Anakinra Versus Placebo for the Treatment of Acute MyocarditIS

Study Overview
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Brief Summary
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There is no specific treatment of acute myocarditis, especially during the inflammatory period. Interleukin (IL) is specifically involved during this period and play a role in myocardial oedema. ANAKINRA, an IL-1β Blocker, is a new treatment that has never been evaluated in myocarditis. The benefit for the patient could be important with a reduction of heart failure and ventricular arrhythmias. Hypothesis : ANAKINRA in addition to standard therapy for treatment of Acute Myocarditis is superior to standard therapy based on an association of beta-blockers and Angiotensin-Converting-Enzyme inhibitor (ACE).

Detailed Description
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It is a Double Blind Randomized clinical trial Phase IIb of superiority, enrolling two groups: one group treated with the standard of care, defined as the maximum tolerated dosage of any beta blockers and ACE, and placebo versus ANAKINRA in addition to the standard of care in patients treated for an acute Myocarditis. Patients will be randomized to receive ANAKINRA 100 mg/daily or placebo subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months. Randomization 1:1 will be conducted centrally using the electronic Case Report Form (eCRF). As an exploratory analysis, a second randomization for ACE discontinuation in patients without left ventricular dysfunction (LVEF > 50%) at one month post discharge will be performed. One group will stopped the treatment at one month and the second group will continued the ACE for 6 months. This second randomization is in open label.

Official Title
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Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS

Conditions
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Acute Myocarditis

Intervention / Treatment
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* Drug: ANAKINRA 100 mg/daily subcutaneously
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients hospitalized for Acute myocarditis defined as: Chest Pain (or modification of the ECG) AND Troponin Rise (*1.5 Normal range) AND Myocarditis proven by MRI in the first 72h after admission Age > 18 and <65 years old Accepting effective contraception during treatment duration (men and women childbearing potential) Signed informed consent Normal Coronary angiography or coronary CT Scan (made during the previous year is acceptable) (normal is defined as stenosis < 50%) (In the case of patients under 40 with typical MRI of myocarditis, coronary angiography is not mandatory and left to the doctor's discretion) Exclusion Criteria: Active coronary disease Clinical Suspicion or proven underlying disease: systemic lupus, antiphospholipid antibodies, Lyme disease, trypanosomiase disease, myositis, signs of sarcoidosis, giant cell myocarditis, treated chronic inflammatory disease, tuberculosis, HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV), Hepatitis B virus (HBV) infection, Latex allergy Pregnancy, breastfeeding Contra-indication to ANAKINRA (known hypersensitivity to the active substance or to any of the excipients, neutropenia < 1,5.10^9/L) Renal failure, Creatine Clearance (CrCl) < 30 ml/min (MDRD) Malignancy or any comorbidity limiting survival or conditions predicting inability to complete the study History of malignancy Non Steroidian Anti Inflammatory drug within the past 14 days Anti Tumor Necrosis Factor (TNF) within the past 14 days No affiliation to the French Health Care System sécurité sociale Hepatic impairment = Child-Pugh Class C Mechanical ventilation Circulatory assistance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: ANAKINRA<br>ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months. | Drug: ANAKINRA 100 mg/daily subcutaneously<br>* ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.<br>* Other names: Kineret;|
| Placebo Comparator: B: Placebo<br>PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months. | Drug: Placebo<br>* PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days alive free of any myocarditis complications | Number of days alive free of any myocarditis complications defined as ventricular arrhythmias, heart failure, chest pain, ventricular dysfunction defined as LVEF<50%, within 28 days post hospitalization | within 28 days post hospitalization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total cost | Total cost | on average 14 days | 
| Total Quality Adjusted Life Year (QALYs), | measure of the perceived utility by patients of a medication (Anakinra) that corresponds to a year of life gained | on average 14 days | 
| Incremental cost effectiveness | cost-effectiveness of ANAKINRA in the setting of acute myocarditis | on average 14 days | 
| Cost utility ratios | Cost utility ratios | on average 14 days | 
| Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI) | Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI) | at 6 month | 
| Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE) | Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE) | at 6 month | 
| LVEF assessed by cardiac MRI | LVEF assessed by cardiac MRI | at 1 year | 
| LVEF assessed by cardiac TTE | LVEF assessed by cardiac TTE | at 1 year | 
| All cause of death rate | All cause of death rate | during the 12 months follow-up | 
| Cardiovascular death | Cardiovascular death | at 12 months | 
| Heart Failure | Heart Failure | at 12 months | 
| Ventricular tachycardia | Ventricular tachycardia | during the 12 months follow-up | 
| NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission | NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission | at Day0 | 
| NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission | NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL | an average of 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myocarditis, ANAKINRA