| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myocarditis, inflammatory cardiomyopathy |
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| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of the heart muscle |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028606 |
| E.1.2 | Term | Myocarditis |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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| 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 |
| The objective of this trial is to assess the efficacy and safety of 12 – month treatment with prednisone and azathioprine comparing to placebo on top of guideline-recommended medical therapy in patients with biopsy-proven virus negative myocarditis or inflammatory cardiomyopathy and reduced ejection fraction (LVEF 10 - 45%). The study will also assess persistence of the treatment effects after 12 months. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for inclusion in this study, patient must fulfill all of the following inclusion criteria:
1. Written informed consent to participate in the IMPROVE-MC study (including two EMBs and two cardiac CMRs) prior to any evaluation or procedure related to the study.
2. Patient with clinically suspected myocarditis or inflammatory cardiomyopathy (according
to the criteria of the ESC Working Group on Myocardial & Pericardial Diseases, and ESC Heart Failure Guidelines 2021);
OR / AND,
Patients with already diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory cardiomyopathy who will undergo diagnostic right ventricular (or/and left ventricular) endomyocardial biopsy during the screening
OR / AND,
Patients with already diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory cardiomyopathy confirmed by right ventricular (or/and left ventricular) endomyocardial biopsy that was performed according to the IMPROVE-MC study protocol within 3 months from screening.
3. Men or women aged 18-65. Women of childbearing age must have a negative pregnancy test result. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (with a failure rate of < 1% per year) for the duration of the study (from the time they sign consent) and for 8 weeks after the last dose of study treatment to prevent pregnancy. Patients agreeing to total sexual abstinence can also be included, assuming it is their usual lifestyle. Women are considered postmenopausal and without the potential to have a child if they have 12 months of natural (spontaneous) amenorrhea with an appropriate clinical picture (e.g. appropriate age, history of vasomotor symptoms) or have undergone bilateral surgical ovariectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of ovariectomy alone, only if the reproductive status of the woman has been confirmed by assessing hormone levels.
4. No significant improvement in clinical condition or worsening course of the disease despite the standard treatment in the investigator’s opinion, in the last ≥ 3 months prior to the screening period.
5. LVEF 10 - 45% measured by echocardiogram taken during the screening period
a) No significant LVEF improvement in the last ≥3 months prior to the screening period
in the investigator’s opinion.
b) LVEF should be measured under stable conditions as assessed by the investigator.
c) LVEF should be verified in the CORE-LAB.
6. Histological and immunohistochemical evidence of active myocarditis (lymphocytic or eosinophilic) OR inflammatory cardiomyopathy during the screening period (EMB during the screening or within last 3 months).
7. Absence of cardiotropic viruses in cardiac tissue at PCR analysis during the screening period (EMB during the screening or within last 3 months).
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| E.4 | Principal exclusion criteria |
Patients fulfilling any of the following exclusion criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.
1. Presence of contraindications to immunosuppressive therapy with steroids and/ or
azathioprine (including hypersensitivity to azathioprine/ 6-mercaptopurine or prednisone, mainly untreated systemic infection, uncontrolled diabetes, poorly controlled endocrine diseases, osteoporosis, active gastric or duodenal ulcer, uncontrolled hypertension, leukocytopenia (leukocyte counts <3.8 x 10^9/l), neutropenia (neutrophils <1.5 x 10^9/l), thrombocytopenia (platelet levels <110-130 x 10^9/l), anemia (hemoglobin levels <9-10 g/dl).
2. Positive screening for active infections: including HIV, HBV, HCV, CMV, EBV, boreliosis. Assessment of tuberculosis infection should be considered before screening, according to the local epidemiologic status and according to investigator’s opinion. Conditionally, after careful evaluation of the activity of the infection (or cure of the infection), the patient may continue participation in the study according to investigator’s opinion.
3. Another specific cause of heart failure (including severe congenital, valvular, hypertensive, and/or coronary artery disease) that could justify the severity of cardiac dysfunction.
4. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), storage diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, genetic hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or known pericardial constriction.
5. Diagnosed or suspected cardiac sarcoidosis or giant cell myocarditis.
6. NYHA class I and IV.
7. Subjects with body mass index >40 kg/m2 or body weight <50 kg.
8. Pregnancy, lactation or women who plan to become pregnant during the trial. Lack of consent to the use of effective forms of contraception.
9. Any documented or suspected active malignant neoplasm or history of malignant neoplasm within the 5 years prior to the screening period.
10. History of cytostatic therapy or radiotherapy.
11. Liver disease defined as any of the following: AST or ALT or ALP above 3x ULN; bilirubin >1.5 mg/dL.
12. Impaired renal function, defined as eGFR <45 mL / min / 1.73 m2 (CKD-EPI) measured under stable condition or requiring dialysis. Conditionally, according to the investigator's decision, patients with eGFR 40-45 ml / min / 1.73 m2 may be included.
13. The need or refusal to stop taking any drug considered to interfere with the safe course of the study (e.g., allopurinol).
14. Currently implanted or planned VAD, CRT or heart transplant.
15. Patients with pacemaker or ICD requiring a high percentage of ventricular pacing (>30%) which could influence the result of LVEF measurement in the investigator’s opinion.
16. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial drug(s) absorption in the investigator’s opinion.
17. History or presence of any other disease with a life expectancy <3 years.
18. Any contraindications or intolerance to CMR*, including but not limited to:
a) the presence of cardiac implantable electronic device implanted <6 weeks ago;
b) pacing capture threshold out of the normal range;
c) additional cardiac leads (particularly abandoned pacemaker leads), epicardial leads,
fractured leads, additional components such as lead adapters or lead extension;
d) aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes,
skin, or body that could be contraindication to CMR;
e) presence of claustrophobia making impossible to perform CMR;
f) or any other clinical history or study that determines that, in the investigator's judgment, the performance of an CMR may pose a potential risk to the patient.
19. Immunization with live organism vaccines in the last 3 months prior to randomization.
20. Chronic alcohol or drug abuse or non-compliance with medical recommendations or any condition that, in the investigator’s opinion, makes patient an unreliable trial subject or unlikely to complete the trial.
21. Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5 half-lives of enrollment, whichever is longer.
22. Subjects directly involved in the execution of this protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
KEY SECONDARY ENDPOINTS:
• Proportion of patients who responded to immunosuppressive therapy as defined by an LVEF increase of ≥ 10% over time.
• LVEF at 12 months in subgroups of patients with baseline LVEF ≤ 30% and > 30%
• Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time.
• Change from baseline in NYHA class over time.
• Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit).
Secondary endpoints for follow up (compared to baseline and/or to the end of treatment) analyzed during follow up (13-24 months):
• LVEF at 24 months (maintenance or further improvement).
• LVEF at 24 months (maintenance or further improvement) in subgroups of patients with baseline LVEF ≤30% and >30%
• Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time.
• Change in NYHA class over time.
• Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Key secondary endpoints will be assessed in 3-month intervals up to 24-months from the randomization. |
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| additional genetic and proteomic tests (optional patient consent) |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| 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 | 7 |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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