Efficacy and Safety of Prednisone and Azathioprine in Biopsy-Proven Virus-Negative Myocarditis or Inflammatory Cardiomyopathy with Reduced Ejection Fraction
- Trial ID
- 2024-517484-23-00
- Protocol
- IMPROVE-MC
- Sponsor
- Medical University Of Warsaw
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and safety of a 12-month treatment regimen with **prednisone** and **azathioprine** compared to placebo, in addition to guideline-recommended medical therapy, for patients with biopsy-proven virus-negative **myocarditis** or inflammatory **cardiomyopathy** and reduced ejection fraction (LVEF 10-45%). This assessment is clinically relevant as it aims to determine the potential benefits of immunosuppressive therapy in improving cardiac function and patient outcomes in this specific patient population. The study will also assess the persistence of treatment effects after 12 months.
Participants
The clinical trial involves participants diagnosed with **myocarditis** or inflammatory cardiomyopathy, specifically those with a reduced ejection fraction (LVEF 10-45%). The study population includes both male and female subjects aged 18 to 65 years. Participants are required to have biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Participants were selected based on specific inclusion criteria, including the absence of significant improvement in clinical condition despite standard treatment and histological evidence of active myocarditis or inflammatory cardiomyopathy. Lifestyle considerations include the requirement for women of childbearing potential to use effective contraception or practice total sexual abstinence. The trial population is considered vulnerable, and the selection process ensures that participants meet the necessary health and diagnostic criteria for inclusion.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of a 12-month treatment regimen involving **prednisone** and **azathioprine** in patients with biopsy-proven virus-negative **myocarditis** or **inflammatory cardiomyopathy**. The trial aims to compare these treatments against a placebo, in addition to standard medical therapy, in patients with reduced left ventricular ejection fraction (LVEF) ranging from 10% to 45%. The study will also assess the persistence of treatment effects after 12 months. The trial is expected to conclude by March 2028, with recruitment having commenced in April 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, LVEF measurements, and absence of cardiotropic viruses in cardiac tissue. The screening will include echocardiograms and endomyocardial biopsies as necessary. Following the screening, participants will be randomly assigned to receive either the active treatment or placebo. The trial will include regular follow-up visits to monitor the participants' health, treatment adherence, and any adverse effects. These visits will also involve assessments of LVEF and other cardiac parameters to evaluate the primary and secondary endpoints, such as changes in LVEF and heart failure symptoms over time.
The expected duration of participant involvement is approximately 12 months, with an additional follow-up period to assess long-term outcomes. Conditions that may lead to early termination from the study include significant adverse reactions to the study medication, withdrawal of consent, or any medical condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The trial's primary endpoint is the LVEF at 12 months, with secondary endpoints including the proportion of patients responding to immunosuppressive therapy, changes in cardiac dimensions and volumes, and the occurrence of heart failure decompensation.
Treatment
The clinical trial involves the administration of several treatments, including both experimental medications and placebo controls. The primary experimental medication is **Encorton**, which contains the active substance **prednisone**. Encorton is available in tablet form with two dosage strengths: 5 mg and 10 mg. The medication is administered orally, with a maximum daily dose of 1 mg/kg. The treatment period for Encorton is up to 6 months. Prednisone is a synthetic glucocorticoid with anti-inflammatory and immunosuppressive properties, commonly used in the management of various inflammatory and autoimmune conditions.
Another experimental medication used in the trial is **AZATHIOPRINE VIS**, which contains the active substance **azathioprine**. This medication is also provided in tablet form, with a dosage strength of 50 mg. Azathioprine is administered orally, with a maximum daily dose of 1.5 mg/kg. The treatment period for azathioprine extends up to 52 weeks. Azathioprine is an immunosuppressive agent often used in the treatment of autoimmune diseases and in organ transplantation to prevent rejection.
The trial also includes the use of placebo controls to ensure the validity of the study results. The placebo treatments are designed to match the appearance of the active medications but do not contain any active substances. The placebo for Encorton is available in two forms, corresponding to the 5 mg and 10 mg dosages of the active medication. Additionally, a placebo for azathioprine is included in the study. These placebos are administered in the same manner as their active counterparts, ensuring blinding of the study participants and investigators.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The study is designed to evaluate the efficacy and safety of the experimental treatments compared to placebo, in conjunction with standard guideline-recommended medical therapy, in patients with biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the measurement of left ventricular ejection fraction (**LVEF**) at 12 months. Secondary endpoints include the proportion of patients who respond to immunosuppressive therapy, defined by an LVEF increase of ≥ 10% over time, and LVEF at 12 months in subgroups of patients with baseline LVEF ≤ 30% and > 30%. Additional secondary endpoints involve changes in left ventricular (LV) end-systolic and end-diastolic dimensions and volumes over time, changes from baseline in New York Heart Association (NYHA) class, and the occurrence of adjudicated heart failure decompensation, either through hospitalization or ambulatory visits. Further assessments will be conducted at 24 months to evaluate the maintenance or further improvement of LVEF, including subgroup analyses based on baseline LVEF, and continued monitoring of LV dimensions, volumes, NYHA class, and heart failure decompensation occurrences.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- Absence of cardiotropic viruses in cardiac tissue at PCR analysis during the screening period (EMB during the screening or within last 3 months).
Exclusion Criteria
- 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).
- 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.
- Another specific cause of heart failure (including severe congenital, valvular, hypertensive, and/or coronary artery disease) that could justify the severity of cardiac dysfunction.
- 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.
- Diagnosed or suspected cardiac sarcoidosis or giant cell myocarditis.
- NYHA class I and IV.
- Subjects with body mass index >40 kg/m2 or body weight <50 kg.
- Pregnancy, lactation or women who plan to become pregnant during the trial. Lack of consent to the use of effective forms of contraception.
- Any documented or suspected active malignant neoplasm or history of malignant neoplasm within the 5 years prior to the screening period.
- History of cytostatic therapy or radiotherapy.
- Liver disease defined as any of the following: AST or ALT or ALP above 3x ULN; bilirubin >1.5 mg/dL.
- 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.
- The need or refusal to stop taking any drug considered to interfere with the safe course of the study (e.g., allopurinol).
- Currently implanted or planned VAD, CRT or heart transplant.
- 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.
- Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial drug(s) absorption in the investigator’s opinion.
- History or presence of any other disease with a life expectancy <3 years.
- 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.
- Immunization with live organism vaccines in the last 3 months prior to randomization.
- 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.
- Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5 half-lives of enrollment, whichever is longer.
- Subjects directly involved in the execution of this protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 01 Apr 2022 | 100 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo Azathioprine | Placebo | N/A | — | — | — | N/A |
Encorton, 10 mg, tabletki | Comparator | TABLETKI | ORAL USE | 1 | 6 | PRD325840 |
Placebo Encorton 10 mg | Placebo | N/A | — | — | — | N/A |
Encorton, 5 mg, tabletki | Comparator | TABLETKI | ORAL USE | 1 | 6 | PRD325682 |
AZATHIOPRINE VIS, 50 mg, tabletki | Test | TABLETKI | ORAL USE | 1.5 | 52 | PRD738904 |
Placebo Encorton 5 mg | Placebo | N/A | — | — | — | N/A |