Overview

Myocarditis can result in numerous complications, but there is paucity of data regarding optimal therapy, short- and long-term effects of possibly effective immunosuppressive therapy. The IMPROVE-MC study will provide high-quality scientific data about efficacy and safety of immunosuppressive therapy, non-invasive (MRI, biomarkers) and invasive diagnostics tests (endomyocardial biopsy), and prognosis in myocarditis. The objective of this multicenter, prospective, randomized, double-blind placebo-controlled trial is to assess the efficacy and safety of 12 - month treatment with prednisone and azathioprine comparing to placebo on top of guideline-recommended medical therapy in patients with biopsy-proven virus negative myocarditis or inflammatory cardiomyopathy and reduced ejection fraction (LVEF ≤ 45%). The study will also assess persistence of the treatment effects after 12 months.

Eligibility

Inclusion Criteria:

        To be eligible for inclusion in this study, patient must fulfill all of the following
        inclusion criteria:
          1. Written informed consent to participate in the IMPROVE-MC study (including two EMBs
             and two cardiac CMRs) prior to any evaluation or procedure related to the study.
          2. Patient with clinically suspected myocarditis or inflammatory cardiomyopathy
             (according to the criteria of the ESC Working Group on Myocardial & Pericardial
             Diseases 2013 and ESC Heart Failure Guidelines 2021); OR/ AND, Patients with already
             diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory
             cardiomyopathy who will undergo diagnostic right ventricular (or/and left ventricular)
             EMB during the screening; OR / AND, Patients with already diagnosed active myocarditis
             (lymphocytic or eosinophilic) or inflammatory cardiomyopathy confirmed by right
             ventricular (or/and left ventricular) EMB that was performed according to the
             IMPROVE-MC study protocol within 3 months from screening.
          3. Men or women aged 18-65. Women of childbearing age must have a negative pregnancy test
             result. Female patients must be 1 year post-menopausal, surgically sterile, or using
             an acceptable method of contraception (with a failure rate of < 1% per year) for the
             duration of the study (from the time they sign consent) and for 8 weeks after the last
             dose of study treatment to prevent pregnancy. Patients agreeing to total sexual
             abstinence can also be included, assuming it is their usual lifestyle. Women are
             considered postmenopausal and without the potential to have a child if they have 12
             months of natural (spontaneous) amenorrhea with an appropriate clinical picture (e.g.
             appropriate age, history of vasomotor symptoms) or have undergone bilateral surgical
             ovariectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
             In the case of ovariectomy alone, only if the reproductive status of the woman has
             been confirmed by assessing hormone levels.
          4. No significant improvement in clinical condition or worsening course of the disease
             despite the standard treatment in the investigator's opinion, in the last ≥ 3 months
             prior to the screening period.
          5. LVEF 10 - 45% measured by echocardiogram taken during the screening period
               1. No significant LVEF improvement in the last ≥3 months prior to the screening
                  period in the investigator's opinion.
               2. LVEF should be measured under stable conditions as assessed by the investigator.
               3. LVEF should be verified in the CORE-LAB.
          6. Histological and immunohistochemical evidence of active myocarditis (lymphocytic or
             eosinophilic) OR inflammatory cardiomyopathy during the screening period (EMB during
             the screening or within last 3 months).
          7. Absence of cardiotropic viruses in cardiac tissue at PCR analysis during the screening
             period (EMB during the screening or within last 3 months).
        Exclusion Criteria:
        Patients fulfilling any of the following exclusion criteria are not eligible for inclusion
        in this study. No additional exclusions may be applied by the investigator, in order to
        ensure that the study population will be representative of all eligible patients.
          1. Presence of contraindications to immunosuppressive therapy with steroids and/ or
             azathioprine (including hypersensitivity to azathioprine/ 6-mercaptopurine or
             prednisone, mainly untreated systemic infection, uncontrolled diabetes, poorly
             controlled endocrine diseases, osteoporosis, active gastric or duodenal ulcer,
             uncontrolled hypertension, leukocytopenia (leukocyte counts <4 x 109/l), neutropenia
             (neutrophils <1.5 x 109/l), thrombocytopenia (platelet levels <130 x 109/l), anemia
             (hemoglobin levels <11 g/dl).
          2. Positive clinical screening for active infections, including HIV, HBV, HCV. Assessment
             of tuberculosis infection should be considered before screening, according to the
             local epidemiologic status and according to investigator's opinion. After careful
             evaluation of the activity of the infection (or cure of the infection), the patient
             may continue participation in the study according to investigator's opinion.
          3. Another specific cause of heart failure (including severe congenital, valvular,
             hypertensive, and/or coronary artery disease) that could justify the severity of
             cardiac dysfunction.
          4. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), storage diseases
             (e.g. haemochromatosis, Fabry disease), muscular dystrophies, genetic hypertrophic
             cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or known pericardial
             constriction.
          5. Diagnosed or suspected cardiac sarcoidosis or giant cell myocarditis, autoimmune/
             systemic immune-mediated disease (i.e. granulomatosis with polyangiitis, lupus
             erythematosus) that might require specific immunosuppressive therapy. Recent, current
             or expected future need for long-term use of immunosuppressive therapy with steroids
             and/ or azathioprine and/ or other immunosuppressive agent (caution - short-term
             course of steroids [i.e. for asthma attack, occasional topical applications] is not an
             exclusion).
          6. NYHA class I and IV.
          7. Subjects with body mass index >40 kg/m2 or body weight <50 kg.
          8. Pregnancy, lactation or women who plan to become pregnant during the trial. Lack of
             consent to the use of effective forms of contraception.
          9. Any documented or suspected active malignant neoplasm or history of malignant neoplasm
             within the 5 years prior to the screening period.
         10. History of cytostatic therapy or radiotherapy.
         11. Liver disease defined as any of the following: AST or ALT or ALP above 3x ULN;
             bilirubin >1.5 mg/dL.
         12. Impaired renal function, defined as eGFR <45 mL / min / 1.73 m2 (CKD-EPI) measured
             under stable condition or requiring dialysis. Conditionally, according to the
             investigator's decision, patients with eGFR 40-45 ml / min / 1.73 m2 may be included.
         13. The need or refusal to stop taking any drug considered to interfere with the safe
             course of the study (e.g., allopurinol).
         14. Currently implanted or planned VAD, CRT or heart transplant.
         15. Patients with pacemaker or ICD requiring a high percentage of ventricular pacing
             (>30%) which could influence the result of LVEF measurement in the investigator's
             opinion.
         16. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial
             drug(s) absorption in the investigator's opinion.
         17. History or presence of any other disease with a life expectancy <3 years.
         18. Any contraindications or intolerance to CMR*, including but not limited to:
               1. the presence of cardiac implantable electronic device implanted <6 weeks ago;
               2. pacing capture threshold out of the normal range;
               3. additional cardiac leads (particularly abandoned pacemaker leads), epicardial
                  leads, fractured leads, additional components such as lead adapters or lead
                  extension;
               4. aneurysm clips, artificial heart valves, ear implants, or foreign metal objects
                  in the eyes, skin, or body that could be contraindication to CMR;
               5. presence of claustrophobia making impossible to perform CMR;
               6. or any other clinical history or study that determines that, in the
                  investigator's judgment, the performance of an CMR may pose a potential risk to
                  the patient.
         19. Immunization with live organism vaccines in the last 3 months prior to randomization.
         20. Chronic alcohol or drug abuse or non-compliance with medical recommendations or any
             condition that, in the investigator's opinion, makes patient an unreliable trial
             subject or unlikely to complete the trial.
         21. Use of other investigational drugs at the time of enrollment, or within 30 days, or
             within 5 half-lives of enrollment, whichever is longer.
         22. Subjects directly involved in the execution of this protocol.
               -  CMR in non-conditional CIED proved to be safe. CMR in CIED patients will be
                  performed according to HRS 2017 and ESC Pacing 2021 guidelines