MYTHS - MYocarditis THerapy With Steroids (MYTHS)
Primary Purpose
Myocarditis Acute
Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Methylprednisolone
saline solution
Sponsored by
About this trial
This is an interventional treatment trial for Myocarditis Acute focused on measuring Acute Myocarditis, Corticosteroid therapy, Myocarditis, Trial, Immunosuppression, Acute heart failure, Fulminant acute myocarditis
Eligibility Criteria
Inclusion Criteria:
- Patients admitted to hospital for suspected AM
- 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 72 hours from hospital admission.
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 giant cell myocarditis (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 of a systemic autoimmune disorder, or cardiac sarcoidosis or GCM;
- 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 peripheral eosinophilia (Eosinophil count >7% of the leukocytes) or known hypereosinophilic syndrome at the time of randomization. Patients in whom eosinophilic myocarditis will be diagnosed on endomyocardial biopsy (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);
- 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;
- Cardiac arrest before randomization or occurrence of out-of-hospital cardiac arrest;
- t-MCS instituted more than 48 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 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.
Sites / Locations
- University of California San DiegoRecruiting
- University of Texas
- University of Virginia
- Virginia Commonwealth University
- Antwerp University HospitalRecruiting
- Jessa Hospital Hasselt
- University Hospitals LeuvenRecruiting
- Masaryk University and St. Anne's University Hospital
- Charles University in Prague and General University Hospital
- Institute for Clinical and Experimental Medicine - IKEM
- Rigshospitalet and University of Copenhagen
- Heart and Lung Center, Helsinki University Hospital
- Hospices Civils de Lyon, Lyon 08, Rhône-Alpes
- Université Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax
- Charité - University Medicine Berlin, Campus Virchow Klinikum
- Onassis Cardiac Surgery Centre
- AOU Ospedali Riuniti Umberto I°-Lancisi-Salesi di AnconaRecruiting
- ASST Papa Giovanni XXIIIRecruiting
- Policlinico S.Orsola-MalpighiRecruiting
- ASST Spedali CiviliRecruiting
- Azienda Ospedaliera "G.Brotzu"Recruiting
- Azienda Ospedaliero-Universitaria CareggiRecruiting
- Ospedale Policlinico San Martino, IRCCSRecruiting
- ASST Grande Ospedale Metropolitano NiguardaRecruiting
- Centro Cardiologico MonzinoRecruiting
- ASST Monza, Ospedale San GerardoRecruiting
- Azienda Ospedaliera Specialistica dei Colli - Ospedale MonaldiRecruiting
- Azienda Ospedaliero Universitaria di ParmaRecruiting
- Fondazione IRCCS Policlinico San MatteoRecruiting
- Fondazione Toscana Gabriele MonasterioRecruiting
- Azienda Ospedaliera San Camillo Forlanini di RomaRecruiting
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSRecruiting
- Azienda Ospedaliera Universitaria Senese, Policlinico Santa Maria alle ScotteRecruiting
- Azienda Ospedaliera Universitaria Città della Salute e della Scienza di TorinoRecruiting
- Presidio Ospedaliero Universitario "Santa Maria della Misericordia"Recruiting
- University Medical Centre LjubljanaRecruiting
- Complexo Hospitalario Universitario A Coruña (CHUAC)Recruiting
- Bellvitge University HospitalRecruiting
- Hospital Universitario Vall d'HebronRecruiting
- Hospital 12 de OctubreRecruiting
- Hospital General Universitario Gregorio Marañón in MadridRecruiting
- Hospital Universitario Puerta de Hierro MajadahondaRecruiting
- Hospital Universitario Virgen de la ArrixacaRecruiting
- Hospital Universitario Virgen de la VictoriaRecruiting
- Sahlgrenska Universitetssjukhuset
- Lund University and Skåne University Hospital
- Karolinska Universitetssjukhuset
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Experimental arm
Control arm
Arm Description
Pulsed corticosteroid therapy (methylprednisolone 1 g IV qd for 3 days diluted in saline solution 250 mL) on top of standard therapy and maximal supportive care
Placebo (saline solution 250 mL IV qd for 3 days) on top of standard therapy and maximal supportive care.
Outcomes
Primary Outcome Measures
Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, need for an upgrading of the t-MCS, VT/VF treated with DC shock, first rehospitalization due to HF or ventricular arrhythmias, or AV block.
The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months on patients treated with pulsed corticosteroid therapy vs. standard therapy and maximal supportive care, among: (1) all-cause death, or (2) heart transplantation (HTx), or (3) long-term left ventricular assist device (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 Atrioventricular (AV) block.
Secondary Outcome Measures
Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
The main secondary composite endpoint is defined as the time from randomization to the first event occurring within 6 months on patients treated pulsed corticosteroid therapy vs. standard therapy and maximal supportive care, 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.
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
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 on t-MCS from randomization
Number of days in ICU from randomization
Number of days in ICU from randomization
Change in LVEF on echocardiogram after 5 days from randomization
Change in LVEF on echocardiogram after 5 days from randomization
Change of troponin levels after 5 days from randomization
Change of troponin levels after 5 days from randomization (ratio of troponin level/local troponin URL).
Change in heart rate (HR) on ECG after 3 days from randomization
Change in heart rate (HR) on ECG after 3 days from randomization (ECG recorded at the hour of initial randomization
Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)
Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)
Proportion of patients with LVEF<55% on 6-month CMRI
Proportion of patients with LVEF<55% on 6-month CMRI
Proportion of patients with LV dilation on 6-month CMRI
Proportion of patients with LV dilation on 6-month CMRI
Full Information
NCT ID
NCT05150704
First Posted
November 14, 2021
Last Updated
September 14, 2023
Sponsor
Niguarda Hospital
Collaborators
Ministry of Health, Italy, Istituto Di Ricerche Farmacologiche Mario Negri, University of Milano Bicocca, Regione Lombardia
1. Study Identification
Unique Protocol Identification Number
NCT05150704
Brief Title
MYTHS - MYocarditis THerapy With Steroids
Acronym
MYTHS
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 7, 2021 (Actual)
Primary Completion Date
March 2028 (Anticipated)
Study Completion Date
December 2028 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Niguarda Hospital
Collaborators
Ministry of Health, Italy, Istituto Di Ricerche Farmacologiche Mario Negri, University of Milano Bicocca, Regione Lombardia
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a phase III, multi-center international, single blind randomized controlled trial to test the efficacy of pulsed intravenous (IV) methylprednisolone versus standard therapy on top of maximal support in patients with Acute myocarditis (AM).
Detailed Description
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.
The primary objective is to demonstrate a reduction in the rate of the primary composite endpoint on patients treated with pulsed methylprednisolone therapy vs. standard therapy and maximal supportive care.
Endpoints will be analyzed according to the following principles:
Intention-to-treat (ITT) population
Per Protocol (PP) population:
"Safety population"
A sensitivity analysis will also be performed on the previously defined populations after excluding patients (1) with histological diagnosis of giant cell myocarditis (GCM) or (2) who did not reach the final diagnosis of acute myocarditis based on CMRI or histology.
Sample size calculation: we plan to recruit a total of 360 patients, and we expect that about 20% of these patients or local physicians will refuse randomization. This would leave a total of 288 randomized patients (144 per arm).
Considering as relevant a reduction in the probability to reach the primary endpoint at 6 months from 25% in the standard therapy on top of maximal supportive care arm to 12% in the pulsed corticosteroid therapy arm (absolute risk reduction of 13% in absolute corresponding to a hazard ratio (HR) pulsed corticosteroid therapy vs. standard therapy of 0.44), the planned sample size will allow achieving a power of 0.80 with a one-sided log-rank test and an overall type I error of 0.025. The 25% figure considered for the standard therapy derives from a retrospective analysis of the patient's cohort spanning over 20 years. The calculation includes an interim analysis planned at 50% recruitment (O'Brien-Fleming method). This interim analysis is accounted for in the sample size calculation with an alpha level of 0.001525 (final analysis 0.023475 alpha level) and is planned on the primary endpoint to assess a possible early treatment effect. No specific stopping rules are planned, given the multiplicity of aspects involved, but the report on safety will be reviewed by the Data and Safety Monitoring Committee (DSMC) will advise on possible aspects of the trial that need reconsideration.
Sample size adaptation: We will consider, based on the DSMC advise an adaptive approach to sample size in two regards:
At the interim analysis, if the baseline incidence is lower than the expected 25%, the sample size calculation may be re-evaluated keeping the same HR of 0.44. For instance, if the observed incidence is 20%, maintaining the same HR of 0.44 (corresponding to an incidence of 9% in the pulsed corticosteroid therapy group, i.e. 11% in absolute risk reduction) the effective sample size needed to achieve 80% power should be increased to 360 patients. If the baseline incidence is higher than 25%, the planned actual sample size will achieve a power greater than 80% to detect a HR of 0.44 and no action will be taken.
Based on the conditional power method, and on the DSMC advise, we may reconsider if a less promising result than HR=0.4444 is worth pursuing, given the current observed estimate. This case would require an increase in sample size that will be discussed in terms of relevance and feasibility. For example, if at the planned interim analysis, the estimated absolute risk reduction is at least 10% (HR=0.56) with 25% baseline, and the conditional power of meeting this 10% target (instead of the planned 13%) would be at least 60%, the sample size may be increased to reach the 80% desired power. In this case, the final effective sample size should be increased to 254 patients per arm to preserve an 80% power of demonstrating the less marked difference. The flexibility allowed in the sample size estimate will be considered based on the evaluation of the interim report by the DSMC and no data will be disclosed on interim treatment estimates to the study coordinator and steering committee.
The overall duration of the study from first patient first visit to last patient last visit will be 39 months. The follow-up will be up to 6 months and with additional 3 months to lock the database. Enrollment will last 30 months.
In parallel, there will be a prospective registry of patients that are eligible for the trial, but they are not randomized.
A second registry, called MYOCARDITIS REGISTRY will prospectively recruit all patients with acute myocarditis demonstrated by CMRI or EMB who are not eligible for randomization (not all centers will take part in this registry).
The study is supported by a grant from Italian Ministry of Health (GR-2019-12368506) and Lombardy Region.
Exemption from the investigational new drug (IND) regulations by FDA on August 2nd, 2021 (PIND: 15727)
EudraCT identifier: 2021-000938-34
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myocarditis Acute
Keywords
Acute Myocarditis, Corticosteroid therapy, Myocarditis, Trial, Immunosuppression, Acute heart failure, Fulminant acute myocarditis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Single blind randomized controlled trial
Masking
Participant
Allocation
Randomized
Enrollment
288 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Experimental arm
Arm Type
Experimental
Arm Description
Pulsed corticosteroid therapy (methylprednisolone 1 g IV qd for 3 days diluted in saline solution 250 mL) on top of standard therapy and maximal supportive care
Arm Title
Control arm
Arm Type
Placebo Comparator
Arm Description
Placebo (saline solution 250 mL IV qd for 3 days) on top of standard therapy and maximal supportive care.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Intervention Description
Pulsed corticosteroid therapy (methylprednisolone 1 g IV qd for 3 days diluted in saline solution 250 mL) on top of standard therapy and maximal supportive care
Intervention Type
Drug
Intervention Name(s)
saline solution
Intervention Description
Placebo (saline solution 250 mL IV qd for 3 days) on top of standard therapy and maximal supportive care.
Primary Outcome Measure Information:
Title
Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, need for an upgrading of the t-MCS, VT/VF treated with DC shock, first rehospitalization due to HF or ventricular arrhythmias, or AV block.
Description
The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months on patients treated with pulsed corticosteroid therapy vs. standard therapy and maximal supportive care, among: (1) all-cause death, or (2) heart transplantation (HTx), or (3) long-term left ventricular assist device (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 Atrioventricular (AV) block.
Time Frame
6 months from patients enrollment
Secondary Outcome Measure Information:
Title
Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
Description
The main secondary composite endpoint is defined as the time from randomization to the first event occurring within 6 months on patients treated pulsed corticosteroid therapy vs. standard therapy and maximal supportive care, 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.
Time Frame
6 months from patients enrollment
Title
Mortality
Description
Time from randomization to all-cause death within 6 months.
Time Frame
6 months from patients enrollment
Title
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
Description
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).
Time Frame
6 months from patients enrollment
Title
Number of days on t-MCS from randomization
Description
Number of days on t-MCS from randomization
Time Frame
6 months from patients enrollment
Title
Number of days in ICU from randomization
Description
Number of days in ICU from randomization
Time Frame
6 months from patients enrollment
Title
Change in LVEF on echocardiogram after 5 days from randomization
Description
Change in LVEF on echocardiogram after 5 days from randomization
Time Frame
5 days from randomization
Title
Change of troponin levels after 5 days from randomization
Description
Change of troponin levels after 5 days from randomization (ratio of troponin level/local troponin URL).
Time Frame
5 days from randomization
Title
Change in heart rate (HR) on ECG after 3 days from randomization
Description
Change in heart rate (HR) on ECG after 3 days from randomization (ECG recorded at the hour of initial randomization
Time Frame
3 days from randomization
Title
Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)
Description
Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)
Time Frame
6 months from patients enrollment
Title
Proportion of patients with LVEF<55% on 6-month CMRI
Description
Proportion of patients with LVEF<55% on 6-month CMRI
Time Frame
6 months from patients enrollment
Title
Proportion of patients with LV dilation on 6-month CMRI
Description
Proportion of patients with LV dilation on 6-month CMRI
Time Frame
6 months from patients enrollment
Other Pre-specified Outcome Measures:
Title
Safety endpoints
Description
Incidence of serious infections within 6 months;
Incidence of infections needing an IV therapy, excluding prophylactic antibiotic therapy within 6 months;
Incidence of upper gastrointestinal bleeding needing therapeutic endoscopy to achieve acute hemostasis;
Acute psychosis leading to the use of neuroleptic agents;
Incidence of critical illness myopathy or/and polyneuropathy (CIM/CIP);
Incidence of aseptic necrosis of femoral and humeral heads;
Incidence of stroke;
Incidence of need for pace-maker (both temporary and permanent);
Incidence of need for pericardiocentesis;
Incidence of need for mechanical ventilation after randomization;
Incidence of need for continuous venovenous hemofiltration (CVVH);
Incidence of bleeding requiring ≥5 units of blood or packed red blood cells.
Time Frame
6 months from patients enrollment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
69 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients admitted to hospital for suspected AM
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.
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 giant cell myocarditis (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 of a systemic autoimmune disorder, or cardiac sarcoidosis or GCM;
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 endomyocardial biopsy (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;
t-MCS instituted more than 48 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Enrico Ammirati, MD, PhD
Phone
+39 0264447791
Email
enrico.ammirati@ospedaleniguarda.it
Facility Information:
Facility Name
University of California San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eric D Adler, MD
Facility Name
University of Texas
City
Houston
State/Province
Texas
ZIP/Postal Code
77204
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Angelo Nascimbene, MD
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22903
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antonio Abbate, MD
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23284
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roshanak Markley, MD
Facility Name
Antwerp University Hospital
City
Edegem
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Caroline Van De Heyning, MD
Facility Name
Jessa Hospital Hasselt
City
Hasselt
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Philippe Jr Timmermans, MD
Facility Name
University Hospitals Leuven
City
Leuven
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christophe Vandenbriele, MD
Facility Name
Masaryk University and St. Anne's University Hospital
City
Brno
Country
Czechia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Krejčí, MD
Facility Name
Charles University in Prague and General University Hospital
City
Prague
Country
Czechia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Petr Kuchynka, MD
Facility Name
Institute for Clinical and Experimental Medicine - IKEM
City
Prague
Country
Czechia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vojtech Melenovsky, MD
Facility Name
Rigshospitalet and University of Copenhagen
City
Copenhagen
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Finn Gustafsson, MD
Facility Name
Heart and Lung Center, Helsinki University Hospital
City
Helsinki
Country
Finland
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jukka Lehtonen, MD
Facility Name
Hospices Civils de Lyon, Lyon 08, Rhône-Alpes
City
Lyon
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas Bochaton, MD
Facility Name
Université Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax
City
Nantes
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas Piriou, MD
Facility Name
Charité - University Medicine Berlin, Campus Virchow Klinikum
City
Berlin
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carsten Tschope, MD
Facility Name
Onassis Cardiac Surgery Centre
City
Athens
Country
Greece
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Angelica Gkouziouta, MD
Facility Name
AOU Ospedali Riuniti Umberto I°-Lancisi-Salesi di Ancona
City
Ancona
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marco Marini, MD
First Name & Middle Initial & Last Name & Degree
Marco Marini, MD
Facility Name
ASST Papa Giovanni XXIII
City
Bergamo
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aurelia Grosu, MD
First Name & Middle Initial & Last Name & Degree
Aurelia Grosu, MD
Facility Name
Policlinico S.Orsola-Malpighi
City
Bologna
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Luciano Potena, MD
First Name & Middle Initial & Last Name & Degree
Luciano Potena, MD
Facility Name
ASST Spedali Civili
City
Brescia
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marco Metra, MD
First Name & Middle Initial & Last Name & Degree
Marco Metra, MD
Facility Name
Azienda Ospedaliera "G.Brotzu"
City
Cagliari
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marco Corda, MD
First Name & Middle Initial & Last Name & Degree
Marco Corda, MD
Facility Name
Azienda Ospedaliero-Universitaria Careggi
City
Firenze
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Iacopo Olivotto, MD
First Name & Middle Initial & Last Name & Degree
Iacopo Olivotto, MD
Facility Name
Ospedale Policlinico San Martino, IRCCS
City
Genova
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roberta Della Bona, MD
First Name & Middle Initial & Last Name & Degree
Roberta Della Bona, MD
Facility Name
ASST Grande Ospedale Metropolitano Niguarda
City
Milano
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Enrico Ammirati, MD
Phone
02 6444 7791
Email
enrico.ammirati@ospedaleniguarda.it
First Name & Middle Initial & Last Name & Degree
Enrico Ammirati, MD
Facility Name
Centro Cardiologico Monzino
City
Milano
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeness Campodonico, MD
First Name & Middle Initial & Last Name & Degree
Jeness Campodonico, MD
Facility Name
ASST Monza, Ospedale San Gerardo
City
Monza
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Davide Corsi, MD
First Name & Middle Initial & Last Name & Degree
Davide Corsi
Facility Name
Azienda Ospedaliera Specialistica dei Colli - Ospedale Monaldi
City
Napoli
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesco Loffredo, MD
First Name & Middle Initial & Last Name & Degree
Francesco Loffredo, MD
Facility Name
Azienda Ospedaliero Universitaria di Parma
City
Parma
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Diego Ardissino, MD
First Name & Middle Initial & Last Name & Degree
Diego Ardissino, MD
Facility Name
Fondazione IRCCS Policlinico San Matteo
City
Pavia
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rita Camporotondo, MD
First Name & Middle Initial & Last Name & Degree
Rita Camporotondo, MD
Facility Name
Fondazione Toscana Gabriele Monasterio
City
Pisa
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michele Emdin, MD
First Name & Middle Initial & Last Name & Degree
Michele Emdin, MD
Facility Name
Azienda Ospedaliera San Camillo Forlanini di Roma
City
Roma
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Leonardo De Luca, MD
First Name & Middle Initial & Last Name & Degree
Leonardo De Luca, MD
Facility Name
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
City
Roma
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Lucia Narducci, MD
First Name & Middle Initial & Last Name & Degree
Maria Lucia Narducci, MD
Facility Name
Azienda Ospedaliera Universitaria Senese, Policlinico Santa Maria alle Scotte
City
Siena
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Serafina Valente, MD
First Name & Middle Initial & Last Name & Degree
Serafina Valente, MD
Facility Name
Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
City
Torino
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaetano De Ferrari, MD
First Name & Middle Initial & Last Name & Degree
Gaetano De Ferrari, MD
Facility Name
Presidio Ospedaliero Universitario "Santa Maria della Misericordia"
City
Udine
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Massimo Imazio, MD
First Name & Middle Initial & Last Name & Degree
Massimo Imazio, MD
Facility Name
University Medical Centre Ljubljana
City
Ljubljana
Country
Slovenia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andreja Černe, MD
Facility Name
Complexo Hospitalario Universitario A Coruña (CHUAC)
City
A Coruña
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria G Crespo-Leiro, MD
Facility Name
Bellvitge University Hospital
City
Barcelona
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Albert Ariza Sole, MD
Facility Name
Hospital Universitario Vall d'Hebron
City
Barcelona
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aitor Uribarri, MD
Facility Name
Hospital 12 de Octubre
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vanesa Bruña, MD
Facility Name
Hospital General Universitario Gregorio Marañón in Madrid
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Manuel Martínez Sellés, MD
Facility Name
Hospital Universitario Puerta de Hierro Majadahonda
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fernando Domínguez, MD
Facility Name
Hospital Universitario Virgen de la Arrixaca
City
Murcia
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Domingo Pascual, MD
Facility Name
Hospital Universitario Virgen de la Victoria
City
Málaga
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jose Manuel Garcia-Pinilla, MD
Facility Name
Sahlgrenska Universitetssjukhuset
City
Göthenburg
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Entela Bollano, MD
Facility Name
Lund University and Skåne University Hospital
City
Lund
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Oscar Braun, MD
Facility Name
Karolinska Universitetssjukhuset
City
Stockholm
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Melin, MD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33176455
Citation
Ammirati E, Frigerio M, Adler ED, Basso C, Birnie DH, Brambatti M, Friedrich MG, Klingel K, Lehtonen J, Moslehi JJ, Pedrotti P, Rimoldi OE, Schultheiss HP, Tschope C, Cooper LT Jr, Camici PG. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. Circ Heart Fail. 2020 Nov;13(11):e007405. doi: 10.1161/CIRCHEARTFAILURE.120.007405. Epub 2020 Nov 12.
Results Reference
background
PubMed Identifier
31902242
Citation
Kociol RD, Cooper LT, Fang JC, Moslehi JJ, Pang PS, Sabe MA, Shah RV, Sims DB, Thiene G, Vardeny O; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association. Circulation. 2020 Feb 11;141(6):e69-e92. doi: 10.1161/CIR.0000000000000745. Epub 2020 Jan 6.
Results Reference
background
PubMed Identifier
29764898
Citation
Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, Mafrici A, Grosu A, Briguglia D, Guglielmetto S, Perego GB, Colombo S, Caico SI, Giannattasio C, Maestroni A, Carubelli V, Metra M, Lombardi C, Campodonico J, Agostoni P, Peretto G, Scelsi L, Turco A, Di Tano G, Campana C, Belloni A, Morandi F, Mortara A, Ciro A, Senni M, Gavazzi A, Frigerio M, Oliva F, Camici PG; Registro Lombardo delle Miocarditi. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation. 2018 Sep 11;138(11):1088-1099. doi: 10.1161/CIRCULATIONAHA.118.035319.
Results Reference
background
PubMed Identifier
31319912
Citation
Ammirati E, Veronese G, Brambatti M, Merlo M, Cipriani M, Potena L, Sormani P, Aoki T, Sugimura K, Sawamura A, Okumura T, Pinney S, Hong K, Shah P, Braun O, Van de Heyning CM, Montero S, Petrella D, Huang F, Schmidt M, Raineri C, Lala A, Varrenti M, Foa A, Leone O, Gentile P, Artico J, Agostini V, Patel R, Garascia A, Van Craenenbroeck EM, Hirose K, Isotani A, Murohara T, Arita Y, Sionis A, Fabris E, Hashem S, Garcia-Hernando V, Oliva F, Greenberg B, Shimokawa H, Sinagra G, Adler ED, Frigerio M, Camici PG. Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction. J Am Coll Cardiol. 2019 Jul 23;74(3):299-311. doi: 10.1016/j.jacc.2019.04.063.
Results Reference
background
PubMed Identifier
17054204
Citation
Chen H, Liu J, Yang M. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004471. doi: 10.1002/14651858.CD004471.pub2.
Results Reference
background
PubMed Identifier
7596370
Citation
Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995 Aug 3;333(5):269-75. doi: 10.1056/NEJM199508033330501.
Results Reference
background
PubMed Identifier
28576783
Citation
Ammirati E, Cipriani M, Lilliu M, Sormani P, Varrenti M, Raineri C, Petrella D, Garascia A, Pedrotti P, Roghi A, Bonacina E, Moreo A, Bottiroli M, Gagliardone MP, Mondino M, Ghio S, Totaro R, Turazza FM, Russo CF, Oliva F, Camici PG, Frigerio M. Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis. Circulation. 2017 Aug 8;136(6):529-545. doi: 10.1161/CIRCULATIONAHA.117.026386. Epub 2017 Jun 2.
Results Reference
background
PubMed Identifier
37014337
Citation
Ammirati E, Moslehi JJ. Diagnosis and Treatment of Acute Myocarditis: A Review. JAMA. 2023 Apr 4;329(13):1098-1113. doi: 10.1001/jama.2023.3371.
Results Reference
background
Learn more about this trial
MYTHS - MYocarditis THerapy With Steroids
We'll reach out to this number within 24 hrs