| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with biopsy-proven virus-negative inflammatory dilated or non-dilated left ventricular cardiomyopathy and persistent deterioration of cardiac function despite optimal medical treatment (OMT) for heart failure |
| Patienten mit in der Myokardbiopsie nachgewiesener virus-negativer inflammatorisch dilatativer oder nicht-dilatativer linksventrikulärer Kardiomyopathy und persistierend eingeschränkter kardialer Funktion trotz optimaler medikamentöser Herzinsuffizienz-Therapie |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with biopsy-proven virus-negative cardiomyopathy and persistent deterioration of cardiac function despite optimal medical treatment for heart failure |
| Patienten mit nachgewiesener virus-negativer Kardiomyopathy und persistierend eingeschränkter kardialer Funktion trotz optimaler medikamentöser Herzinsuffizienz-Therapie |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
| Evaluation des klinischen Nutzens einer immunsuppressiven Therapie mit MMF und Prednisolon im Vergleich zu Placebo hinsichtlich einer absoluten Verbesserung der linksventrikulären Ejektionsfraktion (LVEF) nach 12 Monaten. |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
| Evaluation des klinischen Nutzens hinsichtlich der linksventrikulären kardialen Funktion und Diameter, der Lebensqualität, der körperliche Leistungsfähigkeit, der kardialen autonomen Funktion, des transplantatfreien Überlebens und der Hospitalisierungsrate, Biomarker und unerwünschten Ereignissen nach 6 und 12 Monaten. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. |
|
| E.4 | Principal 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 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints of evaluation of both co-primary endpoints:
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). |
|
| E.5.2 | Secondary end point(s) |
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 six-minute 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints of evaluation of the secondary endpoints:
6 and/or 12 months after randomization, respectively. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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