Study to Evaluate the Efficacy of Immunosuppression in Myocarditis or Inflammatory Cardiomyopathy.

Study Overview
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Brief Summary
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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.

Detailed Description
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Myocarditis/ inflammatory cardiomyopathy, which often leads to HF, is still an under-studied disease with various clinical manifestations. The active myocarditis is found post-mortem even in 42% of sudden deaths of young people and in 9-16% of adults and 46% of children with idiopathic dilated cardiomyopathy. Moreover, an increase in morbidity and mortality from myocarditis was recorded in the years 1990-2015. Myocarditis significantly increases the risk of HF, serious arrhythmias and conduction abnormalities, sudden death, anxiety, depression and it reduces quality of life. Myocarditis affects mainly young people (18-40 years old, and children) who lead active family life and work. Therefore, the disease causes deterioration of entire family life, it reduces individual productivity, creates high and long-term treatment costs. There is an urgent need to improve myocarditis therapy. Current guidelines recommendations in myocarditis consists of standard treatment of already developed HF and long-term avoidance of physical activity. Due to the lack of good quality scientific data, there is no clear recommendation for the targeted treatment - thus patients' prognosis may be poor. The pathogenesis of myocarditis and limited reports suggest the reasonable chance of significant improvement of patients' survival due to immunosuppressive therapy. Aim: Aim of the IMPROVE-MC study is to assess the efficacy and safety of 12-month immunosuppressive treatment with prednisone and azathioprine compared with placebo on the guideline-recommended medical therapy in patients with biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy. Secondary aim is to create ready-to-use diagnostic and therapeutic scheme in polish and international healthcare systems, which can lead to myocarditis guidelines change. Population and methods: In this multicenter (7 recruitment centers), prospective, randomized, double-blind placebo-controlled trial we are going to include 100 patients aged 18-75 years old, with biopsy-proven virus-negative myocarditis in stable or worsening course of the disease despite standard medical treatment, with left ventricular ejection fraction (LVEF) ≤45% and/or significant cardiac arrhythmias refractory to antiarrhythmic treatment. Exclusion criteria consist of ie.: another specific etiology of HF different from myocarditis; already implanted ventricular assist device; a heart transplant recipient; contraindications to immunosuppressive treatment; suspected sarcoidosis or giant cell myocarditis. Intervention: azathioprine for 12 months and prednisone for the first 6 months versus placebo for 12 months Study course: after randomization patients will undergo one-year double-blind treatment and then one-year follow-up to assess the long-term effects of the treatment. The efficacy and safety of the treatment will be assessed during study visits: investigational products/ placebo will be provided and additional tests will be performed - 48-hour Holter monitoring, echocardiography, cardiac magnetic resonance imaging (MRI), laboratory tests and follow-up endomyocardial biopsy after one-year of treatment. In order to broaden knowledge about myocarditis pathogenesis additional genetic, immunology and proteomic tests will be performed. All echo, MRI, Holter and biopsy tests will be evaluated centrally. Study endpoints: primary endpoint is change from baseline in mean LVEF at 12-months. Secondary endpoints (assessed after 3, 6, 12, 18, 24 months since the treatment start) consist of: the percentage of patients with ≥10% increase of LVEF; occurrence of hospitalization; death; heart transplantation; cardiac device implantation; ablation of heart rhythm disorders; change of arrhythmia burden; HF symptoms assessed in New York Heart Association (NYHA) class; distance in 6-minute walk test; quality of life; echocardiographic parameters; cardiac MRI; histopathological exam; biomarkers of fibrosis and myocardial necrosis; concentration of anti-heart auto-antibodies. Summary: 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 of myocarditis patients. This nationwide project will help in creation

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy of Immunosuppression in Biopsy-proven Virus Negative Myocarditis or Inflammatory Cardiomyopathy

Conditions
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Myocarditis, Heart Failure, Endomyocardial Biopsy, Cardiomyopathies, Secondary, Immunosuppression

Intervention / Treatment
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* Drug: Prednisone
* Drug: Azathioprine
* Drug: Placebo Prednisone
* Drug: Placebo Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for inclusion in this study, patient must fulfill all of the following inclusion criteria: Written 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. Patient with clinically suspected myocarditis or inflammatory cardiomyopathy (according to the criteria of the ESC Working Group on Myocardial & Pericardial Diseases 2013); OR/ AND, Patients with already diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory cardiomyopathy who will undergo diagnostic right ventricular EMB during the screening. Men or women aged 18-70. Women of childbearing age must have a negative pregnancy test result. 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. No significant improvement in clinical condition or worsening course of the disease despite the standard treatment in the last ≥ 3 months prior to the screening period (V1). LVEF ≤ 45% measured by echocardiogram taken during the screening period (V1) No LVEF improvement in the last ≥3 months prior to the screening period (V1). LVEF should be measured under stable conditions as assessed by the investigator. LVEF should be verified in the CORE-LAB. Histological and immunohistochemical evidence of active myocarditis (lymphocytic or eosinophilic) OR inflammatory cardiomyopathy during the screening period (V1). Absence of cardiotropic viruses in cardiac tissue at PCR analysis during the screening period (V1). 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. 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, 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). Deficiency or mutation of the enzyme TPMT measured at screening (V1). Positive test for infections: including HIV, HBV, HCV, tuberculosis (Quantiferon), borreliosis. Another specific cause of heart failure (including severe congenital, valvular, hypertensive, and/or coronary artery disease) that could justify the severity of cardiac dysfunction. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, genetic hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or known pericardial constriction. Subjects with body mass index >40 kg/m2 or body weight <50 kg. Pregnancy, lactation or women who plan to become pregnant during the trial. Lack of consent to the use of effective forms of contraception. Diagnosed or suspected cardiac sarcoidosis or giant cell myocarditis. Any documented or suspected active malignant neoplasm or history of malignant neoplasm within the 5 years prior to the screening period. History of cytostatic therapy or radiotherapy. Liver disease defined as any of the following: AST or ALT or ALP above 3x ULN; bilirubin >1.5 mg/dL. Impaired renal function, defined as eGFR <45 mL / min / 1.73 m2 (CKD-EPI) measured under stable condition or requiring dialysis. The need or refusal to stop taking any drug considered to interfere with the safe course of the study (e.g., allopurinol). Currently implanted VAD, CRT or heart transplant recipient. Patients with pacemaker or ICD requiring a high percentage of ventricular pacing (>30%) which could influence the result of LVEF measurement. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial drug(s) absorption in the investigator's opinion. History or presence of any other disease with a life expectancy <3 years. Any contraindications or intolerance to CMR, including but not limited to: the presence of non-CMR-compatible pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that could be contraindication to CMR; 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. Immunization with live organism vaccines in the last 3 months prior to randomization. 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. Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5 half-lives of enrollment, whichever is longer. Persons directly involved in the execution of this protocol. The investigator may consider re-screening the patient at a later time if believes that the patient's condition has changed and may potentially be eligible. A patient may be re-screened once only.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunsuppression<br>Prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months and Azathioprine: 2 mg/kg daily for 12 months | Drug: Prednisone<br>* Prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months<br>Drug: Azathioprine<br>* Azathioprine: 2 mg/kg daily for 12 months<br>|
| Placebo Comparator: Placebo<br>placebo matching prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months and placebo matching azathioprine: 2 mg/kg daily for 12 months | Drug: Placebo Prednisone<br>* Placebo Prednisone<br>Drug: Placebo Azathioprine<br>* Placebo Azathioprine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in LVEF at 12 - months. | Change from baseline in left ventricle ejection fraction (LVEF) at 12 - months. | 12- months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who responded to immunosuppressive therapy. | Proportion of patients who responded to immunosuppressive therapy as defined by an LVEF increase of ≥10% over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time. | Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in NYHA class over time. | Change from baseline in NYHA class over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit). | Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit). | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in percentage of patients in NYHA III/IV and NYHA II class over time. | Change from baseline in percentage of patients in NYHA III/IV and NYHA II class over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Occurrence of need for diuretic i.v. administration. | Occurrence of need for diuretic i.v. administration. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in 6MWT distance over time. | Change from baseline in 6MWT distance over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Time to first adjudicated hospitalization for heart failure. | Time to first adjudicated hospitalization for heart failure. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Time to first all-cause hospitalization. | Time to first all-cause hospitalization. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Occurrence (first and recurrent) of all-cause hospitalization, heart failure hospitalization, heart failure outpatient visit, myocarditis or inflammatory cardiomyopathy recurrence, all-cause death, heart transplantation, implantation of cardiac device | • Occurrence (first and recurrent) of all-cause hospitalization, heart failure hospitalization, heart failure outpatient visit, myocarditis or inflammatory cardiomyopathy recurrence, all-cause death, heart transplantation, implantation of cardiac device (Pacemaker, ICD, CRT, VAD) assessed in combination or independently. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| New onset AF. | New onset AF. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| New onset sustained VT or VF. | New onset sustained VT or VF. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| ≥50% reduction from baseline in VEBs number in 48h Holter monitoring over time. | ≥50% reduction from baseline in VEBs number in 48h Holter monitoring over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| ≥50% reduction from baseline in nonsustained VT number in 48h Holter monitoring over time. | ≥50% reduction from baseline in nonsustained VT number in 48h Holter monitoring over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| ≥50% reduction from baseline in AF burden in 48h Holter monitoring over time. | ≥50% reduction from baseline in AF burden in 48h Holter monitoring over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Changes from baseline in echocardiographic parameters | • Changes from baseline in echocardiographic parameters (left and right ventricular function; dimensions and volumes of the heart cavities; thickness of heart chambers; Doppler velocity of the mitral annulus; strain and strain rate imaging changes) over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Changes from baseline in CMR results | • Changes from baseline in CMR results (EGE, LGE, edema, LV dimensions and volumes, T1/T2 mapping) after one-year. | 12- months | 
| Changes from baseline in concentration of biomarkers of fibrosis and myocardial necrosis (troponin I, NT-proBNP, sST2, Gal-3) over time. | Changes from baseline in concentration of biomarkers of fibrosis and myocardial necrosis (troponin I, NT-proBNP, sST2, Gal-3) over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Changes from baseline in concentration of AHA over time. | Changes from baseline in concentration of AHA over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Qualitative and quantitative change from baseline in inflammatory infiltration, HLA expression and fibrosis in EMB after one-year. | Qualitative and quantitative change from baseline in inflammatory infiltration, HLA expression and fibrosis in EMB after one-year. | 12- months | 
| Change from baseline of patients' health status as assessed by the patients self-reported EQ-5D over time. | Change from baseline of patients' health status as assessed by the patients self-reported EQ-5D over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in clinical summary score (heart failure symptoms and physical limitations domains) of KCCQ Questionnaire over time. | Change from baseline in clinical summary score (heart failure symptoms and physical limitations domains) of KCCQ Questionnaire over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in KCCQ overall summary score over time. | Change from baseline in KCCQ overall summary score over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in KCCQ total symptom score over time. | Change from baseline in KCCQ total symptom score over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in KCCQ individual domains over time. | Change from baseline in KCCQ individual domains over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in KCCQ based on patient-preferred outcome over time. | Change from baseline in KCCQ based on patient-preferred outcome over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in SF-36 questionnaire overall summary score over time. | Change from baseline in SF-36 questionnaire overall summary score over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in PGI-I scale over time. | Change from baseline in PGI-I scale over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in CGI-I scale over time. | Change from baseline in CGI-I scale over time. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 
| Change from baseline in health economic analysis by HCRU. | Change from baseline in health economic analysis by HCRU. | Secondary endpoints will be assessed in 3-month intervals up to 24th month from the randomization (unless otherwise indicated). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myocarditis, cardiomyopathy, immunosuppression, biopsy