Corticoid Therapy in Acute Myocarditis

Official title

Use of Glucocorticoids Therapy in Acute Myocarditis With Severe Left Ventricular Dysfunction: a Multicenter Randomized Controlled Trial

Overview

Refer to the "Detailed Description" section.

Detailed description

Introduction: Acute myocarditis (AM) is an inflammatory disease of the heart. The incidence is approximately 22 out of 100 000 patients annually. Clinically, it ranges from subclinical pauci-symptomatic forms to life-threatening arrhythmias, cardiogenic shock and sudden cardiac death. In approximately more than 70% of cases, AM resolves spontaneously. In the remaining patients, it evolves to a poor prognosis with left ventricular dilatation, reduced cardiac contractility and progression to chronic heart failure.

Complicated AM is defined as an AM with Left Ventricular Ejection Fraction (LVEF) \< 50% and/or a sustained ventricular arrhythmia and/or a hemodynamic instability. Complicated AM is often associated with a poor prognosis (in example risk of heart transplantation of 10.4% at 30 days and 14.7% at 5-year follow up) whereas uncomplicated AM have none.

Administration of immunosuppressive treatment (IT) is still debated. According to experts' consensus, immunosuppressive treatment should be considered in complicated AM and should be used in recommended in case of fulminant myocarditis (acute myocarditis with a presentation of cardiogenic shock, ventricular arrhythmias, or multiorgan system failure). Nevertheless, there is no data on use of glucocorticoids (GC) in complicated AM.

Early application of high dose of GC in AM can control the cytokine storm and the inflammatory response, rather than suppressing the overall immune response. Best timing for their administration remains unknown. The aim of this multicenter controlled randomized study is to demonstrate the benefit of high dose of GC therapy on mortality and cardiac events in patients with AM and left ventricular (LV) dysfunction.

Hypothesis/Objective: The main objective is to evaluate in patients with acute myocarditis with left-ventricular dysfunction the efficacy of a pulse of Methylprednisolone IV for 3 days at diagnosis followed by Prednisone per os versus placebo IV followed by placebo per os in association with conventional Heart Failure (HF) therapy on the occurrence of Major Cardiovascular Events (MACE) and/or persistence of left ventricular dysfunction defined as LVEF \< 50% and/or Global Longitudinal Strain (GLS) \< -16% between baseline and at 6 months.

The primary endpoint is the Major Cardiovascular Events (MACE) and/or persistence of left ventricular dysfunction defined as LVEF \< 50% and/or Global Longitudinal Strain (GLS) \< - 16% between baseline (D-2) and 6 months (M6) follow up. MACE is a combined criterion that includes all-cause mortality, heart failure hospitalization, sustained ventricular arrhythmia, heart transplantation or assistance and recurrent acute myocarditis with LV dysfunction at 6 months.

Method: Phase III, prospective, randomized, placebo controlled, superiority, double blinded trial with 2 parallel groups randomized in a 1:1 ratio:

* Experimental group: Methylprednisolone IV for 3 days followed by Prednisone per os + conventional HF treatment. * Control group: placebo of Methylprednisolone IV followed by placebo of Prednisone per os + conventional HF treatment.

Interventions

• Drug Intravenous administration of Methylprednisolone
  Patients will take intravenous administration of Methylprednisolone (500mg/100ml by IV over 30 minutes per day) for 3 days.
• Drug Oral Prednisone
  After intravenous administration of Methylprednisolone patients will take by oral Prednisone 1mg/kg per day once a day (with a maximum dose of 90 mg per day for patients weighing \> 90kg) for 1 month, followed with a progressive decrease of 10 mg Prednisone every 15 days until a dose of 10mg per day during 15 days (= stop).
• Drug Perfusion of placebo
  Patients will take perfusion of placebo (G5%: 100ml over 30 minutes per day) for 3 days.
• Drug Oral Prednisone placebo
  After the perfusion of placebo, patients will take by oral Prednisone placebo once a day for the same duration as that required if the patient was in the investigational medicinal products group (1 month + progressive decrease).

Primary outcome measures

• Efficacy of treatments [Time frame: 6 months]

Secondary outcome measures (11)

• Changes in LVEF ≥ 50% [Time frame: 6 months]
• Global Longitudinal Strain (GLS) ≥ -16% [Time frame: 6 months]
• All-cause mortality [Time frame: 6 months]
• Heart failure hospitalization [Time frame: 6 months]
• Sustained ventricular arrhythmia [Time frame: 6 months]
• Heart transplantation [Time frame: 6 months]
• Heart assistance by extracorporeal membrane oxygenation (ECMO), Intra-aortic balloon pump (IABP), Impella® device or Left Ventricular Assistance Devices (LVAD) [Time frame: 6 months]
• Recurrence of acute myocarditis with LV dysfunction [Time frame: 6 months]
• Safety of the treatment regimens [Time frame: 6 months]
• Adherence to the treatment regimen [Time frame: 6 months]
• Evaluate quality of life using Minnesota living with heart failure questionnaire (MLHFQ) [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Written signed informed consent
• Affiliation to the French health care system or to another social protection scheme with the exception of State Medical Aid
• Active myocarditis defined by (all items are required):

• Acute chest pain and/or unexplained heart failure and/or syncope and/or sustained ventricular arrhythmias and/or aborted sudden death and/or cardiogenic shock and/or ECG modification (atrioventricular block or bundle branch block or sinus arrest or ST or T waves change or ventricular arrhythmia or atrial fibrillation or abnormal Q waves)
• And troponin rise (1,5 times the normal range)
• And diagnosis of active myocarditis on Cardiac Magnetic Resonance (according to Lake-Louise criteria) or by histological evidence on endomyocardial biopsy (Dallas's criteria)
• Left-ventricular dysfunction defined as LVEF < 50% and/or GLS < -16% assessed with 2D-TTE
• Normal coronary angiography or CT Scan (without stenosis > 50%) during the previous year

Exclusion criteria

• Active coronary disease
• Other causes of chronic heart failure (coronary artery disease, primary valvular heart disease, congenital heart disease)
• Other etiology of myocarditis requiring corticosteroids treatment as giant cells myocarditis, eosinophilic myocarditis and cardiac sarcoidosis or immune checkpoint inhibitor myocarditis
• Other auto-immune or inflammatory disease requiring corticosteroids treatment within 6 months before enrolment
• Pregnancy or breastfeeding
• Woman of childbearing potential without effective method of birth control (included contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices)
• Patient deprived of liberty or under Curatorship/Tutorship, safeguard of justice, according to French law
• Foreseeable inability, according to the investigator, to participate in all the visits, treatments and measures provided for in the protocol
• Patient not speaking or understanding French
• Concomitant participation in another clinical trial on medical product for human use, to a clinical investigation on a medical device, to interventional study involving human participants or in the exclusion period at the end of a previous clinical trial on medical product for human use, a clinical investigation on a medical device, or study involving human participants. Participation in non-interventional research is permitted.
• Any medical and/or cognitive condition which limits the ability of participant to participate in study
• Contra-indication linked to steroids (Methylprednisolone and Prednisone) according to summary of product characteristics:

• Any infectious condition excluding the specified therapeutic indications of Methylprednisolone and Prednisone
• Certain evolving viruses (notably hepatitis, herpes, chickenpox, shingles)
• Psychotic states not yet controlled by treatment
• Recent live vaccines or live attenuated vaccines in patients receiving dosages greater than 20 mg/day of prednisone equivalent for more than two weeks and during the 3 months following the cessation of corticosteroid therapy (risk of generalized vaccine disease possibly fatal)
• Hypersensitivity to the active substances or to any of the excipients
• Contra-indication linked to auxiliary drugs according to respective summary of product characteristics:

• Beta-blockade
• Angiotensin-converting-enzyme inhibitor (ACE-I)
• Angiotensin receptor blockers (ARB)
• Mineralocorticoid antagonists (MRA)
• Angiotensin receptor-neprilysin inhibitor (ARNi)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06522100 · APHP230855

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗