Evaluation of Methylprednisolone and Prednisone in Acute Myocarditis with Severe Left Ventricular Dysfunction: A Multicenter Randomized Controlled Trial

The primary objective of this study is to evaluate the efficacy of a pulse of **Methylprednisolone** IV for 3 days at diagnosis followed by **Prednisone** per os, compared to placebo, in patients with acute myocarditis and left-ventricular dysfunction. The focus is on the occurrence of Major Cardiovascular Events (MACE) and/or the persistence of left ventricular dysfunction, defined as left ventricular ejection fraction (LVEF) < 50% and/or Global Longitudinal Strain (GLS) < -16% between baseline and at 6 months. This is clinically relevant as it aims to determine the potential benefits of glucocorticoid therapy in improving cardiac function and reducing adverse cardiovascular outcomes in this patient population.

Secondary objectives include: - Improvement in LVEF ≥ 50% and GLS ≥ -16% between baseline and 6 months. - All-cause mortality. - Heart failure hospitalization. - Sustained ventricular arrhythmia. - Heart transplantation. - Heart assistance by extracorporeal membrane oxygenation (ECMO), Intra-aortic balloon pump (IABP), Impella device, or Left Ventricular Assistance Devices (LVAD). - Recurrence of acute myocarditis with left ventricular dysfunction. - Safety of adverse events, including nosocomial infection and the appearance of insulin-dependent diabetes. - Adherence to the treatment regimen. - Evaluation of quality of life using the Minnesota Living with Heart Failure Questionnaire (MLHFQ).

The clinical trial involves **patients** diagnosed with acute myocarditis, confirmed through cardiac magnetic resonance imaging or histological evidence from an endomyocardial biopsy. The study population includes both male and female participants aged 18 years and older. Participants are required to have left-ventricular dysfunction, defined as a left ventricular ejection fraction (LVEF) of less than 50% or a global longitudinal strain (GLS) of less than -16%, as assessed by 2D transthoracic echocardiography. The trial population was selected based on specific inclusion criteria, including active myocarditis symptoms such as chest pain, heart failure, or syncope, and a troponin rise of 1.5 times the normal range. Participants must have normal coronary angiography or CT scan results, with no stenosis greater than 50% in the previous year. The trial includes a vulnerable population, and all participants must provide written informed consent and be affiliated with the French healthcare system or a similar social protection scheme. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **methylprednisolone** and **prednisone** in patients with acute myocarditis and severe left ventricular dysfunction. This is a multicenter, randomized, controlled trial with a double-blind design. The trial aims to assess the impact of a three-day intravenous pulse of methylprednisolone followed by oral prednisone, compared to placebo, on the occurrence of major cardiovascular events (MACE) and the persistence of left ventricular dysfunction over a six-month period. The trial is expected to commence recruitment on March 1, 2025, and conclude by September 16, 2028.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are confirmed, including age (≥18 years), informed consent, and diagnosis of active myocarditis with left ventricular dysfunction. The inclusion visit will also involve baseline assessments such as cardiac magnetic resonance imaging or endomyocardial biopsy to confirm myocarditis, and 2D trans-thoracic echocardiography (2D-TTE) to evaluate left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Follow-up visits will occur at regular intervals to monitor treatment compliance, adverse events, and changes in cardiac function, with the primary endpoint being assessed at six months. The end-of-study visit will finalize data collection and evaluate long-term outcomes.

Participant involvement is expected to last approximately six months, with conditions for early termination including withdrawal of consent, significant adverse events, or non-compliance with the study protocol. The primary endpoint focuses on the occurrence of MACE and/or persistence of left ventricular dysfunction, while secondary endpoints include changes in LVEF and GLS, all-cause mortality, hospitalization for heart failure, and quality of life improvements. The trial will utilize both active treatment and placebo groups to ensure robust data collection and analysis.

The clinical trial involves the administration of **PREDNISONE**, marketed as PREDNISONE ARROW 20 mg, comprimé sécable. This medication is provided in tablet form and is intended for oral administration. The active substance, prednisone, is of chemical origin. The maximum daily dose is 90 mg, with a total maximum dose of 7740 mg over a treatment period of up to 174 days. The administration schedule involves a daily oral intake, and participant compliance is monitored through regular assessments.

In addition to the experimental medication, a **placebo** of prednisone is utilized in the study. This placebo is designed to mimic the appearance and administration route of the active prednisone tablets but contains no active pharmaceutical ingredients. The placebo is administered orally in a similar dosing schedule to the active treatment to maintain blinding in the trial.

The trial also includes the use of **Methylprednisolone**, provided as a 500 mg powder and solvent for solution for injection/infusion. This medication is administered intravenously. The active substance, methylprednisolone, is also of chemical origin. The maximum daily dose is 500 mg, with a total maximum dose of 1500 mg over a treatment period of 3 days. The administration involves a pulse therapy approach, with compliance monitored through infusion records and participant follow-up.

A **placebo** of methylprednisolone, consisting of glucose 5%, is used as a comparator in the study. This placebo is administered intravenously and is designed to match the administration schedule of the active methylprednisolone treatment, ensuring the study remains double-blind. The placebo contains no active pharmaceutical ingredients and serves to maintain the integrity of the trial's blinding process.

The efficacy of the clinical trial will be assessed by evaluating the impact of glucocorticoid therapy on patients with acute myocarditis and severe left ventricular dysfunction. The primary endpoint for efficacy evaluation is the occurrence of Major Cardiovascular Events (MACE) and/or the persistence of left ventricular dysfunction, defined as a left ventricular ejection fraction (LVEF) of less than 50% and/or a Global Longitudinal Strain (GLS) of less than -16%, measured between baseline (D-2) and at 6 months (M6). MACE is a composite criterion that includes all-cause mortality, heart failure hospitalization, sustained ventricular arrhythmia, heart transplantation or assistance, and recurrent acute myocarditis with left ventricular dysfunction at 6 months.

Secondary endpoints include changes in LVEF and GLS at 6 months, all-cause mortality, hospitalization for heart failure, sustained ventricular arrhythmia, heart transplantation, heart assistance by devices such as extracorporeal membrane oxygenation (ECMO), and time to recurrence of acute myocarditis with left ventricular dysfunction. Additional secondary measures include adverse events, compliance to treatment, and quality of life improvements assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Efficacy parameters will be collected and analyzed using 2D trans-thoracic echocardiography (2D-TTE) at specified timepoints, including baseline and 6 months, to ensure accurate and reliable assessment of treatment outcomes.