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

• ClinicalTrials.gov Identifier: NCT03018834
• Recruitment Status: Completed
• First Posted: January 12, 2017
• Last Update Posted: March 6, 2024
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Acute Myocarditis	Drug: ANAKINRA 100 mg/daily subcutaneously; Drug: Placebo	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS
• Actual Study Start Date: May 30, 2017
• Actual Primary Completion Date: June 28, 2021
• Actual Study Completion Date: May 30, 2022

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Number of days alive free of any myocarditis complications [ Time Frame: within 28 days post hospitalization ]
   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

Secondary Outcome Measures :

1. Total cost [ Time Frame: on average 14 days ]
   Total cost
2. Total Quality Adjusted Life Year (QALYs), [ Time Frame: on average 14 days ]
   measure of the perceived utility by patients of a medication (Anakinra) that corresponds to a year of life gained
3. Incremental cost effectiveness [ Time Frame: on average 14 days ]
   cost-effectiveness of ANAKINRA in the setting of acute myocarditis
4. Cost utility ratios [ Time Frame: on average 14 days ]
   Cost utility ratios
5. Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI) [ Time Frame: at 6 month ]
   Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
6. Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE) [ Time Frame: at 6 month ]
   Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
7. LVEF assessed by cardiac MRI [ Time Frame: at 1 year ]
   LVEF assessed by cardiac MRI
8. LVEF assessed by cardiac TTE [ Time Frame: at 1 year ]
   LVEF assessed by cardiac TTE
9. All cause of death rate [ Time Frame: during the 12 months follow-up ]
   All cause of death rate
10. Cardiovascular death [ Time Frame: at 12 months ]
    Cardiovascular death
11. Heart Failure [ Time Frame: at 12 months ]
    Heart Failure
12. Ventricular tachycardia [ Time Frame: during the 12 months follow-up ]
    Ventricular tachycardia
13. 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
14. 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: an average of 14 days ]
    NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

France

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

Paris, France, 75013

Sponsors and Collaborators

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

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03018834
• Other Study ID Numbers: P150921; 2016-003433-20 ( EudraCT Number )
• First Posted: January 12, 2017
• Last Update Posted: March 6, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Acute Myocarditis; ANAKINRA

Additional relevant MeSH terms:

Myocarditis; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents