (IV) dose of the IL-6 antagonist Tocilizumab administered after percutaneous coronary intervention (PCI) to patients with acute myocardial infarction (AMI) presenting < 24 hours from onset of chest pain and an intermediate to high risk of cardiogenic shock (CS) by assessment with the ORBI risk score (≥10 - not in overt shock at hospital admission). Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NTproBNP) as a proxy for development of cardiogenic shock (CS) and hemodynamic instability will be sampled for primary endpoint analysis. Effects on clinical parameters, mortality, morbidity as well as specific indicators of inflammation, cardiac function, and infarct size will secondarily be assessed noninvasively. The rationale behind the current study is that inflammatory and neurohormonal responses are associated with subclinical hemodynamic instability in patients with AMI with high risk of CS have worse outcomes. The potentially unstable condition may be targeted pharmacologically as an add-on to existing therapy. This is investigated in patients at elevated risk of CS by sampling biomarkers reflecting the inflammatory and neurohormonal responses, as well as determining effects on patient outcomes and infarct size.

Detailed Description
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The planned study is an investigator-initiated, randomized, double blinded clinical trial. Consecutive patients at Copenhagen University Hospital, Rigshospitalet admitted with AMI < 24 hours from chest pain will be screened. Patients eligible for trial inclusion will be randomized 2:2 to receive a continuous IV dobutamine infusion of 5 mcg/kg/minute versus placebo for 24 hours and to receive a single IV dose of tocilizumab (1-hour infusion) versus placebo administered after PCI. Treatment with the investigational drug will be initiated as soon as possible but no later than 2 hours after transfer to the coronary care unit (CCU) and after informed consent. All included patients will follow usual treatment according to current guidelines. The biomarker NTproBNP will be measured in blood samples drawn upon hospital admission in patients with ORBI risk score ≥10, and after 12, 24, 36 and 48 hours from admission. After treatment termination, 2D-echocardiography will be performed acutely and within 2 days to evaluate left ventricular ejection fraction (LVEF), and cardiac magnetic resonance imaging (cMRi) with late gadolinium enhancement technique prior to hospital discharge as close to 48 hours post-MI and after 3 months after discharge will be performed to calculate area at risk and salvage index after AMI.Blood samples (40 mL) will be obtained and stored in a biobank for subsequent measurement of biomarkers reflecting inflammation, neurohormonal activation, neuronal injury, connective tissue function and other relevant pathophysiological processes. These biomarkers will solely have research interest and no clinical implications. Furthermore, no genetic biomarkers and markers associated with malignancy development will be measured. Any leftover blood from the research biobank will be transferred to a biobank for future research and stored for up to 10 years solely for research purposes. After this period blood samples will be destroyed.

Official Title
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Low-dose Dobutamine Infusion and Single-dose Tocilizumab in Acute Myocardial Infarction Patients With High Risk of Cardiogenic Shock Development - a 2x2 Multifactorial, Double-blinded, Randomized, Placebo Controlled Trial

Conditions
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Acute Myocardial Infarction, Cardiogenic Shock

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Dobutamine
* Drug: NaCl 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myocardial infarction Revascularization with PCI Presentation within 24 hours of chest pain ORBI risk score ≥ 10 Age ≥ 18 Exclusion Criteria: Unwilling to give informed consent to study participation Unable to give consent due to language barrier Comatose after cardiac arrest Cardiogenic shock with systolic blood pressure < 100 mmHg for more than 30 minutes or need for vasopressor to maintain blood pressure and arterial lactate > 2,5 (2,0) mmol/L developed before leaving the cath. lab. Other major clinical non-coronary condition (stroke, sepsis etc.), which can explain a high ORBI risk score Referral for acute coronary artery bypass grafting (CABG) (< 24 hours) after the CAG Contraindications against dobutamine infusion (sustained ventricular tachycardia prior to admission or noted in the cath.lab., known pheochromocytoma, idiopathic hypertrophic subaortic stenosis) Tocilizumab allergy Pregnant- or breastfeeding women Known liver disease/dysfunction Ongoing uncontrollable infection Immune deficiency/treatment with immunosuppressants Known, uncontrolled gastrointestinal (GI) disease predisposing to GI perforation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tocilizumab + Dobutamine<br>Tocilizumab IV 280 mg (100mL/hour, 1 hour) Dobutamine IV 5 micrograms/kg/minute (5mL/hour, 24 hours) | Drug: Tocilizumab<br>* Single bolus<br>* Other names: RoActemra (Actemra);Drug: Dobutamine<br>* Continous weight-adjusted infusion<br>* Other names: Dobutrex;|
| Active Comparator: Tocilizumab + Placebo<br>Tocilizumab IV 280 mg (100mL/hour, 1 hour) NaCl 0,9% IV (5mL/hour, 24 hours) | Drug: Tocilizumab<br>* Single bolus<br>* Other names: RoActemra (Actemra);Drug: NaCl 0.9%<br>* Placebo comparator and diluent<br>* Other names: Saline isotonic;|
| Active Comparator: Placebo + Dobutamine<br>NaCl 0,9% IV (100mL/hour, 1 hour) Dobutamine IV 5 micrograms/kg/minute (5mL/hour, 24 hours) | Drug: Dobutamine<br>* Continous weight-adjusted infusion<br>* Other names: Dobutrex;Drug: NaCl 0.9%<br>* Placebo comparator and diluent<br>* Other names: Saline isotonic;|
| Placebo Comparator: Placebo + Placebo<br>NaCl 0,9% IV (100mL/hour, 1 hour) NaCl 0,9% IV (5mL/hour, 24 hours) | Drug: NaCl 0.9%<br>* Placebo comparator and diluent<br>* Other names: Saline isotonic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NT-proBNP | NT-proBNP plasma concentration being assessed at multiple time points (including the primary endpoint) will be analyzed by application of a linear mixed model of covariance. As the biomarker will be measured prior to initiation of the study drug, the models will be baseline corrected (i.e., constrained linear mixed models, CLMM). The main result of these analyses will be the treatment-by-time interaction as a marker of whether the NTproBNP levels change differently over time in the treatment versus the placebo arm. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CS and/or cardiac arrest | Number of patients developing in-hospital CS and/or in-hospital cardiac arrest | Index admission | 
| Acute Infarct Size | Magnetic-resonance imaging-estimated infarct size | Admission | 
| Post-infarction Salvaged Myocardium | Magnetic-resonance imaging-estimated infarct size | 3 months | 
| Additional biomarkers | Reflecting neurohormonal activation, endothelial function/damage, inflammation (pro- and anti-inflammatory processes - including IL-6 and C-reactive peptide (CRP)), connective tissue damage, organ dysfunction, and other relevant physiological processes | Index admission | 
| Post-procedure assessment | Survey of PCI operator's post-procedure clinical assessment of the patient's survival at discharge (yes/no) | Index admission | 
| Development of non-cardiac arrest arrythmia | Number of patients and number of per-patient episodes of sustained ventricular tachycardia or atrial fibrillation with a frequency above 120 for more than 30 minutes | Index admission | 
| 2D echocardiographic measurements of hemodynamics | VTI and left ventricular function including strain measurements according to protocol | Admisson, 3 months | 
| Re-admission | Number of all cause and cardiovascular admissions during the first year after index hospitalization | One year | 
| Heart Quality of Life (HeartQoL) | Heart-specific Quality of Life Questionnaire | Admission, 3 months | 
| EuroQol Group EQ-5D Quality of Life (EQ-5D-5L) | Quality of Life Questionnaire | Admission, 3 months | 
| HADS (Hospital Anxiety and Depression Scale) | In-patient Anxiety and Depression Questionnaire | Admission, 3 months | 
| The Montreal Cognitive Assessment (MOCA) | Clinician-administered Cognitive Test | Admission, 3 months | 
| Clinical Frailty Scale (CFS) | Clinician-administered Assessment | Admission, 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myocardial infarction, cardiogenic shock, AMI, inflammation, NTproBNP, AMI-CS, infarct size, STEMI