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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Myocarditis Acute

Intervention / Treatment
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* Drug: Methylprednisolone 125 MG [Solu-Medrol]
* Other: IV saline solution 250 mL [Placebo]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: LVEF<50% and LV-EDD<56 mm (parasternal long-axis view) on echocardiogram; Increased troponin (3x URL) at the time of randomization; Clinical onset of cardiac symptoms within 3 weeks from randomization; Excluded coronary artery disease by coronary angiogram in subjects ≥46 years of age, in case myocarditis is not histologically proven; Randomization within 120 hours from hospital admission. Endomyocardial biopsy (EMB) is not considered necessary before randomization and performing EMB is based on the decision of the local team. Exclusion Criteria: Known systemic autoimmune disorder or other conditions at the time of randomization where immunosuppression is assumed useful. Patients in whom a systemic autoimmune disorder will be diagnosed during hospitalization will be included in the study if randomized, including patients with a diagnosis of cardiac sarcoidosis or GCM). Both patients included in the corticosteroids-treatment arm or in the placebo-treatment arm can receive the standard immunosuppressive therapy used in the center since the diagnosis; Patients already on oral/IV chronic corticosteroid therapy or other chronic immunosuppressive therapies (colchicine or nonsteroidal anti-inflammatory drugs [NSAIDs] are not considered immunosuppressive drugs); Contraindication to corticosteroids, including allergies to this medication and its excipients; Patients with persistent peripheral eosinophilia (persistent eosinophil count >7% of the leukocytes) or known hypereosinophilic syndrome at the time of randomization. Patients in whom eosinophilic myocarditis will be diagnosed on EMB will be included in the study if already randomized. Both patients included in the corticosteroids-treatment arm or in the placebo-treatment arm can receive the standard immunosuppressive therapy used in the center since the diagnosis; Myocarditis associated with the ongoing administration of anti-cancer immune checkpoint inhibitor (ICI) agents; Previously known chronic cardiac (i.e., previous cardiomyopathy, that does NOT include previous myocarditis if there is a functional recovery at the time of screening); Evidence of active bacterial or fungal infectious disease (presence of fever or increased C-reactive protein are not considered exclusion criteria), or suspected bacterial/fungal infection associated with increased levels of procalcitonin (cut-off >10 ng/mL), if the laboratory exam is available in the center; Known chronic infective disease, such as HIV infection or tuberculosis; Out-of-hospital cardiac arrest; Echocardiographic presence of images suggestive of other cardiac diseases (i.e. endocarditis) Participants involved in another clinical trial; Pregnant women (known pregnancy) or POSITIVE human chorionic gonadotropin (HCG) test measures (urine/blood) for women of 18-50 years of age. Any other significant disease with expected life expectancy <12 months (i.e., evidence of irreversible severe brain injury) or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial. If LVEF<41%, an 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; (if LVEF 41%-<50% any NT-proBNP or BNP concentration is allowed).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single Blind, Investigator-initiated, Randomized Controlled Trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Standard therapy<br>IV saline solution 250 mL daily for 3 days on top of standard therapy. | Other: IV saline solution 250 mL [Placebo]<br>* Saline solution 250 mL<br>|
| Experimental: Pulsed corticosteroid therapy<br>IV methylprednisolone 125 mg daily for 3 days diluted in saline solution 250 ml on top of standard therapy. | Drug: Methylprednisolone 125 MG [Solu-Medrol]<br>* 125 mg daily for 3 days diluted in saline solution 250 mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction | LVEF ≥55% or an absolute increase in LVEF≥10% on echocardiogram after 5 days from randomization (echocardiographic clips will be centrally reviewed in a blind fashion by readers). | Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of the composite endpoint | Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI) (CMRI clips will be centrally reviewed in a blind fashion by readers) | 6 months | 
| Composite endpoint defined as the time from randomization to the first event | among: (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. | Within 6 months and 2 years |