Study to evaluate the efficacy of immunosuppression (drugs that suppres natural immunologic response of the human body) in treatment of patients with inflammatory disease of cardiac muscle.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Warsaw

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

26 Jul 2022 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-517484-23-00

EudraCT number

2020-003877-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Pharmacogenetic, Pharmacokinetic, Safety, Therapy, Pharmacogenomic

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.

Conditions and MedDRA coding

Myocarditis, inflammatory cardiomyopathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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).

Exclusion criteria 22

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. LVEF at 12 – months.

Secondary endpoints 10

1. Proportion of patients who responded to immunosuppressive therapy as defined by an LVEF increase of ≥ 10% over time.
2. LVEF at 12 months in subgroups of patients with baseline LVEF ≤ 30% and > 30%
3. Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time.
4. Change from baseline in NYHA class over time.
5. Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit).
6. LVEF at 24 months (maintenance or further improvement).
7. LVEF at 24 months (maintenance or further improvement) in subgroups of patients with baseline LVEF ≤30% and >30%
8. Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time. (13-24 months)
9. Change in NYHA class over time. (13-24 months)
10. Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit). (13-24 months)

Investigational products

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

Test 1

Comparator 2

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Warsaw

Sponsor organisation

Medical University Of Warsaw

Address

Ul. Zwirki I Wigury 61

City

Warsaw

Postcode

02-091

Country

Poland

Scientific contact point

Organisation

Medical University Of Warsaw

Contact name

Krzysztof Ozierański

Public contact point

Organisation

Medical University Of Warsaw

Contact name

Krzysztof Ozierański

Locations

1 EU/EEA country · 6 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

Documents 7 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