Anakinra Versus Placebo for the Treatment of Acute MyocarditIS

Assistance Publique - Hôpitaux de Paris120 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

120

Conditions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 64 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: within 28 days post hospitalization

Secondary Outcomes

Total cost

Time frame: 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

Time frame: on average 14 days

Incremental cost effectiveness

cost-effectiveness of ANAKINRA in the setting of acute myocarditis

Time frame: on average 14 days

Cost utility ratios

Time frame: on average 14 days

Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)

Time frame: at 6 month

Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)

Time frame: at 6 month

LVEF assessed by cardiac MRI

Time frame: at 1 year

LVEF assessed by cardiac TTE

Time frame: at 1 year

All cause of death rate

Time frame: during the 12 months follow-up

Cardiovascular death

Time frame: at 12 months

Heart Failure

Time frame: at 12 months

Ventricular tachycardia

Time frame: 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

Time frame: 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

Time frame: an average of 14 days

Anakinra Versus Placebo for the Treatment of Acute MyocarditIS

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes