Corticoid Therapy in Acute Myocarditis

Phase 3

Not yet recruiting

• Conditions: Acute Myocarditis
• Interventions: Drug: Perfusion of placebo; Drug: Intravenous administration of Methylprednisolone; Drug: Oral Prednisone placebo; Drug: Oral Prednisone

• Registration Number: NCT06522100
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

Refer to the "Detailed Description" section.

Detailed Description

Introduction: Acute myocarditis (AM) is an inflammatory disease of the heart. The incidence is approximately 22 out of 100 000 patients annually. Clinically, it ranges from subclinical pauci-symptomatic forms to life-threatening arrhythmias, cardiogenic shock and sudden cardiac death. In approximately more than 70% of cases, AM resolves spontaneously. In the remaining patients, it evolves to a poor prognosis with left ventricular dilatation, reduced cardiac contractility and progression to chronic heart failure.

Complicated AM is defined as an AM with Left Ventricular Ejection Fraction (LVEF) \< 50% and/or a sustained ventricular arrhythmia and/or a hemodynamic instability. Complicated AM is often associated with a poor prognosis (in example risk of heart transplantation of 10.4% at 30 days and 14.7% at 5-year follow up) whereas uncomplicated AM have none.

Administration of immunosuppressive treatment (IT) is still debated. According to experts' consensus, immunosuppressive treatment should be considered in complicated AM and should be used in recommended in case of fulminant myocarditis (acute myocarditis with a presentation of cardiogenic shock, ventricular arrhythmias, or multiorgan system failure). Nevertheless, there is no data on use of glucocorticoids (GC) in complicated AM.

Early application of high dose of GC in AM can control the cytokine storm and the inflammatory response, rather than suppressing the overall immune response. Best timing for their administration remains unknown. The aim of this multicenter controlled randomized study is to demonstrate the benefit of high dose of GC therapy on mortality and cardiac events in patients with AM and left ventricular (LV) dysfunction.

Hypothesis/Objective: The main objective is to evaluate in patients with acute myocarditis with left-ventricular dysfunction the efficacy of a pulse of Methylprednisolone IV for 3 days at diagnosis followed by Prednisone per os versus placebo IV followed by placebo per os in association with conventional Heart Failure (HF) therapy on the occurrence of Major Cardiovascular Events (MACE) and/or persistence of left ventricular dysfunction defined as LVEF \< 50% and/or Global Longitudinal Strain (GLS) \< -16% between baseline and at 6 months.

The primary endpoint is the Major Cardiovascular Events (MACE) and/or persistence of left ventricular dysfunction defined as LVEF \< 50% and/or Global Longitudinal Strain (GLS) \< - 16% between baseline (D-2) and 6 months (M6) follow up. MACE is a combined criterion that includes all-cause mortality, heart failure hospitalization, sustained ventricular arrhythmia, heart transplantation or assistance and recurrent acute myocarditis with LV dysfunction at 6 months.

Method: Phase III, prospective, randomized, placebo controlled, superiority, double blinded trial with 2 parallel groups randomized in a 1:1 ratio:

* Experimental group: Methylprednisolone IV for 3 days followed by Prednisone per os + conventional HF treatment.

* Control group: placebo of Methylprednisolone IV followed by placebo of Prednisone per os + conventional HF treatment.

Study Timeline

• Status Verified: 2024-07
• Study First Submitted: 2024-07-22
• Study First Submitted QC: 2024-07-22
• Study First Posted: 2024-07-26
• Last Update Submitted: 2024-07-26
• Last Update Posted: 2024-07-29
• Study Start: 2025-02-01
• Primary Completion: 2028-08-16
• Study Completion: 2028-08-16

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 420

Inclusion Criteria

• Age ≥ 18 years

• Written signed informed consent

• Affiliation to the French health care system or to another social protection scheme with the exception of State Medical Aid

• Active myocarditis defined by (all items are required):

  • Acute chest pain and/or unexplained heart failure and/or syncope and/or sustained ventricular arrhythmias and/or aborted sudden death and/or cardiogenic shock and/or ECG modification (atrioventricular block or bundle branch block or sinus arrest or ST or T waves change or ventricular arrhythmia or atrial fibrillation or abnormal Q waves)
  • And troponin rise (1,5 times the normal range)
  • And diagnosis of active myocarditis on Cardiac Magnetic Resonance (according to Lake-Louise criteria) or by histological evidence on endomyocardial biopsy (Dallas's criteria)

• Left-ventricular dysfunction defined as LVEF < 50% and/or GLS < -16% assessed with 2D-TTE

• Normal coronary angiography or CT Scan (without stenosis > 50%) during the previous year

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Exclusion Criteria

• Active coronary disease

• Other causes of chronic heart failure (coronary artery disease, primary valvular heart disease, congenital heart disease)

• Other etiology of myocarditis requiring corticosteroids treatment as giant cells myocarditis, eosinophilic myocarditis and cardiac sarcoidosis or immune checkpoint inhibitor myocarditis

• Other auto-immune or inflammatory disease requiring corticosteroids treatment within 6 months before enrolment

• Pregnancy or breastfeeding

• Woman of childbearing potential without effective method of birth control (included contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices)

• Patient deprived of liberty or under Curatorship/Tutorship, safeguard of justice, according to French law

• Foreseeable inability, according to the investigator, to participate in all the visits, treatments and measures provided for in the protocol

• Patient not speaking or understanding French

• Concomitant participation in another clinical trial on medical product for human use, to a clinical investigation on a medical device, to interventional study involving human participants or in the exclusion period at the end of a previous clinical trial on medical product for human use, a clinical investigation on a medical device, or study involving human participants. Participation in non-interventional research is permitted.

• Any medical and/or cognitive condition which limits the ability of participant to participate in study

• Contra-indication linked to steroids (Methylprednisolone and Prednisone) according to summary of product characteristics:

  • Any infectious condition excluding the specified therapeutic indications of Methylprednisolone and Prednisone
  • Certain evolving viruses (notably hepatitis, herpes, chickenpox, shingles)
  • Psychotic states not yet controlled by treatment
  • Recent live vaccines or live attenuated vaccines in patients receiving dosages greater than 20 mg/day of prednisone equivalent for more than two weeks and during the 3 months following the cessation of corticosteroid therapy (risk of generalized vaccine disease possibly fatal)
  • Hypersensitivity to the active substances or to any of the excipients

• Contra-indication linked to auxiliary drugs according to respective summary of product characteristics:

  • Beta-blockade
  • Angiotensin-converting-enzyme inhibitor (ACE-I)
  • Angiotensin receptor blockers (ARB)
  • Mineralocorticoid antagonists (MRA)
  • Angiotensin receptor-neprilysin inhibitor (ARNi)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control group	Perfusion of placebo	Randomization in control group in addition to conventional HF therapy for 6 months.
Control group	Oral Prednisone placebo	Randomization in control group in addition to conventional HF therapy for 6 months.
Experimental group	Intravenous administration of Methylprednisolone	Randomization in experimental group in addition to conventional HF therapy for 6 months.
Experimental group	Oral Prednisone	Randomization in experimental group in addition to conventional HF therapy for 6 months.

Primary Outcome Measures

Name	Time	Method
Efficacy of treatments	6 months	Major Cardiovascular Events (MACE) and/or persistence of left ventricular dysfunction defined as LVEF \< 50% and/or Global Longitudinal Strain (GLS) \< - 16%. MACE is a combined criterion that includes all-cause mortality, heart failure hospitalization, sustained ventricular arrhythmia, heart transplantation or assistance and recurrent acute myocarditis with LV dysfunction.

Secondary Outcome Measures

Name	Time	Method
Adherence to the treatment regimen	6 months	Compliance to the treatment (premature ending of the treatment or proportion of non-administered doses of the treatment)
Global Longitudinal Strain (GLS) ≥ -16%	6 months	Changes in Global Longitudinal Strain (GLS) ≥ -16% at 6 months using 2D-TTE
Changes in LVEF ≥ 50%	6 months	Changes in LVEF ≥ 50% at 6 months using 2D trans-thoracic echocardiography (2D-TTE)
All-cause mortality	6 months	Occurred of a death
Safety of the treatment regimens	6 months	Adverse events and serious adverse events
Heart failure hospitalization	6 months	Occurred of hospitalization for heart failure
Sustained ventricular arrhythmia	6 months	Occurred of sustained ventricular arrhythmia
Recurrence of acute myocarditis with LV dysfunction	6 months	Time to recurrence of acute myocarditis with LV dysfunction
Evaluate quality of life using Minnesota living with heart failure questionnaire (MLHFQ)	6 months	Increased quality of life evaluated by Minnesota living with heart failure questionnaire during follow up. 21 questions rated from 0 to 5. Overall score from 0 to 105. The score increase with the adverse impact of heart failure.
Heart transplantation	6 months	Occurred of heart transplantation
Heart assistance by extracorporeal membrane oxygenation (ECMO), Intra-aortic balloon pump (IABP), Impella® device or Left Ventricular Assistance Devices (LVAD)	6 months	Need for heart assistance by extracorporeal membrane oxygenation (ECMO), Intra-aortic balloon pump (IABP), Impella® device or Left Ventricular Assistance Devices (LVAD)