MYTHS-MR Trial (MYocarditis THerapy With Steroids in Patients With Mildly Reduced Ejection Fraction) — MYTHS-MR  

Myocarditis Acute Clinical Trial

Official title: Single-blind, Investigator-initiated, Randomized, Controlled Trial to Assess the Safety and Efficacy of Intravenous Corticosteroid Therapy to Treat Patients With Acute Myocarditis With Mildly Reduced Left Ventricular Ejection Fraction

Status Not yet recruiting

Clinical Trial Summary

The goal of this clinical trial is to demonstrate the efficacy of pulsed intravenous methylprednisolone in a single-blind randomized controlled trial versus standard therapy in patients with acute myocarditis and a mildly reduced LVEF. The main question[s] it aims to answer are: - is there an increase in LVEF (≥55% or an absolute increase in LVEF ≥ 10%) on echocardiogram after 5 days from randomization in patients treated with pulsed corticosteroid therapy vs. standard therapy? - is there a reduction in the proportion of patients with LVEF < 55% AND/OR LV dilation on a 6-month CMRI in patients treated pulsed corticosteroid therapy vs. standard therapy? - To assess the effect of corticosteroids on the occurrence of the combined endpoint(1) all-cause death or (2) HTx or (3) long-term LVAD implant or (4) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block. Participants will be randomized in two arms in a 1:1 ratio. The experimental group will receive pulsed corticosteroid therapy on top of the standard therapy and patients in the control group will be treated with a saline solution on top of their standard therapy. All other tests are executed according to standard of care.

Clinical Trial Description

Acute myocarditis (AM) is a common condition characterized by histological evidence of inflammatory infiltrates associated with myocyte necrosis of non-ischemic origin. The clinical presentation spans from indolent to mildly symptomatic forms complicated by ventricular arrhythmias or acute heart failure (HF). Patients can be stratified based on their clinical presentation: patients with left ventricular (LV) ejection fraction (EF)<50% at first echocardiogram, and those with sustained ventricular arrhythmias, called complicated AM, have a worse prognosis compared with uncomplicated cases with preserved LVEF and without arrhythmias. The pathogenesis of AM is felt to be due to an autoimmune response to the myocardium. As such, the investigator's overall objective is to evaluate the efficacy of pulsed intravenous (IV) corticosteroids therapy for the treatment of AM. The investigators propose to test the efficacy of pulsed intravenous methylprednisolone in a single-blind randomized controlled trial versus standard therapy in patients with AM and a mildly reduced LVEF. In the companion clinical trial called MYTHS trial (MYocarditis THerapy with Steroids - EudraCT number 2021-000938-34) more severe patients are recruited. Patients in the MYTHS trial present an AM with a LVEF<41% and signs of acute HF defined by a significant increase in natriuretic peptides (N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 1600 pg/mL or more or a B-type natriuretic peptide [BNP] concentration of 400 pg/mL or more). The MYTHS trial tests whether IV methylprednisolone (1 g daily for 3 days diluted in saline solution 250 mL) on top of standard therapy and maximal supportive care can reduced a composite outcome at 6-month follow up compared to patients in the control arm receiving placebo (IV saline solution 250 mL daily for 3 days). The rationale for using pulsed corticosteroid therapy in the acute setting (within 3 weeks from cardiac symptoms' onset) to reduce myocardial inflammatory infiltrates favouring recovery appears strong, even if no evidence exists from available clinical trials. Nevertheless, no trial has tested this hypothesis in the very acute phase of AM, despite the relatively high mortality rate of this condition and the fact that AM mainly affects young patients. Currently, no specific medications in patients with AM and mildly reduced LVEF are recommended beyond the initiation of recommended HF therapies. One Cochrane review on corticosteroids showed that almost all studies focused on inflammatory cardiomyopathies with 6 months of symptoms of HF, and despite an improvement of cardiac function observed in low-quality and small-size studies, there was no improvement in the survival. In the past, only one study assessed the efficacy of immunosuppression in AM, the Myocarditis Treatment Trial (MTT) that reported no benefit from immunosuppression. Neutral results in the MTT could be ascribed to a delay in the initiation of this potentially effective treatment, in fact per protocol patients were enrolled between 2 weeks and 1 year from cardiac symptoms' onset. Thus, 55% of patients started immunosuppressive therapy after 1 month from the onset of myocarditis, when the LV was already dilated, as highlighted by a mean LV end-diastolic diameter (EDD) of 64 mm. It is expected that patients with AM and mildly reduced LVEF have normal LV dimension during the acute phase. Based on a study from the study group, researchers observed that FM patients recover most of the LVEF in the first 2 weeks after admission, with a median absolute increase of 30%. This finding further suggests that an immunosuppressive treatment should be started as soon as possible to demonstrate effectiveness. As little has changed in the medical treatment of this condition in the last 30 years, identification of effective drugs is needed. Within the associated MYTHS trial the primary composite endpoint that is assessed at 6 months is defined as the time from randomization to the first event occurring within 6 months including (1) all-cause death, or (2) heart transplantation (HTx), or (3) long-term LV assist device (LVAD) implant, or (4) need for an upgrading of the temporary mechanical circulatory support (t-MCS), or (5) a ventricular tachycardia (VT)/fibrillation (VF) treated with direct current (DC) shock (excluding VT/VF in patients on t-MCS other than intra-aortic balloon pump [IABP]), or (6) first rehospitalization due to HF or ventricular arrhythmias, or advanced atrioventricular (AV) block. Although fulminant myocarditis is associated with worse outcome, patients with AM complicated by LV systolic dysfunction (LVEF<50% on initial echocardiogram exam) can also experience clinical events and have decreased LVEF at discharge and long-term followup. For this reason, the investigators would like to assess whether methylprednisolone (at a dosage that is lower than in the MYTHS trial) can speed up the recovery of the LVEF and potentially improve the outcome of these patients in the follow up without increasing the risk of significant safety endpoints. In the MYHTS-MR the investigators will therefore focus on AM with a mildly reduced ejection fraction (LVEF <50% on initial echocardiogram exam). ;

Related Conditions & MeSH terms

• Myocarditis
• Myocarditis Acute

• NCT number: NCT05974462
• Study type: Interventional
• Source: University Hospital, Antwerp
• Contact: Caroline Van De Heyning, MD PhD
• Phone: +32 821 3538
• Email: caroline.vandeheyning@uza.be
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 1, 2024
• Completion date: October 1, 2028