Single blind randomized controlled trial to assess the safety and efficacy of high dose pulse intravenous corticosteroid therapy to treat patients with complicated/fulminant acute myocarditis
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 49
- 主要终点
- The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months among: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the 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 IABP), or (6) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
研究概览
简要总结
The primary objective is to demonstrate a reduction in the rate of the primary composite endpoint on patients treated with pulsed corticosteroid therapy vs. standard therapy and maximal supportive care.
详细描述
Acute myocarditis (AM) is a common condition characterized by histological evidence of inflammatory infiltrates associated with myocyte necrosis of non-ischemic origin. Clinical presentation spans from indolent form to cardiogenic shock also called fulminant myocarditis (FM). Patients can be stratified on the basis of 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 left ventricular ejection fraction (LVEF) and without arrhythmias. Among complicated AM, FM patients are those ones at the highest risk, presenting with severely impaired LVEF (generally <40%), and with need for inotropes and/or temporary mechanical circulatory supports (t-MCS).The pathogenesis of AM is felt to be due to an immune-mediated response against the myocardium.
As such, the overall objective is to evaluate the efficacy of pulsed IV corticosteroids therapy for the treatment of AM. It is proposed to test the efficacy of pulsed IV methylprednisolone in a single blind randomized controlled trial versus standard therapy on top of maximal support. The rationale for using pulsed corticosteroid therapy in the acute setting (within 3 weeks from cardiac symptoms' onset) to reduce myocardial inflammatory infiltrates favoring recovery appears strong. Nevertheless, no trial has tested this hypothesis in the very acute phase of AM, despite the high mortality rate of this condition and the fact that AM mainly affects young patients.
Currently, no specific medications in the acute phase of lymphocytic AM are recommended beyond supportive therapy with inotropes and t-MCS. One Cochrane review on corticosteroids showed that almost all studies focused on inflammatory cardiomyopathies with 6 months of symptoms of heart failure (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. Thus, 55% of patients started immunosuppressive therapy after 1 month from the onset of myocarditis, when the left ventricle (LV) was already dilated, as highlighted by a mean LV end-diastolic diameter (EDD) of 64 mm. It is expected that patients with FM have normal LV dimension during the acute phase despite severe LV systolic dysfunction. Based on a study from PI group, it was 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.
Patients admitted to hospital for suspected AM complicated by acute HF/cardiogenic shock and LV systolic dysfunction will be screened for randomization.
Patients will be randomized in the two arms in a 1:1 ratio (Pulsed methylprednisolone therapy vs Placebo). Randomization will be performed with stratification by country.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Age 18 years or older and below 70 years (18-69 years)
- •Acute HF with clinically suspected acute myocarditis based on 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;
- •Left ventricular ejection fraction (LVEF)<41% and left ventricular end diastolic diameter (LV-EDD)<56 mm (parasternal long-axis view) on echocardiogram.
- •Increased troponin (3x upper reference limit [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.
排除标准
- •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.
- •t-MCS instituted more than 72 hours before randomization.
- •Patients clinically judged too sick to initiate t-MCS (i.e., irreversible multiorgan failure).
- •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.
- •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 disease (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.
结局指标
主要结局
The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months among: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the 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 IABP), or (6) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months among: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the 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 IABP), or (6) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
次要结局
- Relative reduction of troponin levels after 5 days from randomization (ratio of troponin level/local troponin URL).
- The time from randomization to the first event occurring within 6 months 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.
- Mortality: time from randomization to all-cause death within 6 months.
- In-hospital composite endpoint is defined as the proportion of patients who experience at least one of the following events during index hospitalization: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the t-MCS, or (5) a VT/VF treated with DC shock (excluding VT/VF in patients on t-MCS other than IABP).
- Number of days on t-MCS from randomization.
- Number of days in ICU from randomization.
- Increase in LVEF on echocardiogram after 5 days from randomization (ECHO clips will be centrally reviewed in a blind fashion by readers).
- Reduction in heart rate (HR) on ECG after 3 days from randomization (ECG recorded at the hour of initial randomization - ECGs will be centrally reviewed in a blind fashion by readers).
- 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).
- Proportion of patients with LVEF<55% on 6-month CMRI (CMRI clips will be centrally reviewed in a blind fashion by readers).
- Proportion of patients with LV dilation on 6-month CMRI (CMRI clips will be centrally reviewed in a blind fashion by readers).
研究者
Dottor Enrico Ammirati
Scientific
ASST Grande Ospedale Metropolitano Niguarda