A multicenter, randomized, double-blind, placebo-controlled TRial evaluating Immunosuppressive treatment in patients with chronic virus-Negative Inflammatory cardiomyopaThY (TRINITY trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Klinikum der Universitaet Muenchen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

28 Feb 2023 → 14 Apr 2025

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512451-20-00

EudraCT number

2021-005875-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To assess the clinical benefit 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.

Secondary objectives 1

1. To assess the clinical benefit with respect to left ventricular function and diameters, quality of life, physical capacity, cardiac autonomic function, transplant-free survival and hospitalization rate, biomarkers and adverse events at 6 and 12 months follow-up.

Conditions and MedDRA coding

Patients with biopsy-proven virus-negative inflammatory dilated or nondilated left ventricular cardiomyopathy and persistent deterioration of cardiac function despite optimal medical treatment (OMT) for heart failure

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age ≥18 years
2. Medical therapy for HF at least 3 months but not longer than 10 years according to current guideline recommendations,
3. Persistent reduction of LVEF <50% on 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 childbearing potential (according to CTFG recommendations)
7. Written informed consent

Exclusion criteria 7

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 baseline examinations
4. Known coronary artery disease responsible for cardiac dysfunction (i.e., prior myocardial infarction, chronic total occlusion, persistent stenosis ≥70%)
5. Pregnancy or lactation
6. Contraindications to immunosuppressive treatment with MMF + corticosteroids
7. Inability to provide informed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Two co-primary endpoints (hierarchical testing): 1. Absolute increase in LVEF at 12 months follow-up as assessed by blinded investigators of the MRI core lab (metric endpoint) 2. 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 endpoints 15

1. Composite clinical outcome: cardiac death, heart transplantation, LVAD implantation 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.
2. Absolute increase in LVEF and rate of increase by ≥10% at 6 months follow-up (MRI, metric, and binary endpoint).
3. Absolute decrease of left ventricular diameters, volumes, mass and sphericity from baseline to 6 and 12 months follow-up (MRI).
4. Changes in global longitudinal strain from baseline to 6 and 12 months follow-up (MRI).
5. Absolute increase in LVEF and rate of increase by ≥10% at 6 and 12 months follow-up (echo, metric and binary).
6. Decrease of left ventricular diameters and volumes by ≥10% at 6 and 12 months follow-up (echo).
7. Changes in global longitudinal (LV), free wall (RV) and left atrial strain (LA) from baseline to 6 and 12 months follow-up (echo).
8. Changes in diastolic parameters from baseline to 6 and 12 months follow-up (echo).
9. Presence of MR/TR >2 at baseline and at 6 and 12 months follow-up (echo).
10. Changes in cardiopulmonary exercise capacity: Distance in the sixminute walk test (6MWT) from baseline to 6 and 12 months follow-up and (optionally) VO2max, anaerobic threshold and VE/VCO2 on spiroergometry.
11. Changes in NYHA functional class from baseline to 6 and 12 months follow-up.
12. Changes in patient-reported outcome (quality of life; QOL) from baseline to follow-up as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ).
13. Changes in cardiac autonomic function (PRD, DC) from baseline to 6 and 12 months follow-up.
14. 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.
15. Time-averaged proportional change in NT-proBNP.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Klinikum der Universitaet Muenchen AöR

Sponsor organisation

Klinikum der Universitaet Muenchen AöR

Address

Marchioninistrasse 15, Hadern Hadern

City

Munich

Postcode

81377

Country

Germany

Scientific contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

LMU Klinikum, Medizinische Klinik und Poliklinik I

Public contact point

Organisation

Klinikum der Universitaet Muenchen AöR

Contact name

LMU Klinikum, Medizinische Klinik und Poliklinik I

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications