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

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Recruiting

CT.gov ID

NCT05350592

Collaborator

Novo Nordisk A/S (Industry), Simon Spies Fonden (Other), Helge Peetz og Verner Peetz og hustru Vilma Peetz Legat (Other)

100

Enrollment

Location

Arms

35.8

Anticipated Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

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 (≥11 - 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myocardial Infarction Cardiogenic Shock	Drug: Tocilizumab Drug: Dobutamine Drug: NaCl 0.9%	Phase 2

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 NTproBNP will be measured in blood samples drawn upon hospital admission in patients with ORBI risk score ≥11, 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 Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

2x22x2

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 7, 2022

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

NT-proBNP [48 hours]
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.

Secondary Outcome Measures

CS and/or cardiac arrest [Index admission]
Number of patients developing in-hospital CS and/or in-hospital cardiac arrest
Acute Infarct Size [Admission]
Magnetic-resonance imaging-estimated infarct size
Post-infarction Salvaged Myocardium [3 months]
Magnetic-resonance imaging-estimated infarct size
Additional biomarkers [Index admission]
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
Post-procedure assessment [Index admission]
Survey of PCI operator's post-procedure clinical assessment of the patient's survival at discharge (yes/no)
Development of non-cardiac arrest arrythmia [Index admission]
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
2D echocardiographic measurements of hemodynamics [Admisson, 3 months]
VTI and left ventricular function including strain measurements according to protocol
Re-admission [One year]
Number of all cause and cardiovascular admissions during the first year after index hospitalization
Heart Quality of Life (HeartQoL) [Admission, 3 months]
Heart-specific Quality of Life Questionnaire
EuroQol Group EQ-5D Quality of Life (EQ-5D-5L) [Admission, 3 months]
Quality of Life Questionnaire
HADS (Hospital Anxiety and Depression Scale) [Admission, 3 months]
In-patient Anxiety and Depression Questionnaire
The Montreal Cognitive Assessment (MOCA) [Admission, 3 months]
Clinician-administered Cognitive Test
Clinical Frailty Scale (CFS) [Admission, 3 months]
Clinician-administered Assessment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Acute myocardial infarction
Revascularization with PCI
Presentation within 24 hours of chest pain
ORBI risk score ≥ 11
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rigshospitalet, Copenhagen University Hospital	Copenhagen		Denmark	2100

Sponsors and Collaborators

Rigshospitalet, Denmark
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, Dept. of Cardiology, Rigshospitalet