Pulse Corticosteroids Or/and Immunoglobulins to Treat Fulminant Myocarditis

Official title

Pulse Corticosteroids Or/and Immunoglobulins to Treat Fulminant Myocarditis: a Double-blind Randomized Controlled Adaptive Trial the CORIUM Study

Overview

Fulminant myocarditis (FM) is the most severe manifestation of acute myocarditis, an acute inflammatory myocardial disease most often triggered by viral infections. Currently, the most accepted definition of FM requires acute illness, hemodynamic compromise due to cardiogenic shock, and need for hemodynamic support (inotropes and/or temporary mechanical circulatory support (t-MCS) in the absence of an ischemic cause or other pre-existing cardiomyopathies. Unfortunately, there is a paucity of evidence-based management strategies for this disease and the management of patients affected by FM often varies according to local experience and practice with the role of immunosuppression being the most debated issue. Besides, due to inconsistent results obtained in several studies and frequent spontaneous recovery with supportive therapy alone, immunosuppression is largely debated in the setting of lymphocytic myocarditis (LM). Among available medications for this disease, corticosteroids are often used despite a lack of clear evidence in the context of FM. Similarly, intravenous immunoglobulin (IVIG) has both antiviral and anti-inflammatory effects on myocarditis. In adults, a recent meta-analysis based on case series showed that IVIG therapy significantly reduced in-hospital mortality, improved the left ventricular ejection fraction, and significantly increased the survival rate in patients with FM. More recently, FM among patients with COVID-19, including post-infectious multisystem inflammatory syndrome, has been reported in young adult patients. These severe forms have been successfully treated with intravenous corticosteroids and IVIG, highlighting the relevance of the systemic inflammatory response in determining cardiac injury in COVID-19, even though more evidence is needed.

Interventions

• Drug Pulse bolus corticosteroids
  Treatment administration
• Drug Pulse bolus corticosteroids and IVIG
  Treatment administration
• Drug Pulse bolus corticosteroids (G5%) and IVIG (G5 %)
  Treatment administration

Primary outcome measures

• A composite hierarchical outcome composed of four components : 1) mortality at D28 2) heart transplant/VAD/persisting t-MCS at D28, and 3) number of days alive without t-MCS and inotropes at D28 [Time frame: Day 28]

Secondary outcome measures (12)

• Mortality [Time frame: Day 28, Day 60, Day 90]
• Number of temporary mechanical circulatory support free days [Time frame: Day 28]
• Number of inotropes-free days [Time frame: Day 28]
• Incidence of ventricular assisted device use [Time frame: Day 28, Day 60, Day 90]
• Incidence of heart transplant [Time frame: Day 28, Day 60, Day 90]
• Left ventricular function (%) assessed by echocardiography (Simpson method) [Time frame: Day 3, Day 7, Day 14, Day 28]
• Time to normalize troponin [Time frame: From randomization to Day 14]
• Time to normalize N-terminal pro-B-type natriuretic peptide [Time frame: From randomization to Day 14]
• Incidence of drugs side effects [Time frame: From randomization to Day 28]
• Proportion of patients with left ventricular ejection fraction < 55% [Time frame: Day 28, 6 months]
• Proportion of patients with left ventricular dilatation [Time frame: Day 28, 6 months]
• Proportion of patients with late gadolinium enhancement evaluated by cardiac magnetic resonance imaging [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• 1\. Fulminant myocarditis defined by

• the acute illness (<1 month from symptom onset),
• hemodynamic compromise due to cardiogenic shock (confirmed by echocardiography) or electrical storm,
• elevated plasma cardiac troponin > twice normal value
• need for hemodynamic support (inotropes or temporary mechanical circulatory support) for less than 72 hours in the absence of an ischemic cause or other pre-existing cardiomyopathies Noticeably, a coronary angiogram should be performed in patients ≥40 years of age when myocarditis has not been proven histologically. Besides, an endomyocardial biopsy will not be mandatory to fulfill the definition of fulminant myocarditis.

2\. Signed informed consent from the patient, a close relative or surrogate or a family member or a legal representative for minor patient.

• Adult : According to the specifications of emergency inclusion, randomization without the close relative/surrogate consent could be performed if the patientis unable to give his/her consent and when the close relative/surrogate/family member are absent. Close relative/surrogate/family member consent will be asked as soon as possible after randomization. The patient will be asked as soon as possible to give his/her consent for the continuation of the trial when his/her condition will allow.
• Minor : According to the specifications of emergency inclusion, randomization could be performed when legal representative are absent. Legal representative consent will be asked as soon as possible after randomization 3. Social security registration (AME excluded)

Exclusion criteria

• 1\. Age <15 2. Pregnancy or breastfeeding or baby delivery <6 months 3. Initiation of inotropes or temporary mechanical circulatory support >72 hours 4. Resuscitation >20 minutes (cumulative low-flow time > 20 minutes ) 5. Pre-existing ischemic or dilated cardiomyopathy or Tako-Tsubo evaluated by echocardiography.

6\. Known systemic autoimmune disorder or other conditions requiring immunosuppression 7. Patients with peripheral eosinophilia (≥1000 G/L) 8. Myocarditis associated with anti-cancer immune checkpoint inhibitor agents 9. Active severe bacterial or fungal infectious disease 10. Patient moribund on the day of randomization, SAPS II >90 11. Contraindication or allergies to corticosteroids or immunoglobulins or any components of the formulations or their excipients 12. Patients already on corticosteroids or receiving IVIG 13. Participation in another interventional study or being in the exclusion period at the end of a previous study.

14\. Patients with an uncontrolled psychotic condition Patients with known anti-IgA antibodies in line with the contraindications of methylprednisolone IV and of IVIg based products respectively

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06896253 · APHP220808 · 2023-506599-28-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗