Immunosuppressive Treatment in Chronic Virus-Negative Inflammatory Cardiomyopathy

Study Overview
=================
Brief Summary
-----------------
Evaluating Immunosuppressive treatment (Mycophenolate mofetil and prednisolon compared to placebo) for 6 months in patients with chronic virus- Negative Inflammatory cardiomyopathy - a multicenter, randomized, double-blind, placebo-controlled trial.

Detailed Description
-----------------
Inflammatory cardiomyopathy constitutes a relevant part of the cohort of hypokinetic non-dilated cardiomyopathy (HNDC)/ dilated cardiomyopathy (DCM) and is associated with adverse outcome. Urgent medical needs remain with respect to the therapeutic options for inflammatory cardiomyopathy. So far, no specific therapy for patients with inflammatory cardiomyopathy is available. Existing data on immunosuppression for inflammatory cardiomyopathy is preliminary and needs further validation by larger randomized, controlled, multicenter trials. Patients with biopsy-proven virus-negative inflammatory dilated or hypokinetic non-dilated cardiomyopathy and moderate to severe deterioration of cardiac function despite optimal medical treatment (OMT) for heart failure (HF) will be randomized (1:1) in a double-blinded way to Mycophenolate mofetil (MMF) 1g bid and prednisolone at initially 1mg/kg in a step-down regime for 6 months or placebo. The clinical benefit will be measured with respect to absolute increase in LVEF (metric and binary co-primary endpoints assessed by MRI core lab) of immunosuppressive treatment with MMF and prednisolone compared to placebo at 12 months follow-up.

Official Title
-----------------
A Multicenter, Randomized, Double-blind, Placebo-controlled TRial Evaluating Immunosuppressive Treatment in Patients With Chronic Virus-Negative Inflammatory cardiomyopaThY (TRINITY Trial)

Conditions
-----------------
Inflammatory Cardiomyopathy

Intervention / Treatment
-----------------
* Drug: Mycophenolate Mofetil
* Drug: Prednisolone
* Drug: Mycophenolate Mofetil Placebo
* Drug: Prednisolone Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-75 years Heart failure NYHA II-III Medical therapy for HF for ≥6 months and <5 years including betablockers, ACE-inhibitors/sartans and/or ARNI, MRA, SGLT2i and diuretics according to current guideline recommendations Persistent reduction of LVEF <45% on a routine echocardiographic evaluation (Simpson's biplane) not older than 1 month at time of inclusion EMB >3 months after first diagnosis of HNDC/DCM and not older than 3 months at time of inclusion with immunohistochemical evidence of lymphocytic myocarditis defined as ≥14 leukocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD3 positive T-lymphocytes ≥7 cells/mm2 and increased MHC-II expression as approved by the histopathology core lab Absence of established cardiotropic virus infection in EMBs (i.e. enteroviruses, HHV-6, EBV, CMV, adenoviruses, parvovirus B19 >500 copies) as approved by the histopathology core lab Negative pregnancy test and the use of a highly effective contraceptive measure in women with child-bearing potential (according to CTFG recommendations) Written informed consent. Exclusion Criteria: Age <18 or >75 years Histopathological (as approved by the histopathology core lab) and/ or clinical evidence of acute lymphocytic myocarditis, sarcoidosis, GCM or eosinophilic myocarditis Known or possible systemic inflammatory disease Hemodynamic instability/shock Atrial fibrillation with low probability for restoration of a stable sinus rhythm Recent (<3 months) initiation of any of the following medications: betablocker, ACEi/sartans/ARNI, SGLT2-inhibitors, MRA Recent major surgery within <6 weeks, recent ICD implantation within <6 weeks or recent CRT implantation within <6 months prior to baseline examinations Congenital, hypertensive, or valvular heart disease Familial DCM/HNDC (two or more first- or second-degree relatives have DCM or HNDC, or a first-degree relative has autopsy proven DCM and sudden death at <50 years of age) Known coronary artery disease responsible for cardiac dysfunction (i.e. prior myocardial infarction, chronic total occlusion, persistent stenosis >50%) Life expectancy <1 year Therapy with immunosuppression (with comparable regimen) before enrolment Drug or alcohol abuse Pregnancy or lactation Contraindications to immunosuppressive treatment with MMF + corticosteroids (e.g., known allergic reaction to the study drug or any of its components, severe and uncontrollable diabetes mellitus, severe osteoporosis, active peptic ulceration, uncontrolled psychiatric illness, severe liver disease, infectious diseases such as tuberculosis, HIV, viral hepatitis, any history of malignancy) Inability to undergo repetitive MRI scans Inability to provide informed consent Current participation or previous participation in another clinical trial within the preceding 6 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator-initiated, multicenter, randomized, double-blind, placebocontrolled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppressive treatment<br>Mycophenolate mofetil (MMF) 1g bid and prednisolone at initially 1mg/kg in a step-down regime | Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil 1g bid for 6 months<br>* Other names: MMF;Drug: Prednisolone<br>* initially 1mg/kg in a step-down regime for 6 months<br>|
| Placebo Comparator: Placebo<br>Mycophenolate mofetil (MMF) and prednisolone Placebo | Drug: Mycophenolate Mofetil Placebo<br>* MMF matching Placebo<br>* Other names: MMF Placebo;Drug: Prednisolone Placebo<br>* Prednisolone matching placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LVEF increase (metric) | Absolute increase in LVEF at 12 months follow-up as assessed by blinded investigators of the MRI core lab (metric endpoint)lab) of immunosuppressive treatment with MMF and prednisolone compared to placebo | 12 months follow-up | 
| LVEF increase (binary) | Proportion of patients with an absolute increase in LVEF ≥10% at 12 months follow-up as assessed by blinded investigators of the MRI core lab (binary endpoint). | 12 months follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite clinical outcome | Composite clinical outcome: cardiac death, heart transplantation or a heart failure event (hospitalization for heart failure or the equivalent, i.e., an urgent HF visit) within 12 months from randomization, analyzed as time to first event.physical capacity, cardiac autonomic function, transplant-free survival and hospitalization rate, biomarkers and adverse events | 12 months | 
| LVEF increase 6 months (MRI) | Absolute increase in LVEF and rate of increase by ≥10% at 6 months follow-up (MRI, metric, and binary endpoint). | 6 months follow-up | 
| Ventricular remodelling (MRI) | Absolute decrease of left ventricular diameters, volumes, mass, and sphericity from baseline to 6 and 12 months follow-up (MRI). | 6 and 12 months follow-up | 
| Strain (MRI) | Changes in global longitudinal, radial, and circumferential strain from baseline to 6 and 12 months follow-up (MRI). | 6 and 12 months follow-up | 
| LVEF increase (echo) | Absolute increase in LVEF and rate of increase by ≥10% at 6 and 12 months follow-up (echo, metric, and binary). | 6 and 12 months follow-up | 
| Ventricular remodelling (echo) | Decrease of left ventricular diameters and volumes by ≥10% at 6 and 12 months follow-up (echo). | 6 and 12 months follow-up | 
| Strain (echo) | Changes in global longitudinal, radial, circumferential, early, and late diastolic strain (LV), free wall and septal strain (RV), left atrial strain (LA) from baseline to 6 and 12 months follow-up (echo). | 6 and 12 months follow-up | 
| Diastolic parameters (echo) | Changes in diastolic parameters from baseline to 6 and 12 months follow-up (echo). | 6 and 12 months follow-up | 
| Mitral and tricuspid regurgitation (echo) | Presence of MR/TR >2 at baseline and at 6 and 12 months followup (echo). | 6 and 12 months follow-up | 
| Cardiopulmonary exercise capacity | Changes in cardiopulmonary exercise capacity: Distance in the sixminute walk test (6MWT) from baseline to 6 and 12 months followup and (optionally) VO2max, anaerobic threshold and VE/VCO2 on spiroergometry. | 6 and 12 months follow-up | 
| NYHA | Changes in NYHA functional class from baseline to 6 and 12 months follow-up. | 6 and 12 months follow-up | 
| QoL | Changes in patient-reported outcome (quality of life; QOL) from baseline to follow-up as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). | 12 months | 
| Cardiac autonomic function | Changes in cardiac autonomic function (PRD, DC) from baseline to 6 and 12 months follow-up. | 6 and 12 months follow-up | 
| Composite safety outcome | Time to the first occurrence of any of the components of the composite safety outcome: death of any cause, arrhythmias requiring intervention, severe adverse events requiring hospitalization. | 12 months | 
| Biomarker | Time-averaged proportional change in NT-proBNP | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
chronic myocarditis, myocarditis, enomyocardial biopsy, immunosupression, inflammatory cardiomyopathy, heart failure, Mycophenolate mofetil