Evaluation of Anakinra Combined with Azathioprine and Prednisone in Virus-Negative Myocarditis: A Double-Blind, Phase IIa, Placebo-Controlled Trial

Trial ID: 2024-515472-13-00
Sponsor: Ospedale San Raffaele S.r.l.

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Diseases & Conditions

Viral myocarditis

Objectives

The primary objective of this clinical trial is to evaluate the benefit of **Anakinra** combined with standard immunosuppressive therapy, specifically azathioprine and prednisone, in the treatment of virus-negative myocarditis. This study aims to determine whether the addition of Anakinra to the standard of care can improve clinical outcomes in patients with endomyocardial biopsy-proven virus-negative myocarditis. The clinical relevance of this objective lies in the potential to enhance therapeutic strategies for this condition, which could lead to improved patient management and outcomes.

Participants

The clinical trial involves participants diagnosed with **virus-negative myocarditis**, confirmed through endomyocardial biopsy and cardiac magnetic resonance imaging according to the Lake Louise Criteria. The study population includes both male and female subjects, aged between 18 and 75 years, with any impairment of left ventricular ejection fraction (LV-EF) below 55% as determined by Trans Thoracic Echocardiography. Participants are required to have the ability to provide informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that the study population is representative of individuals with the specified medical condition, without additional significant lifestyle restrictions.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **anakinra** in combination with standard immunosuppressive therapy for the treatment of virus-negative myocarditis. This study is a **randomized**, **double-blind**, **placebo-controlled** trial, classified as a Phase IIa study. The trial aims to assess the benefit of anakinra in improving left ventricular ejection fraction (LVEF) as measured by trans-thoracic echocardiography (TTE) at two months. The trial is expected to run from September 23, 2021, to December 31, 2025, with a maximum treatment period of six months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 75 years), myocarditis diagnosis via cardiac magnetic resonance, virus-negativity confirmed by endomyocardial biopsy, and impaired LVEF (<55%). Following the screening, eligible participants will be randomized to receive either anakinra or placebo, administered subcutaneously. The study will include regular follow-up visits to monitor safety and efficacy, with assessments of LVEF and other health parameters. The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any adverse events.

Participant involvement is expected to last up to six months, with conditions for early termination including significant adverse reactions, withdrawal of consent, or non-compliance with study procedures. The trial's primary endpoint is the improvement of LVEF at two months, with no secondary endpoints specified. The study is not classified as a low-intervention trial, and the investigational product, anakinra, is not a pediatric formulation. The trial is conducted under strict regulatory compliance to ensure the safety and well-being of all participants.

Treatment

The clinical trial involves the administration of **Anakinra**, a biological medicinal product classified under the ATC code L04AC03. Anakinra is a protein-based therapeutic agent, specifically categorized as "Protein - Other." The pharmaceutical form of Anakinra used in this study is denoted by the code PHF00231MIG. The medication is administered via the **subcutaneous route**. The dosing regimen for Anakinra in this trial is set at a maximum daily dose of 100 mg, with the total dose not exceeding 100 mg per day. The treatment period with Anakinra is limited to a maximum of six months. The study aims to evaluate the efficacy and safety of Anakinra in the treatment of virus-negative myocarditis when used in conjunction with standard immunosuppressive therapy.

In addition to Anakinra, participants in the trial will receive standard-of-care therapy, which includes the administration of **azathioprine** and **prednisone**. These medications are part of the standard immunosuppressive regimen for the treatment of myocarditis. Azathioprine is an immunosuppressive agent, while prednisone is a corticosteroid, both of which are commonly used to manage inflammatory conditions. The dosing schedules for azathioprine and prednisone will follow standard clinical guidelines, ensuring that participants receive optimal care alongside the experimental treatment. Compliance with the dosing regimen will be monitored throughout the study to ensure adherence and to evaluate the therapeutic outcomes accurately.

Efficacy

The efficacy of Anakinra in the treatment of virus-negative **myocarditis** will be assessed in a double-blind, phase IIa, placebo-controlled, randomized clinical trial. The primary endpoint for evaluating efficacy is the improvement in Left Ventricular Ejection Fraction (LVEF), which will be assessed using Trans Thoracic Echocardiography (TTE) at 2 months. This parameter is chosen to determine the benefit of Anakinra when combined with standard immunosuppressive therapy, including azathioprine and prednisone. The trial aims to provide a comprehensive evaluation of Anakinra's efficacy in enhancing cardiac function in patients with virus-negative myocarditis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 Years to 75 Years
Myocarditis defined by cardiac magnetic resonance (according with Lake Louise Criteria) and virus-negativity defined by on endomyocardial biopsy.
Any impairment of left ventricular ejection fraction (LV-EF) <55% on Trans Thoracic Echocardiography.
Ability to sign an informed consent.

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Exclusion Criteria

Coronary artery stenosis > 50% at angiography or coronary CT Scan (acceptable if performed during the last 12 months).
Evidence of genome of cardiotropic viruses by Polymerase chain reaction on EBM.
Clinical suspicion or proven underlying disease: Lyme disease, any other bacterial disease possibly responsible for myocarditis, trypanosomiase disease, giant cell myocarditis.
Known presence or suspicion of active or recurrent bacterial, fungal or viral infections, including tuberculosis, or HIV infection or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
Pregnancy, breastfeeding. Female patients of childbearing potential may participate if adequate contraception is used during the study. (For the purposes of this trial, women of childbearing potential are defined as “All female subjects after puberty unless they are post-menopausal for at least 2 years or are surgically sterile.”
Contra-indication to ANAKINRA (known hypersensitivity to the active substance or to any of the excipients or to Escherichia coli-derived proteins).
Presence of neutropenia < 1,5.109/L).
Renal failure as defined by estimated glomerular filtration rate (eGFR) <30 ml/min, according to Cockcroft-Gault.
Any comorbidity limiting survival or conditions predicting inability to complete the study.
History of malignancy in the previous 5 years. Exceptions are basal cell skin cancer, carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy.
Any other previous biological treatment administered within 5 -half lives of the specific drug.
Any concomitant immune-suppressive medications other than those included in the study protocol.
Therapy with prednisone >10 mg daily and/or immuno-suppressive agents within 3 months before the enrolment.
Hepatic impairment = Child-Pugh Class C
Mechanical ventilation circulatory assistance.
Congenital and/or acquired valvular disease or any other heart disease that could justify the severity of cardiac dysfunction.
Major surgery within 2 weeks prior to randomization, or unhealed operation wounds.