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

Primary Purpose

Acute Myocarditis

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
ANAKINRA 100 mg/daily subcutaneously
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myocarditis focused on measuring Acute Myocarditis, ANAKINRA

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

A: ANAKINRA

B: Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Total cost
Total cost
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
Incremental cost effectiveness
cost-effectiveness of ANAKINRA in the setting of acute myocarditis
Cost utility ratios
Cost utility ratios
Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
LVEF assessed by cardiac MRI
LVEF assessed by cardiac MRI
LVEF assessed by cardiac TTE
LVEF assessed by cardiac TTE
All cause of death rate
All cause of death rate
Cardiovascular death
Cardiovascular death
Heart Failure
Heart Failure
Ventricular tachycardia
Ventricular tachycardia
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
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

Full Information

First Posted
December 12, 2016
Last Updated
June 14, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT03018834
Brief Title
Anakinra Versus Placebo for the Treatment of Acute MyocarditIS
Acronym
ARAMIS
Official Title
Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
May 30, 2017 (Actual)
Primary Completion Date
June 28, 2021 (Actual)
Study Completion Date
May 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

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
Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myocarditis
Keywords
Acute Myocarditis, ANAKINRA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
120 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A: ANAKINRA
Arm Type
Experimental
Arm Description
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.
Arm Title
B: Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ANAKINRA 100 mg/daily subcutaneously
Other Intervention Name(s)
Kineret
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of days alive free of any myocarditis complications
Description
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 Outcome Measure Information:
Title
Total cost
Description
Total cost
Time Frame
on average 14 days
Title
Total Quality Adjusted Life Year (QALYs),
Description
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
Title
Incremental cost effectiveness
Description
cost-effectiveness of ANAKINRA in the setting of acute myocarditis
Time Frame
on average 14 days
Title
Cost utility ratios
Description
Cost utility ratios
Time Frame
on average 14 days
Title
Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
Description
Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
Time Frame
at 6 month
Title
Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
Description
Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
Time Frame
at 6 month
Title
LVEF assessed by cardiac MRI
Description
LVEF assessed by cardiac MRI
Time Frame
at 1 year
Title
LVEF assessed by cardiac TTE
Description
LVEF assessed by cardiac TTE
Time Frame
at 1 year
Title
All cause of death rate
Description
All cause of death rate
Time Frame
during the 12 months follow-up
Title
Cardiovascular death
Description
Cardiovascular death
Time Frame
at 12 months
Title
Heart Failure
Description
Heart Failure
Time Frame
at 12 months
Title
Ventricular tachycardia
Description
Ventricular tachycardia
Time Frame
during the 12 months follow-up
Title
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
Description
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
Title
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
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mathieu KERNEIS, MD
Organizational Affiliation
ACTION Study Group - Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fleur COHEN AUBART, MD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gilles MONTALESCOT, MD, PhD
Organizational Affiliation
ACTION Study Group - Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
Facility Information:
Facility Name
ACTION Study Group - Department of Cardiology - Pitié Salpétrière Hospital, 47 Bd de l'Hopital
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Department of internal medicine - Pitié Salpétrière Hospital, 47 Bd de l'Hopital
City
Paris
ZIP/Postal Code
75013
Country
France

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Anakinra Versus Placebo for the Treatment of Acute MyocarditIS

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