Trial to assess the safety and efficacy of high dose pulse intravenous corticosteroid therapy to treat patients with complicated/fulminant acute myocarditis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ASST Grande Ospedale Metropolitano Niguarda

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

31 Jul 2024 → ongoing

Decision date (initial)

2025-02-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministry of Health, Italy

External identifiers

EU CT number

2023-504169-22-02

ClinicalTrials.gov

NCT05150704

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective is to demonstrate a reduction in the rate of the primary composite endpoint on patients treated with pulsed corticosteroid therapy vs. standard therapy and maximal supportive care.

Secondary objectives 1

1. The main secondary objectives are to demonstrate a reduction in the rate of the main secondary composite endpoint on patients treated pulsed corticosteroid therapy vs. standard therapy and maximal supportive care.

Conditions and MedDRA coding

Severe cardiac inflammation

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age 18 years or older and below 70 years (18-69 years)
2. Acute HF with clinically suspected acute myocarditis based on an N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration of 1600 pg/mL or more or a B-type natriuretic peptide (BNP) concentration of 400 pg/mL or more;
3. Left ventricular ejection fraction (LVEF)<41% and left ventricular end diastolic diameter (LV-EDD)<56 mm (parasternal long-axis view) on echocardiogram.
4. Increased troponin (3x upper reference limit [URL]) at the time of randomization.
5. Clinical onset of cardiac symptoms within 3 weeks from randomization.
6. Excluded coronary artery disease by coronary angiogram in subjects ≥46 years of age, in case myocarditis is not histologically proven.
7. Randomization within 120 hours from hospital admission.

Exclusion criteria 15

1. Known systemic autoimmune disorder or other conditions at the time of randomization where immunosuppression is assumed useful. Patients in whom a systemic autoimmune disorder will be diagnosed during hospitalization will be included in the study if randomized, including patients with a diagnosis of cardiac sarcoidosis or GCM). Both patients included in the corticosteroids-treatment arm or in the placebo-treatment arm can receive the standard immunosuppressive therapy used in the center since the diagnosis.
2. Patients already on oral/IV chronic corticosteroid therapy or other chronic immunosuppressive therapies (colchicine or nonsteroidal anti-inflammatory drugs [NSAIDs] are not considered immunosuppressive drugs)
3. Contraindication to corticosteroids, including allergies to this medication and its excipients.
4. Patients with persistent peripheral eosinophilia (persistent eosinophil count >7% of the leukocytes) or known hypereosinophilic syndrome at the time of randomization. Patients in whom eosinophilic myocarditis will be diagnosed on EMB will be included in the study if already randomized. Both patients included in the corticosteroids-treatment arm or in the placebo-treatment arm can receive the standard immunosuppressive therapy used in the center since the diagnosis.
5. Myocarditis associated with the ongoing administration of anti-cancer immune checkpoint inhibitor (ICI) agents.
6. Previously known chronic cardiac disease (i.e., previous cardiomyopathy, that does NOT include previous myocarditis if there is a functional recovery at the time of screening).
7. Evidence of active bacterial or fungal infectious disease (presence of fever or increased C-reactive protein are not considered exclusion criteria), or suspected bacterial/fungal infection associated with increased levels of procalcitonin (cut-off >10 ng/mL), if the laboratory exam is available in the center.
8. Known chronic infective disease, such as HIV infection or tuberculosis.
9. Out-of-hospital cardiac arrest.
10. t-MCS instituted more than 72 hours before randomization.
11. Patients clinically judged too sick to initiate t-MCS (i.e., irreversible multiorgan failure).
12. Echocardiographic presence of images suggestive of other cardiac diseases (i.e. endocarditis).
13. Participants involved in another clinical trial.
14. Pregnant women (known pregnancy) or POSITIVE human chorionic gonadotropin (HCG) test measures (urine/blood) for women of 18-50 years of age.
15. Any other significant disease with expected life expectancy <12 months (i.e., evidence of irreversible severe brain injury) or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The Primary composite endpoint is defined as the time from randomization to the first event occurring within 6 months among: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the t-MCS, or (5) a ventricular tachycardia (VT)/fibrillation (VF) treated with direct current (DC) shock (excluding VT/VF in patients on t-MCS other than IABP), or (6) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.

Secondary endpoints 11

1. The time from randomization to the first event occurring within 6 months among: (1) all-cause death or (2) HTx or (3) long-term LVAD implant or (4) first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
2. Mortality: time from randomization to all-cause death within 6 months.
3. In-hospital composite endpoint is defined as the proportion of patients who experience at least one of the following events during index hospitalization: (1) all-cause death, or (2) HTx, or (3) long-term LVAD implant, or (4) need for an upgrading of the t-MCS, or (5) a VT/VF treated with DC shock (excluding VT/VF in patients on t-MCS other than IABP).
4. Number of days on t-MCS from randomization.
5. Number of days in ICU from randomization.
6. Increase in LVEF on echocardiogram after 5 days from randomization (ECHO clips will be centrally reviewed in a blind fashion by readers).
7. Relative reduction of troponin levels after 5 days from randomization (ratio of troponin level/local troponin URL).
8. Reduction in heart rate (HR) on ECG after 3 days from randomization (ECG recorded at the hour of initial randomization - ECGs will be centrally reviewed in a blind fashion by readers).
9. Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI) (CMRI clips will be centrally reviewed in a blind fashion by readers).
10. Proportion of patients with LVEF<55% on 6-month CMRI (CMRI clips will be centrally reviewed in a blind fashion by readers).
11. Proportion of patients with LV dilation on 6-month CMRI (CMRI clips will be centrally reviewed in a blind fashion by readers).

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ASST Grande Ospedale Metropolitano Niguarda

Sponsor organisation

ASST Grande Ospedale Metropolitano Niguarda

Address

Piazza Dell'ospedale Maggiore 3

City

Milan

Postcode

20162

Country

Italy

Scientific contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Dottor Enrico Ammirati

Public contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Dottor Enrico Ammirati

Locations

7 EU/EEA countries · 43 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 40 files

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

Application history

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