Immunosuppressive Treatment in Chronic Virus-Negative Inflammatory Cardiomyopathy (TRINITY)

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

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.

Study Overview

• Status: Terminated
• Conditions: Inflammatory Cardiomyopathy
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Prednisolone; Drug: Mycophenolate Mofetil Placebo; Drug: Prednisolone Placebo

Detailed Description

Inflammatory cardiomyopathy constitutes a relevant part of the cohort of non-dilated left ventricular cardiomyopathy / 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 non-dilated left ventricular 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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Bad Nauheim, Germany
    • Kerckhoff-Klinik GmbH
  • Berlin, Germany
    • Charite - University Hospital Berlin
  • Essen, Germany
    • University Hospital Essen
  • Frankfurt, Germany, 60590
    • UHF- Universitäres Herz- und Gefässzentrum
  • Freiburg, Germany
    • University Hospital Freiburg - Bad Krozingen
  • Greifswald, Germany
    • University Hospital Greifswald
  • Göttingen, Germany, 37035
    • Universitatsmedizin Gottingen
  • Hamburg, Germany
    • UKE Hamburg
  • Heidelberg, Germany
    • University Hospital Heidelberg
  • Lübeck, Germany, 23538
    • Universitäres Herzzentrum Lübeck
  • Munich, Germany
    • LMU Klinikum
  • Munich, Germany
    • Klinikum Rechts der Isar
  • München, Germany, 80336
    • LMU Klinikum Standort Innenstadt
  • Regensburg, Germany
    • University Hospital Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years
2. Medical therapy for HF for ≥3 months and <10 years according to current guideline recommendations
3. Persistent reduction of LVEF <50% on a routine echocardiographic evaluation (Simpson's biplane) not older than 1 month at time of inclusion
4. EMB 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
5. 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
6. Negative pregnancy test and the use of a highly effective contraceptive measure in women with child-bearing potential (according to CTFG recommendations)
7. Written informed consent.

Exclusion Criteria:

1. Histopathological (as approved by the histopathology core lab) and/ or clinical evidence of acute lymphocytic myocarditis, sarcoidosis, GCM or eosinophilic myocarditis,
2. Known systemic inflammatory disease,
3. Recent major surgery within <6 weeks, recent ICD implantation within <6 weeks or recent CRT implantation within <3 months prior to,
4. Known coronary artery disease responsible for cardiac dysfunction (i.e., prior myocardial infarction, persistent stenosis ≥ 70%),
5. Pregnancy or lactation,
6. Contraindications to immunosuppressive treatment with MMF + corticosteroids,
7. Inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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
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
Cardiac autonomic function	Changes in cardiac autonomic function from baseline to 6 and 12 months follow-up.	6 and 12 months follow-up

Collaborators and Investigators

• Sponsor: LMU Klinikum
• Collaborators: Charite University, Berlin, Germany; University Hospital, Essen; University Hospital Tuebingen; Technical University of Munich; University Hospital Erlangen; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
• Investigators: Principal Investigator: Steffen Massberg, Prof Dr. med., LMU Klinikum

Publications and helpful links

Helpful Links

• study website
• sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2023
• Primary Completion (Actual): April 14, 2025
• Study Completion (Actual): April 14, 2025

Study Registration Dates

• First Submitted: September 28, 2022
• First Submitted That Met QC Criteria: October 5, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): July 25, 2025
• Last Update Submitted That Met QC Criteria: July 22, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: heart failure; myocarditis; inflammatory cardiomyopathy; Mycophenolate mofetil; chronic myocarditis; enomyocardial biopsy; immunosupression
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Cardiomyopathies; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Protective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Neuroprotective Agents; Methylprednisolone Acetate; Prednisolone; Mycophenolic Acid; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: TRINITY

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No