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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myocardial Infarction; Cardiogenic Shock
• Intervention / Treatment: Drug: Tocilizumab; Drug: Dobutamine; Drug: NaCl 0.9%

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Copenhagen University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Novo Nordisk A/S; Simon Spies Fonden; Helge Peetz og Verner Peetz og hustru Vilma Peetz Legat
• Investigators: Principal Investigator: Helle Søholm, MD, PhD, Dept. of Cardiology, Rigshospitalet; Principal Investigator: Martin Frydland, MD, PhD, Dept. of Cardiology, Rigshospitalet

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2022
• Primary Completion (Actual): June 30, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: March 8, 2022
• First Submitted That Met QC Criteria: April 21, 2022
• First Posted (Actual): April 28, 2022

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: STEMI; cardiogenic shock; inflammation; AMI; acute myocardial infarction; infarct size; AMI-CS; proBNP
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Necrosis; Myocardial Ischemia; Ischemia; Shock, Cardiogenic; Shock; Myocardial Infarction; Infarction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Protective Agents; Adrenergic Agonists; Adrenergic Agents; Cardiotonic Agents; Adrenergic beta-Agonists; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Dobutamine
• Other Study ID Numbers: RH-CARD-Pharma001; 2021-002028-19 (EudraCT Number); H-21045751 (Registry Identifier: National Committee on Health Research Ethics); U1111-1277-8523 (Registry Identifier: WHO Universal Trial Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data is planned to be available upon reasonable request via the Principal Investigator pending final, complete publication of the study.
• IPD Sharing Time Frame: Access and final IPD criteria is pending final, complete publication of the study.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No