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

Trial ID: 2022-501547-33-01
Protocol: MYTHSMR2023-07
Sponsor: Universitair Ziekenhuis Antwerpen

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Diseases & Conditions

Myocarditis Viral myocarditis Myocarditis post infection

Objectives

The primary objective of this study is to evaluate the efficacy of **intravenous corticosteroid therapy** in patients with **acute myocarditis** and a mildly reduced left ventricular ejection fraction (LVEF). The study aims to demonstrate an increase in the rate of achieving the primary composite endpoint, defined as LVEF ≥55% or an absolute increase in LVEF ≥10% on echocardiogram, after 5 days from randomization in patients treated with pulsed corticosteroid therapy compared to those receiving standard therapy. This objective is clinically relevant as it seeks to improve cardiac function and outcomes in patients with acute myocarditis, a condition that can lead to significant morbidity.

Secondary objectives include demonstrating the superiority of treatment with corticosteroids compared to maximal supportive therapy. This aspect of the study is important for determining the potential benefits of corticosteroids in enhancing treatment efficacy beyond standard supportive measures.

Participants

The clinical trial focuses on patients diagnosed with **acute myocarditis**. The study population includes both male and female participants aged between 18 and 69 years. Participants are required to have a left ventricular ejection fraction (LVEF) of less than 50% and a left ventricular end-diastolic dimension (LV-EDD) of less than 56 mm, as measured by echocardiogram. Additionally, participants must exhibit increased troponin levels, specifically three times the upper reference limit, at the time of randomization. The trial excludes individuals with coronary artery disease, confirmed by coronary angiogram, in subjects aged 46 years or older unless myocarditis is histologically proven. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific clinical criteria, including the onset of cardiac symptoms within three weeks from randomization and randomization occurring within 120 hours from hospital admission. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial does not require an endomyocardial biopsy before randomization, leaving the decision to perform such a procedure to the discretion of the local medical team. All participants have provided informed consent approved by an Ethics Committee or institutional review board.

Plans and Procedures

The clinical trial is designed as a **single-blind**, investigator-initiated, randomized, controlled study to evaluate the safety and efficacy of intravenous corticosteroid therapy in patients with **acute myocarditis** and mildly reduced left ventricular ejection fraction (LVEF). The trial aims to demonstrate an increase in the rate of the primary composite endpoint, which includes achieving an LVEF of 55% or an absolute increase in LVEF of 10% on echocardiogram after five days from randomization. The study will involve the administration of **methylprednisolone sodium succinate** and **sodium chloride** as a solution for infusion, with a maximum treatment period of three days.

Participants will be randomly assigned to receive either the corticosteroid therapy or standard therapy. The trial is expected to commence recruitment on March 1, 2024, and conclude by May 1, 2028. The inclusion criteria require participants to be aged between 18 and 69 years, with an LVEF of less than 50% and left ventricular end-diastolic dimension (LV-EDD) of less than 56 mm on echocardiogram, among other specific clinical parameters. Exclusion criteria are not explicitly detailed in the provided data.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by randomization within 120 hours of hospital admission. Participants will undergo an endomyocardial biopsy if deemed necessary by the local team. Follow-up visits will be conducted to assess primary and secondary endpoints, including cardiac magnetic resonance imaging (CMRI) at six months, and quality of life assessments at two and six months. The end-of-study visit will occur at the conclusion of the participant's involvement, which may last up to two years, depending on the occurrence of specific clinical events.

Participant involvement is expected to last for the duration of the trial, with early termination possible if adverse events occur or if the participant withdraws consent. The trial will monitor several secondary endpoints, such as the reduction in the proportion of patients with LVEF less than 55% on six-month CMRI, and the time to first event of all-cause death or hospitalization due to heart failure within six months and two years. The study will also evaluate the recurrence of acute myocarditis and other related clinical outcomes.

Treatment

The clinical trial involves the administration of **Sodium Chloride** as a **solution for infusion**. This experimental medication is utilized as a vehicle for the delivery of other active substances. The **Sodium Chloride** solution is administered via infusion, with a maximum daily dose of 250 ml and a total maximum dose of 750 ml over a treatment period of up to 3 days. The solution is not a pediatric formulation and is classified under the role of a test product in the trial. The chemical origin of the active substance ensures its suitability for the intended use in the study.

**Solu-Medrone 125 mg**, containing the active substance **Methylprednisolone Sodium Succinate**, is employed as the primary experimental treatment in this trial. It is provided as a **solution for injection** and is administered via infusion. The maximum daily dose is 125 mg, with a total maximum dose of 375 mg over a treatment period of up to 3 days. This medication is not formulated for pediatric use and serves as the primary investigational product in the study. The chemical origin of **Methylprednisolone Sodium Succinate** aligns with the trial's objective to evaluate the efficacy of intravenous corticosteroid therapy in patients with acute myocarditis.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the increase in the rate of the primary composite endpoint, defined as left ventricular ejection fraction (LVEF) greater than 55% or an absolute increase in LVEF of 10% on echocardiogram after 5 days from randomization. This will be evaluated in patients treated with pulsed corticosteroid therapy compared to those receiving standard therapy and maximal supportive care.

Secondary endpoints include a variety of measures assessed at different time points. These include the reduction in the proportion of patients with LVEF less than 55% and/or left ventricular dilation on 6-month cardiac magnetic resonance imaging (CMRI), with CMRI clips being centrally reviewed in a blind fashion. Other secondary endpoints involve the proportion of patients with left ventricular dilation on 6-month CMRI, the burden of late gadolinium enhancement (LGE) on 6-month CMRI, and a composite endpoint defined as the time from randomization to the first event such as all-cause death, heart transplantation (HTx), long-term left ventricular assist device (LVAD) implantation, or rehospitalization due to heart failure or ventricular arrhythmias within 6 months and 2 years.

Additional secondary endpoints include mortality, time to hospitalization for heart failure, presence of non-sustained ventricular tachycardia (NSVT) or burden of premature ventricular contractions (PVCs) greater than 10% on 24-hour ECG ambulatory monitoring at 6 months follow-up, and quality of life assessments using the EuroQol 5-dimension, 5-level questionnaire at 2 and 6 months follow-up. The recurrence of acute myocarditis, hospitalization due to recurrence of acute myocarditis, pericarditis, or recurrence of chest pain or atrial fibrillation, and in-hospital composite endpoints are also evaluated. These assessments will be conducted at specified intervals to ensure comprehensive evaluation of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18 years or older and below 70 years (18-69 years)
LVEF<50% and LV-EDD<56 mm (parasternal long-axis view) on echocardiogram
Increased troponin (3x URL) at the time of randomization
Clinically suspected myocarditis with 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
Patient has voluntarily signed and dated an informed consent form (ICF), approved by an Ethics Committee (EC) or institutional review board (IRB), after the nature of the study has been explained and the patient has had the opportunity to ask questions.

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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
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).
Patients already on oral/IV chronic corticosteroid therapy or other chronic immunosuppressive therapies
Contraindication to corticosteroids, including history of previous (steroid) psychosis, 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
Myocarditis associated with the ongoing administration of anti-cancer immune checkpoint inhibitor (ICI) agents
Previously known chronic cardiac disease
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 before randomisation
Contraindication for CMRI