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

Acute Myocardial Infarction Clinical Trial

— DOBERMANN  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05350592
• Other study ID #: RH-CARD-Pharma001
• Secondary ID: 2021-002028-19H-
• Status: Recruiting
• Phase: Phase 2
• Start date: March 7, 2022
• Est. completion date: June 1, 2025

Study information

• Verified date: April 2024
• Source: Rigshospitalet, Denmark
• Contact: Ginette Wedel
• Phone: +45 35452664
• Email: ginette.wedel[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: June 1, 2025
• Est. primary completion date: March 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Cardiogenic Shock
• Infarction
• Myocardial Infarction
• Shock
• Shock, Cardiogenic

Intervention

Drug:
• Tocilizumab
Single bolus
• Dobutamine
Continous weight-adjusted infusion
• NaCl 0.9%
Placebo comparator and diluent

Locations

Country	Name	City	State
Denmark	Rigshospitalet, Copenhagen University Hospital	Copenhagen

Sponsors (4)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Helge Peetz og Verner Peetz og hustru Vilma Peetz Legat, Novo Nordisk A/S, Simon Spies Fonden

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ProBNP	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 proBNP levels change differently over time in the treatment versus the placebo arm.	48 hours
Secondary	CS and/or cardiac arrest	Number of patients developing in-hospital CS and/or in-hospital cardiac arrest	Index admission
Secondary	Acute Infarct Size	Magnetic-resonance imaging-estimated infarct size	Admission
Secondary	Post-infarction Salvaged Myocardium	Magnetic-resonance imaging-estimated infarct size	3 months
Secondary	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
Secondary	Post-procedure assessment	Survey of PCI operator's post-procedure clinical assessment of the patient's survival at discharge (yes/no)	Index admission
Secondary	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
Secondary	2D echocardiographic measurements of hemodynamics	VTI and left ventricular function including strain measurements according to protocol	Admisson, 3 months
Secondary	Re-admission	Number of all cause and cardiovascular admissions during the first year after index hospitalization	One year
Secondary	Heart Quality of Life (HeartQoL)	Heart-specific Quality of Life Questionnaire	Admission, 3 months
Secondary	EuroQol Group EQ-5D Quality of Life (EQ-5D-5L)	Quality of Life Questionnaire	Admission, 3 months
Secondary	HADS (Hospital Anxiety and Depression Scale)	In-patient Anxiety and Depression Questionnaire	Admission, 3 months
Secondary	The Montreal Cognitive Assessment (MOCA)	Clinician-administered Cognitive Test	Admission, 3 months
Secondary	Clinical Frailty Scale (CFS)	Clinician-administered Assessment	Admission, 3 months