Clinical trial NCT03018834: Anakinra Versus Placebo for the Treatment of Acute MyocarditIS
Official title: Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Myocarditis
Keywords: Acute Myocarditis
ANAKINRA
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-01-12
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of days alive free of any myocarditis complications
timeFrame: within 28 days post hospitalization
Secondary outcomes:
measure: Total cost
timeFrame: on average 14 days
measure: Total Quality Adjusted Life Year (QALYs),
timeFrame: on average 14 days
measure: Incremental cost effectiveness
timeFrame: on average 14 days
measure: Cost utility ratios
timeFrame: on average 14 days
measure: Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
timeFrame: at 6 month
measure: Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
timeFrame: at 6 month
measure: LVEF assessed by cardiac MRI
timeFrame: at 1 year
measure: LVEF assessed by cardiac TTE
timeFrame: at 1 year
measure: All cause of death rate
timeFrame: during the 12 months follow-up
measure: Cardiovascular death
timeFrame: at 12 months
measure: Heart Failure
timeFrame: at 12 months
measure: Ventricular tachycardia
timeFrame: during the 12 months follow-up
measure: 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
timeFrame: at Day0
measure: 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
timeFrame: an average of 14 days
Other outcomes:
Locations:
city: Paris
country: France
facility: ACTION Study Group - Department of Cardiology - Pitié Salpétrière Hospital, 47 Bd de l'Hopital
city: Paris
country: France
facility: Department of internal medicine - Pitié Salpétrière Hospital, 47 Bd de l'Hopital
Study officials:
affiliation: ACTION Study Group - Assistance Publique - Hôpitaux de Paris
name: Mathieu KERNEIS, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Fleur COHEN AUBART, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ACTION Study Group - Assistance Publique - Hôpitaux de Paris
name: Gilles MONTALESCOT, MD, PhD
role: STUDY_DIRECTOR
References: