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

Primary Purpose

Inflammatory Cardiomyopathy

Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Mycophenolate Mofetil
Prednisolone
Mycophenolate Mofetil Placebo
Prednisolone Placebo
Sponsored by
LMU Klinikum
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Inflammatory Cardiomyopathy focused on measuring inflammatory cardiomyopathy, heart failure, Mycophenolate mofetil, chronic myocarditis, myocarditis, enomyocardial biopsy, immunosupression

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 18-75 years
  2. Heart failure NYHA II-III
  3. 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
  4. Persistent reduction of LVEF <45% on a routine echocardiographic evaluation (Simpson's biplane) not older than 1 month at time of inclusion
  5. 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
  6. 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
  7. Negative pregnancy test and the use of a highly effective contraceptive measure in women with child-bearing potential (according to CTFG recommendations)
  8. Written informed consent.

Exclusion Criteria:

  1. Age <18 or >75 years
  2. Histopathological (as approved by the histopathology core lab) and/ or clinical evidence of acute lymphocytic myocarditis, sarcoidosis, GCM or eosinophilic myocarditis
  3. Known or possible systemic inflammatory disease
  4. Hemodynamic instability/shock
  5. Atrial fibrillation with low probability for restoration of a stable sinus rhythm
  6. Recent (<3 months) initiation of any of the following medications: betablocker, ACEi/sartans/ARNI, SGLT2-inhibitors, MRA
  7. Recent major surgery within <6 weeks, recent ICD implantation within <6 weeks or recent CRT implantation within <6 months prior to baseline examinations
  8. Congenital, hypertensive, or valvular heart disease
  9. 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)
  10. Known coronary artery disease responsible for cardiac dysfunction (i.e. prior myocardial infarction, chronic total occlusion, persistent stenosis >50%)
  11. Life expectancy <1 year
  12. Therapy with immunosuppression (with comparable regimen) before enrolment
  13. Drug or alcohol abuse
  14. Pregnancy or lactation
  15. 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)
  16. Inability to undergo repetitive MRI scans
  17. Inability to provide informed consent
  18. Current participation or previous participation in another clinical trial within the preceding 6 months

Sites / Locations

  • Kerckhoff-Klinik GmbH
  • Charité - University Hospital Berlin
  • University Hospital Essen
  • University Hospital Freiburg - Bad Krozingen
  • University Hospital Greifswald
  • UKE Hamburg
  • University Hospital Heidelberg
  • Klinikum rechts der Isar
  • LMU KlinikumRecruiting
  • University Hospital Regensburg

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Immunosuppressive treatment

Placebo

Arm Description

Mycophenolate mofetil (MMF) 1g bid and prednisolone at initially 1mg/kg in a step-down regime

Mycophenolate mofetil (MMF) and prednisolone Placebo

Outcomes

Primary Outcome Measures

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
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).

Secondary Outcome Measures

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
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).
Ventricular remodelling (MRI)
Absolute decrease of left ventricular diameters, volumes, mass, and sphericity from baseline to 6 and 12 months follow-up (MRI).
Strain (MRI)
Changes in global longitudinal, radial, and circumferential strain from baseline to 6 and 12 months follow-up (MRI).
LVEF increase (echo)
Absolute increase in LVEF and rate of increase by ≥10% at 6 and 12 months follow-up (echo, metric, and binary).
Ventricular remodelling (echo)
Decrease of left ventricular diameters and volumes by ≥10% at 6 and 12 months follow-up (echo).
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).
Diastolic parameters (echo)
Changes in diastolic parameters from baseline to 6 and 12 months follow-up (echo).
Mitral and tricuspid regurgitation (echo)
Presence of MR/TR >2 at baseline and at 6 and 12 months followup (echo).
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.
NYHA
Changes in NYHA functional class from baseline to 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).
Cardiac autonomic function
Changes in cardiac autonomic function (PRD, DC) from baseline to 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.
Biomarker
Time-averaged proportional change in NT-proBNP

Full Information

First Posted
September 28, 2022
Last Updated
May 22, 2023
Sponsor
LMU Klinikum
Collaborators
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Technical University of Munich, Charite University, Berlin, Germany, University Hospital, Essen, University Hospital Erlangen, University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT05570409
Brief Title
Immunosuppressive Treatment in Chronic Virus-Negative Inflammatory Cardiomyopathy
Acronym
TRINITY
Official Title
A Multicenter, Randomized, Double-blind, Placebo-controlled TRial Evaluating Immunosuppressive Treatment in Patients With Chronic Virus-Negative Inflammatory cardiomyopaThY (TRINITY Trial)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 28, 2023 (Actual)
Primary Completion Date
March 28, 2027 (Anticipated)
Study Completion Date
March 28, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
LMU Klinikum
Collaborators
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Technical University of Munich, Charite University, Berlin, Germany, University Hospital, Essen, University Hospital Erlangen, University Hospital Tuebingen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Inflammatory Cardiomyopathy
Keywords
inflammatory cardiomyopathy, heart failure, Mycophenolate mofetil, chronic myocarditis, myocarditis, enomyocardial biopsy, immunosupression

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Investigator-initiated, multicenter, randomized, double-blind, placebocontrolled clinical trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Immunosuppressive treatment
Arm Type
Experimental
Arm Description
Mycophenolate mofetil (MMF) 1g bid and prednisolone at initially 1mg/kg in a step-down regime
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Mycophenolate mofetil (MMF) and prednisolone Placebo
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
MMF
Intervention Description
Mycophenolate mofetil 1g bid for 6 months
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Description
initially 1mg/kg in a step-down regime for 6 months
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil Placebo
Other Intervention Name(s)
MMF Placebo
Intervention Description
MMF matching Placebo
Intervention Type
Drug
Intervention Name(s)
Prednisolone Placebo
Intervention Description
Prednisolone matching placebo
Primary Outcome Measure Information:
Title
LVEF increase (metric)
Description
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
Time Frame
12 months follow-up
Title
LVEF increase (binary)
Description
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).
Time Frame
12 months follow-up
Secondary Outcome Measure Information:
Title
Composite clinical outcome
Description
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
Time Frame
12 months
Title
LVEF increase 6 months (MRI)
Description
Absolute increase in LVEF and rate of increase by ≥10% at 6 months follow-up (MRI, metric, and binary endpoint).
Time Frame
6 months follow-up
Title
Ventricular remodelling (MRI)
Description
Absolute decrease of left ventricular diameters, volumes, mass, and sphericity from baseline to 6 and 12 months follow-up (MRI).
Time Frame
6 and 12 months follow-up
Title
Strain (MRI)
Description
Changes in global longitudinal, radial, and circumferential strain from baseline to 6 and 12 months follow-up (MRI).
Time Frame
6 and 12 months follow-up
Title
LVEF increase (echo)
Description
Absolute increase in LVEF and rate of increase by ≥10% at 6 and 12 months follow-up (echo, metric, and binary).
Time Frame
6 and 12 months follow-up
Title
Ventricular remodelling (echo)
Description
Decrease of left ventricular diameters and volumes by ≥10% at 6 and 12 months follow-up (echo).
Time Frame
6 and 12 months follow-up
Title
Strain (echo)
Description
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).
Time Frame
6 and 12 months follow-up
Title
Diastolic parameters (echo)
Description
Changes in diastolic parameters from baseline to 6 and 12 months follow-up (echo).
Time Frame
6 and 12 months follow-up
Title
Mitral and tricuspid regurgitation (echo)
Description
Presence of MR/TR >2 at baseline and at 6 and 12 months followup (echo).
Time Frame
6 and 12 months follow-up
Title
Cardiopulmonary exercise capacity
Description
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.
Time Frame
6 and 12 months follow-up
Title
NYHA
Description
Changes in NYHA functional class from baseline to 6 and 12 months follow-up.
Time Frame
6 and 12 months follow-up
Title
QoL
Description
Changes in patient-reported outcome (quality of life; QOL) from baseline to follow-up as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ).
Time Frame
12 months
Title
Cardiac autonomic function
Description
Changes in cardiac autonomic function (PRD, DC) from baseline to 6 and 12 months follow-up.
Time Frame
6 and 12 months follow-up
Title
Composite safety outcome
Description
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.
Time Frame
12 months
Title
Biomarker
Description
Time-averaged proportional change in NT-proBNP
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ulrich Grabmaier, PD Dr. med.
Phone
+49-(0)152-5484-8309
Email
ulrich.grabmaier@med.uni-muenchen.de
First Name & Middle Initial & Last Name or Official Title & Degree
Anna-Luisa Häcker, Dr. rer. nat.
Email
annaluisa.haecker@med.uni-muenchen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Urlich Grabmaier, PD Dr. med.
Organizational Affiliation
LMU Klinikum
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kerckhoff-Klinik GmbH
City
Bad Nauheim
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andreas Rieth, Dr. med.
Facility Name
Charité - University Hospital Berlin
City
Berlin
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bettina Heidecker, PD Dr. med.
Facility Name
University Hospital Essen
City
Essen
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tienush Rassaf, Prof. Dr. med.
Facility Name
University Hospital Freiburg - Bad Krozingen
City
Freiburg
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ingo Hilgendorf, PD Dr. med.
Facility Name
University Hospital Greifswald
City
Greifswald
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephan Felix, Prof. Dr.
Facility Name
UKE Hamburg
City
Hamburg
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christina Magnussen, PD Dr. med.
Facility Name
University Hospital Heidelberg
City
Heidelberg
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benjamin Meder, Prof. Dr. med.
Facility Name
Klinikum rechts der Isar
City
Munich
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karl-Ludwig Laugwitz, Prof. Dr. med.
Facility Name
LMU Klinikum
City
Munich
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ulrich Grabmaier, PD Dr. med.
Email
ulrich.grabmaier@med.uni-muenchen.de
First Name & Middle Initial & Last Name & Degree
Massberg Steffen, Prof. Dr. med.
Email
steffen.massberg@med.uni-muenchen.de
Facility Name
University Hospital Regensburg
City
Regensburg
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bernhard Unsöld, Prof. Dr. med.

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://trinity.dzhk.de/
Description
study website
URL
https://www.lmu-klinikum.de/kardiologie/forschung-und-lehre/klinische-forschung/klinische-studien/0890f576db839fe4
Description
sponsor website

Learn more about this trial

Immunosuppressive Treatment in Chronic Virus-Negative Inflammatory Cardiomyopathy

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