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MYTHS - MYocarditis THerapy With Steroids (MYTHS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05150704
Recruitment Status : Recruiting
First Posted : December 9, 2021
Last Update Posted : May 30, 2024
Sponsor:
Collaborators:
Ministry of Health, Italy
Istituto Di Ricerche Farmacologiche Mario Negri
University of Milano Bicocca
Regione Lombardia
Information provided by (Responsible Party):
Niguarda Hospital

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).

Condition or disease Intervention/treatment Phase
Myocarditis Acute Drug: Methylprednisolone Drug: saline solution Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 288 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Single blind randomized controlled trial
Masking: Single (Participant)
Primary Purpose: Treatment
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
Actual Study Start Date : October 7, 2021
Estimated Primary Completion Date : March 2028
Estimated Study Completion Date : December 2028


Arm Intervention/treatment
Experimental: Experimental arm
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
Drug: Methylprednisolone
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 Comparator: Control arm
Placebo (saline solution 250 mL IV qd for 3 days) on top of standard therapy and maximal supportive care.
Drug: saline solution
Placebo (saline solution 250 mL IV qd for 3 days) on top of standard therapy and maximal supportive care.




Primary Outcome Measures :
  1. 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. [ Time Frame: 6 months from patients enrollment ]
    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 :
  1. 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. [ Time Frame: 6 months from patients enrollment ]
    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.

  2. Mortality [ Time Frame: 6 months from patients enrollment ]
    Time from randomization to all-cause death within 6 months.

  3. 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 [ Time Frame: 6 months from patients enrollment ]
    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).

  4. Number of days on t-MCS from randomization [ Time Frame: 6 months from patients enrollment ]
    Number of days on t-MCS from randomization

  5. Number of days in ICU from randomization [ Time Frame: 6 months from patients enrollment ]
    Number of days in ICU from randomization

  6. Change in LVEF on echocardiogram after 5 days from randomization [ Time Frame: 5 days from randomization ]
    Change in LVEF on echocardiogram after 5 days from randomization

  7. Change of troponin levels after 5 days from randomization [ Time Frame: 5 days from randomization ]
    Change of troponin levels after 5 days from randomization (ratio of troponin level/local troponin URL).

  8. Change in heart rate (HR) on ECG after 3 days from randomization [ Time Frame: 3 days from randomization ]
    Change in heart rate (HR) on ECG after 3 days from randomization (ECG recorded at the hour of initial randomization

  9. 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 ]
    Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)

  10. Proportion of patients with LVEF<55% on 6-month CMRI [ Time Frame: 6 months from patients enrollment ]
    Proportion of patients with LVEF<55% on 6-month CMRI

  11. Proportion of patients with LV dilation on 6-month CMRI [ Time Frame: 6 months from patients enrollment ]
    Proportion of patients with LV dilation on 6-month CMRI


Other Outcome Measures:
  1. Safety endpoints [ Time Frame: 6 months from patients enrollment ]
    • 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.



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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05150704


Contacts
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Contact: Enrico Ammirati, MD, PhD +39 0264447791 enrico.ammirati@ospedaleniguarda.it

Locations
Show Show 46 study locations
Sponsors and Collaborators
Niguarda Hospital
Ministry of Health, Italy
Istituto Di Ricerche Farmacologiche Mario Negri
University of Milano Bicocca
Regione Lombardia
Publications:

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Responsible Party: Niguarda Hospital
ClinicalTrials.gov Identifier: NCT05150704    
Other Study ID Numbers: MYTHS
First Posted: December 9, 2021    Key Record Dates
Last Update Posted: May 30, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Niguarda Hospital:
Acute Myocarditis
Corticosteroid therapy
Myocarditis
Trial
Immunosuppression
Acute heart failure
Fulminant acute myocarditis
Additional relevant MeSH terms:
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Myocarditis
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents