Micophenolate Mofetil Versus Azathioprine in Myocarditis

Heart Failure Clinical Trial

Official title: The Efficacy and Safety of Mycophenolate Mofetil in the Treatment of Lymphocytic Myocarditis in Comparison With Azathioprine

Status Recruiting

Clinical Trial Summary

The study is aimed at studying the direct efficacy of mycophenolate mofetil (mycophenolate mofetil, CellCept, Genentech, N015393/02, 12.08.2009) (in combination with corticosteroids (methylprednisolone, Metypred, Orion, 003467, 26.02.2016)) in the treatment of lymphocytic myocarditis: the effect on symptoms, structural and functional parameters of the heart, on the outcomes of lymphocytic myocarditis: mortality, the need for transplantation, other surgical interventions, the incidence of unwanted side effects, and forced cancellation (replacement) of the drug. To compare the data on the efficacy and safety of therapy with mycophenolate mofetil (in combination with corticosteroids) with the standard regimen of therapy for lymphocytic myocarditis (corticosteroids in combination with azathioprine), including in cases of forced replacement of drugs with each other.

Clinical Trial Description

From October 2020 to December 2022, it is planned to enroll 50 patients in "case-control" study diagnosed with virus negative lymphocytic myocarditis at the University Clinical Hospital No. 1, who meet the inclusion criteria. In this study, counting the sample is impossible and such a number of patients is explained by both the rarity of the pathology and the expensive diagnostic endomyocardial biopsy for mandatory confirmation of the diagnosis. Further, the patients will be divided into 2 groups. The main group is methylprednisolone at a starting dose of 24-40 mg / day + mycophenolate 2 g / day per os for 1 month, followed by a decrease in the dose of methylprednisolone to a maintenance dose (4-8 mg / day). The comparison group is methylprednisolone at a starting dose of 24-40 mg / day per os in combination with azathioprine 2 mg / kg per os (100-150 mg / day). All patients will receive standard heart failure therapy including beta-blockers, angiotensin converting enzyme inhibitors or angiotensin II receptor blocker, mineralocorticoid receptor antagonist, angiotensin receptor-neprilysin inhibitor (if required), diuretics (if required).

The first stage is the patient screening (medical history, newly admitted with suspected myocarditis) which includes examination to verify the diagnosis of severe and moderate subacute/chronic myocarditis. Basic research methods: anamnesis, physical examination, blood tests (general, biochemical), electrocardiogram, daily monitoring of electrocardiogram by Holter, transthoracic echocardiography, determination of the level of anticardial antibodies in the blood: regardless of the meal, venous blood is collected in a sterile test tube, then on the same day it is transported under normal conditions to the laboratory of the city clinical hospital №52 for immunomorphological examination. Reference values: antibodies to antigens of cardiomyocyte nuclei (no antibody titer), antibodies to endothelial antigens (antibody titer 1:40), antibodies to cardiomyocyte antigens (antibody titer 1:40), antibodies to smooth muscle antigens (antibody titer 1:40), antibodies to the antigens of the fibers of the cardiac conduction system (antibody titer 1:40) Endomyocardial biopsy of the right ventricle with determination of the genome of cardiotropic viruses in the myocardium by polymerase chain reaction, standard histological examination (staining with hematoxylin-eosin, according to Van Gieson), immunohistochemistry-specific antibodies for leukocytes (CD45), macrophages (CD68), T cells (CD3) and their main subtypes, helper (CD4) and cytotoxic (CD8) cells, and B cells (CD19/CD20): quantitative criteria to improve the diagnostic yield of endomyocardial biopsy in myocarditis include the Marburg criteria, based on the presence of >14 mononuclear leukocytes/mm2 on bioptic samples, with the presence of >7 T lymphocytes per mm2. These criteria were adopted in a position statement by the European Society of Cardiology experts). Additionally (for special indications): multislice computer tomography scanning and / or magnetic resonance imaging of the heart with intravenous contrasting with gadolinium (CAS: 88344-16-5), coronary angiography and myocardial scintigraphy (for patients with suspected coronary artery disease, high pretest likelihood of coronary heart disease more than 65%, positive exercise test, coronary atherosclerosis on computed tomography or previous myocardial infarction), genetic counseling (the process of genetic counseling is about sharing information regarding genetic and disease risks in a manner useful to an individual, couple, or family copes with a possible cause of genetically determined heart diseases: hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, canalopathy or restrictive cardiomyopathy).

Endomyocardial biopsy is performed according to indications developed in the clinic and consistent with the European recommendations for myocardial biopsy (2007).

At the second stage, patients who confirmed virus-negative lymphocytic myocarditis during endomyocardial biopsy, are included in the study according to the inclusion and non-inclusion criteria. All patients sign informed consent to participate in the study. The second stage involves the determination of indications for the appointment of immunosuppressive therapy (verified diagnosis of severe and moderate myocarditis, resistance to standard cardiotropic therapy for 2 months, the absence of markers of active viral infection in the blood and viral genome in the myocardium (adenovirus, enterovirus, citomegalovirus, Epstein-Barr virus, human herpes virus 6, hepatitis C virus, the human immunodeficiency virus, influenza, coronavirus (MERS-CoV, SARS-CoV, SARS-CoV-2), with the exception of parvovirus B19, the absence of other active infection). The distribution into two groups is made by the researcher. All patients are matched by gender and age. If the patient has previously received azathioprine with insufficient effect or side effects were present, then the patient is included in the main group and vice versa. The observation period is at least 6 months. The frequency of control examinations: 2 months after the start of therapy (with a stable course of myocarditis, studies are performed in absentia): blood tests (general, biochemical), electrocardiogram, 24 hour monitoring of electrocardiogram by Holter, transthoracic echocardiography, determination of the level of anticardial antibodies in the blood) and then every 6 months (with a stable course of myocarditis, studies are performed in absentia): blood tests (general, biochemical), electrocardiogram, daily monitoring of electrocardiogram by Holter, transthoracic echocardiogram, determination of the level of anticardial antibodies in the blood). observation median - one year. Statistical processing: SPSS version 23 software package.

Qualitative, quantitative variables:

Discrete data will be presented in the form of absolute values and percentages, continuous data - in the form of arithmetic mean ± standard deviation in the case of normal distribution or in the form of quartiles 50 [25; 75], if the distribution differs from normal.

Determination of the type of distribution:

To assess the normality of the distribution, the Kolmogorov-Smirnov test will be used.

Comparison of indicators between groups depending on the type of distribution:

Comparison of patients by groups will be carried out using χ2 or Fisher's exact test for categorical dichotomous variables, for the rest - using the Student's t-test (with a normal distribution and the number of observations over 25) or Mann-Whitney U-test.

Survival assessment:

Survival analysis will be performed with Kaplan-Meier curves.

Regression analysis:

Correlation analysis followed by linear regression will be performed to identify possible predictors of outcomes.

Differences will be considered significant at a significance level of p≤0.05. ;

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Death
• Death, Sudden, Cardiac
• Dilated Cardiomyopathy
• Heart Failure
• Myocarditis
• Sudden Cardiac Death

• NCT number: NCT05237323
• Study type: Interventional
• Source: I.M. Sechenov First Moscow State Medical University
• Contact: Olga Blagova
• Phone: 89168349169
• Email: blagovao@mail.ru, blagova_o_v@staff.sechenov.ru
• Status: Recruiting
• Phase: Phase 3
• Start date: October 1, 2020
• Completion date: May 29, 2023