Clinical trial NCT01877746: CZECH-ICIT (CZECH Inflammatory Cardiomyopathy Immunosuppression Trial)
Official title: RANDOMIZED, MULTICENTRIC STUDY COMPARING THE EFFECT OF TWO REGIMENS OF COMBINED IMMUNOSUPPRESSIVE THERAPY IN THE TREATMENT OF INFLAMMATORY CARDIOMYOPATHY CZECH-ICIT (CZECH INFLAMMATORY CARDIOMYOPATHY IMMUNOSUPPRESSION TRIAL)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Inflammatory Cardiomyopathy
Keywords: ICM
myocarditis
cardiomyopathy
endomyocardial biopsy
immunosuppression
Lead sponsor: St. Anne's University Hospital Brno, Czech Republic
Sponsor class: OTHER
First posted: 2013-06-14
Enrollment: 234
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to compare the effect of combined immunosuppressive therapy given on the top standard medical therapy of chronic heart failure according to current guidelines with standard medical therapy of chronic heart failure alone in patients with infammatory cardiomyopathy (ICM).

Suitable subjects are characterized by EMB established presence of myocardial inflammation / negative polymerase chain reaction assay (PCR) findings of cardiotropic infectious agents and with varying duration of heart failure symptoms and left ventricular (LV) systolic dysfunction (phase A).

Further, to compare the effect of two regimens of combined immunosuppressive therapy in these patients with ICM (phase B).


Eligibility criteria: Inclusion Criteria:

1. Males and females aged 18 to 65 years at the time of signing the informed consent
2. Signing of the informed consent.
3. LV systolic dysfunction defined by ejection fraction less than/or equal 40% as assessed by echocardiography and symptoms of heart failure (minimum NYHA class II) lasting for at least 2 weeks at the time of randomization. This criterion also determines the inclusion of the study subjects in one of two substudies (CZECH-ICIT 1 or CZECH-ICIT 2).

   * LV systolic dysfunction (defined by ejection fraction less than/or equal 40%) and symptoms of heart failure (minimum NYHA class II) lasting 2 weeks to 6 months, with standard medical therapy of chronic heart failure given for at least 2 weeks - the subject fulfills criterion for inclusion in CZECH-ICIT 1 substudy
   * LV systolic dysfunction (defined by ejection fraction less than/or equal 40%) and symptoms of heart failure (minimum NYHA class II) lasting more than 6 months, with standard medical therapy of chronic heart failure given for at least 2 weeks - the subject fulfills criterion for inclusion in CZECH-ICIT 2 substudy
4. Positive immunohistochemistry finding of myocardial inflammation in endomyocardial biopsy (EMB). EMB must have been be performed no more than 6 weeks prior to the inclusion in the study. Positive immunohistochemistry EMB finding demonstrating myocardial inflammation is defined by the presence of at least 7/mm2 cluster of differentiation 3 (CD3) positive lymphocytes and/or at least 14 infiltrating leucocytes (LCA+ cells)/mm2 in the specimen.
5. The absence of infectious agent in EMB is defined by negative results of PCR testing of EMB specimens. PCR testing will be aimed to exclude the presence of enteroviruses (ECHO, coxsackie), adenoviruses, herpes viruses (herpes simplex virus (HSV-1), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus (HHV-6)), Borrelia burgdorferi and parvovirus B19. In the case of parvovirus B19, a negative PCR result will be considered when less than 500 viral copies/ug genomic DNA are detected. EMB must have been performed no more than 6 weeks prior to the inclusion in the study.
6. Negative blood pregnancy test in fertile females.
7. Usage of the effective method of contraception (hormonal or 2 barrier method of contraception)

Exclusion Criteria:

1. The presence of coronary artery disease, defined by angiographic findings of one or more coronary artery stenosis \> 50%, history of previous myocardial infarction and/or percutaneous or surgical myocardial revascularization. Coronary angiography must not have been performed more than 2 years before randomization into the study.
2. Permanent pacemaker including cardiac resynchronization therapy.
3. The presence of uncontrolled, persistent supraventricular tachyarrhythmia, with ventricular rate \> 120/min, lasting more than 1 week before EMB.
4. The presence of uncontrolled arterial hypertension, defined by blood pressure values \> 180mmHg (for systolic pressure) and/or 110mmHg (for diastolic pressure) lasting more than 3 months.
5. The presence of at least moderately hemodynamically significant primary valvulopathy or congenital heart disease (apart from patent foramen ovale and non-significant atrial septal defect).
6. Previous heart valve surgery (replacement or reconstruction) or surgical correction of congenital heart disease. adu.
7. A history of cytostatic therapy or radiotherapy.
8. Alcoholism defined as ethanol intake \>90 g/day.
9. The presence of uncontrolled endocrine of metabolic disorder.
10. Gravidity and lactation.
11. Known hypersensitivity to investigational drugs.
12. All contraindications of immunosuppressive therapy according to Summary of product characteristics (SmPC) of both investigational medicinal products: untreated systemic infection, poorly manageable diabetes mellitus, osteoporosis, florid gastric or duodenal ulcer, uncontrolled arterial hypertension, history of malignant disease with oncological treatment finished less than 5 years, proven immunodeficiency, renal of hepatic insufficiency (serum creatinine \> 200 µmol/l; alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) activity greater than three times the standard), leukocytopenia (leucocytes less than 4 x 10 9/l), thrombocytopenia (platelets less than 100 x 10 9/l), anemia (hemoglobin concentration less than 100 g/l).

Primary outcomes:
measure: comparison of the change in LV ejection fraction
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
Secondary outcomes:
measure: comparison of the change of LV end-diastolic and end-systolic diameters
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
measure: comparison of the change of New York Heart Association (NYHA) class
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
measure: comparison of total mortality
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
measure: comparison of the combined end-point
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
measure: comparison of the change in the number of infiltrating inflammatory cells in EMB
timeFrame: baseline and in 12 months after the initiation of immunosuppressive therapy
Other outcomes:
Locations:
city: Brno
country: Czech Republic
facility: St. Anne's University Hospital Brno
city: Prague
country: Czech Republic
facility: General University hospital in Prague
Study officials:
affiliation: employee
name: Jan Krejci, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: without affiliation
name: Tomas Palecek, Assoc. prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation. 2001 Jul 3;104(1):39-45. doi: 10.1161/01.cir.104.1.39.
citation: Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009 Aug;30(16):1995-2002. doi: 10.1093/eurheartj/ehp249. Epub 2009 Jun 25.