Clinical trial NCT05350592: Low-Dose Dobutamine and Single-Dose Tocilizumab in Acute Myocardial Infarction With High Risk of Cardiogenic Shock
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myocardial Infarction
Cardiogenic Shock
Keywords: acute myocardial infarction
cardiogenic shock
AMI
inflammation
proBNP
AMI-CS
infarct size
STEMI
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Novo Nordisk A/S
name: Simon Spies Fonden
name: Helge Peetz og Verner Peetz og hustru Vilma Peetz Legat
First posted: 2022-04-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2x2
Primary purpose: TREATMENT

Brief summary: 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 pro-B-type natriuretic peptide (proBNP) 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: 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 proBNP 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.

Eligibility criteria: 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

Primary outcomes:
measure: ProBNP
timeFrame: 48 hours
Secondary outcomes:
measure: CS and/or cardiac arrest
timeFrame: Index admission
measure: Acute Infarct Size
timeFrame: Admission
measure: Post-infarction Salvaged Myocardium
timeFrame: 3 months
measure: Additional biomarkers
timeFrame: Index admission
measure: Post-procedure assessment
timeFrame: Index admission
measure: Development of non-cardiac arrest arrythmia
timeFrame: Index admission
measure: 2D echocardiographic measurements of hemodynamics
timeFrame: Admisson, 3 months
measure: Re-admission
timeFrame: One year
measure: Heart Quality of Life (HeartQoL)
timeFrame: Admission, 3 months
measure: EuroQol Group EQ-5D Quality of Life (EQ-5D-5L)
timeFrame: Admission, 3 months
measure: HADS (Hospital Anxiety and Depression Scale)
timeFrame: Admission, 3 months
measure: The Montreal Cognitive Assessment (MOCA)
timeFrame: Admission, 3 months
measure: Clinical Frailty Scale (CFS)
timeFrame: Admission, 3 months
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Copenhagen University Hospital
Study officials:
affiliation: Dept. of Cardiology, Rigshospitalet
name: Helle Søholm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. of Cardiology, Rigshospitalet
name: Martin Frydland, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Holle SLD, Kunkel JB, Hassager C, Pecini R, Wiberg S, Palm P, Holmvang L, Bang LE, Kjaergaard J, Thomsen JH, Engstrom T, Moller JE, Lonborg JT, Soholm H, Frydland M. Low-dose dobutamine in acute myocardial infarction with intermediate to high risk of cardiogenic shock development (the DOBERMANN-D trial): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial. Trials. 2024 Oct 30;25(1):731. doi: 10.1186/s13063-024-08567-y.
citation: Kunkel JB, Holle SLD, Hassager C, Pecini R, Wiberg S, Palm P, Holmvang L, Bang LE, Kjaergaard J, Thomsen JH, Engstrom T, Moller JE, Lonborg JT, Frydland M, Soholm H. Interleukin-6 receptor antibodies (tocilizumab) in acute myocardial infarction with intermediate to high risk of cardiogenic shock development (DOBERMANN-T): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial. Trials. 2024 Nov 5;25(1):739. doi: 10.1186/s13063-024-08573-0.