Immunosuppressive Treatment in Chronic Virus-Negative Inflammatory Cardiomyopathy

Inflammatory Cardiomyopathy Clinical Trial

— TRINITY  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05570409
• Other study ID #: TRINITY
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 28, 2023
• Est. completion date: March 28, 2028

Study information

• Verified date: January 2024
• Source: LMU Klinikum
• Contact: Ulrich Grabmaier, PD Dr. med.
• Phone: +49-(0)152-5484-8309
• Email: ulrich.grabmaier[@]med.uni-muenchen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: March 28, 2028
• Est. primary completion date: March 28, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiomyopathies
• Inflammatory Cardiomyopathy

Intervention

Drug:
• Mycophenolate Mofetil
Mycophenolate mofetil 1g bid for 6 months
• Prednisolone
initially 1mg/kg in a step-down regime for 6 months
• Mycophenolate Mofetil Placebo
MMF matching Placebo
• Prednisolone Placebo
Prednisolone matching placebo

Locations

Country	Name	City	State
Germany	Kerckhoff-Klinik GmbH	Bad Nauheim
Germany	Charité - University Hospital Berlin	Berlin
Germany	University Hospital Essen	Essen
Germany	UHF- Universitäres Herz- und Gefässzentrum	Frankfurt
Germany	University Hospital Freiburg - Bad Krozingen	Freiburg
Germany	Universitätsmedizin Göttingen	Göttingen
Germany	University Hospital Greifswald	Greifswald
Germany	UKE Hamburg	Hamburg
Germany	University Hospital Heidelberg	Heidelberg
Germany	Universitäres Herzzentrum Lübeck	Lübeck
Germany	LMU Klinikum Standort Innenstadt	München
Germany	Klinikum rechts der Isar	Munich
Germany	LMU Klinikum	Munich
Germany	University Hospital Regensburg	Regensburg

Sponsors (7)

Lead Sponsor	Collaborator
LMU Klinikum	Charite University, Berlin, Germany, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Technical University of Munich, University Hospital Erlangen, University Hospital Tuebingen, University Hospital, Essen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Diastolic parameters (echo)	Changes in diastolic parameters from baseline to 6 and 12 months follow-up (echo).	6 and 12 months follow-up
Secondary	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
Secondary	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
Secondary	NYHA	Changes in NYHA functional class from baseline to 6 and 12 months follow-up.	6 and 12 months follow-up
Secondary	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
Secondary	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
Secondary	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
Secondary	Biomarker	Time-averaged proportional change in NT-proBNP	12 months

External Links

•   sponsor website
•   study website