Anakinra Versus Placebo for the Treatment of Acute MyocarditIS (ARAMIS)

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

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).

Study Overview

• Status: Completed
• Conditions: Acute Myocarditis
• Intervention / Treatment: Drug: ANAKINRA 100 mg/daily subcutaneously; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • ACTION Study Group - Department of Cardiology - Pitié Salpétrière Hospital, 47 Bd de l'Hopital
  • Paris, France, 75013
    • Department of internal medicine - Pitié Salpétrière Hospital, 47 Bd de l'Hopital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 62 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: ANAKINRA; 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; 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.; Other Names: Kineret
Placebo Comparator: B: Placebo; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Mathieu KERNEIS, MD, ACTION Study Group - Assistance Publique - Hôpitaux de Paris; Principal Investigator: Fleur COHEN AUBART, MD, Assistance Publique - Hôpitaux de Paris; Study Director: Gilles MONTALESCOT, MD, PhD, ACTION Study Group - Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2017
• Primary Completion (Actual): June 28, 2021
• Study Completion (Actual): May 30, 2022

Study Registration Dates

• First Submitted: December 12, 2016
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (Estimated): January 12, 2017

Study Record Updates

• Last Update Posted (Actual): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myocarditis; ANAKINRA
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Myocarditis; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: P150921; 2016-003433-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No