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Acute MyocarditisPhase 3MYTHS-MRNCT05974462

MYTHS-MR Trial (MYocarditis THerapy With Steroids in Patients With Mildly Reduced Ejection Fraction)

A Phase 3 study testing Methylprednisolone 125 MG and IV saline solution 0.9% in people with Acute Myocarditis, run by University Hospital, Antwerp at 19 sites in 4 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

The goal of this clinical trial is to demonstrate the efficacy of pulsed intravenous methylprednisolone in a single-blind randomized controlled trial versus standard therapy in patients with acute myocarditis and a mildly reduced LVEF. Read more about this study

Who is it for?
Ages 18 to 69 years
Conditions the study is for
Acute Myocarditis
What is being tested?
Methylprednisolone 125 MG and IV saline solution 0.9%
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
174 participants
Where
19 sitesin 4 countries
Study dates
24 May 2024to 1 Oct 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 69 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • LVEF<50% and LV-EDD<56 mm (parasternal long-axis view) on echocardiogram;
  • Increased troponin (3x URL) at the time of randomization;
  • Clinical onset of cardiac symptoms within 3 weeks from randomization;
  • Excluded coronary artery disease by coronary angiogram in subjects ≥46 years of age, in case myocarditis is not histologically proven;
  • Randomization within 120 hours from hospital admission.
  • Endomyocardial biopsy (EMB) is not considered necessary before randomization and performing EMB is based on the decision of the local team.

Who cannot join

  • 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;
  • 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);
  • Contraindication to corticosteroids, including allergies to this medication and its excipients;
  • 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;
  • Myocarditis associated with the ongoing administration of anti-cancer immune checkpoint inhibitor (ICI) agents;
  • Previously known chronic cardiac (i.e., previous cardiomyopathy, that does NOT include previous myocarditis if there is a functional recovery at the time of screening);
Show all 14Show fewer
  • 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;
  • Known chronic infective disease, such as HIV infection or tuberculosis;
  • Out-of-hospital cardiac arrest;
  • Echocardiographic presence of images suggestive of other cardiac diseases (i.e. endocarditis)
  • Participants involved in another clinical trial;
  • Pregnant women (known pregnancy) or POSITIVE human chorionic gonadotropin (HCG) test measures (urine/blood) for women of 18-50 years of age.
  • 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.
  • If LVEF<41%, 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; (if LVEF 41%-<50% any NT-proBNP or BNP concentration is allowed).

Trial locations and contacts

19 sites in 4 countries. Contact the study team or a site near you to ask about taking part.

Caroline Van De Heyning, MD PhD contact

+32 821 3538

caroline.vandeheyning@uza.be

Nicole Sturkenboom, MD contact

+32 821 3538

nicole.sturkenboom@uza.be

19 sites in 4 countries

Italy12 sites, 12 recruiting

  • Azienda USL Toscane SUD Est

    Arezzo

    Maurizio Pieroni

    Not yet recruiting

  • Azienda Ospedaliera Papa Giovanni XXIII

    Bergamo

    Aurelia Grosu

    Not yet recruiting

  • ASST Spedali Civili di Brescia

    Brescia, 25123

    Daniela Tomasoni

    Not yet recruiting

  • Careggi University Hospital

    Florence

    Francesco Cappelli

    Not yet recruiting

  • Alessandro Manzoni hospital

    Lecco, 23900

    Roberto Spoladore

    Not yet recruiting

  • Niguarda Hospital

    Milan, Milan, 20125

    Enrico Ammirati, MD PhD

    Recruiting

  • San Raffaele Hospital

    Milan, 20132

    Not yet recruiting

  • Ospedale Maggiore di Milano

    Milan

    Margherita Calcagnino

    Not yet recruiting

  • Fondazione IRCCS Policlinico San Matteo

    Pavia

    Rossana Totaro

    Not yet recruiting

  • Fondazione Toscana Gabriele Monasterio

    Pisa

    Michele Emdin

    Not yet recruiting

  • Policlinico Universitario Agostino Gemelli

    Roma

    Maria Lucia Narducci

    Not yet recruiting

  • Azienda Sanitaria Universitaria Friuli Centrale

    Udine

    Massimo Imazio

    Not yet recruiting

Other trials in Italy

Belgium5 sites, 5 recruiting

  • Onze-Lieve-Vrouwziekenhuis (OLV ziekenhuis)

    Aalst

    Ward Heggermont

    Recruiting

  • Middelheim Ziekenhuis

    Antwerp

    Gaëlle Vermeersch

    Recruiting

  • Antwerp University Hospital

    Edegem, Antwerp

    Caroline Van De Heyning

    Recruiting

  • Jessa ziekenhuis

    Hasselt

    Philippe Timmermans

    Recruiting

  • Universitair ziekenhuis Leuven

    Leuven

    Walter Droogné, 003216 33 22 11

    Recruiting

Other trials in Belgium

Slovenia1 site, 1 recruiting

  • University Medical Centre of Ljubljana

    Ljubljana

    Andreja Cerne

    Recruiting

Other trials in Slovenia

Spain1 site, 1 recruiting

  • Hospital Universitario A Coruña (CHUAC)

    A Coruña, 15006

    Marisa Crespo

    Not yet recruiting

Other trials in Spain

About this study

Official title: Single-blind, Investigator-initiated, Randomized, Controlled Trial to Assess the Safety and Efficacy of Intravenous Corticosteroid Therapy to Treat Patients With Acute Myocarditis With Mildly Reduced Left Ventricular Ejection Fraction

The goal of this clinical trial is to demonstrate the efficacy of pulsed intravenous methylprednisolone in a single-blind randomized controlled trial versus standard therapy in patients with acute myocarditis and a mildly reduced LVEF.

The main question[s] it aims to answer are:

Read more
  • is there an increase in LVEF (≥55% or an absolute increase in LVEF ≥ 10%) on echocardiogram after 5 days from randomization in patients treated with pulsed corticosteroid therapy vs. standard therapy?
  • is there a reduction in the proportion of patients with LVEF < 55% AND/OR LV dilation on a 6-month CMRI in patients treated pulsed corticosteroid therapy vs. standard therapy?
  • To assess the effect of corticosteroids on the occurrence of the combined endpoint(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.

Participants will be randomized in two arms in a 1:1 ratio. The experimental group will receive pulsed corticosteroid therapy on top of the standard therapy and patients in the placebo group will be treated with a saline solution on top of their standard therapy. All other tests are executed according to standard of care.

Read the detailed description

Acute myocarditis (AM) is a common condition characterized by histological evidence of inflammatory infiltrates associated with myocyte necrosis of non-ischemic origin. Clinical presentation spans from indolent form to cardiogenic shock also called fulminant myocarditis (FM). Patients can be stratified on the basis of their clinical presentation: patients with left ventricular (LV) ejection fraction (EF)<50% at first echocardiogram, and those with sustained ventricular arrhythmias, called complicated AM, have a worse prognosis compared with uncomplicated cases with preserved left ventricular ejection fraction (LVEF) and without arrhythmias. Among complicated AM, FM patients are those ones at the highest risk, presenting with severely impaired LVEF (generally <40%), and with need for inotropes and/or temporary mechanical circulatory supports (t-MCS).The pathogenesis of AM is felt to be due to an immune-mediated response against the myocardium.

As such, the overall objective is to evaluate the efficacy of pulsed IV corticosteroids therapy for the treatment of AM. It is proposed to test the efficacy of pulsed IV methylprednisolone in a single blind randomized controlled trial versus standard therapy on top of maximal support. The rationale for using pulsed corticosteroid therapy in the acute setting (within 3 weeks from cardiac symptoms' onset) to reduce myocardial inflammatory infiltrates favoring recovery appears strong. Nevertheless, no trial has tested this hypothesis in the very acute phase of AM, despite the high mortality rate of this condition and the fact that AM mainly affects young patients.

Currently, no specific medications in the acute phase of lymphocytic AM are recommended beyond supportive therapy with inotropes and t-MCS. One Cochrane review on corticosteroids showed that almost all studies focused on inflammatory cardiomyopathies with 6 months of symptoms of heart failure (HF), and despite an improvement of cardiac function observed in low quality and small size studies, there was no improvement in the survival. In the past, only one study assessed the efficacy of immunosuppression in AM, the Myocarditis Treatment Trial (MTT) that reported no benefit from immunosuppression. Neutral results in the MTT could be ascribed to a delay in the initiation of this potentially effective treatment. Thus, 55% of patients started immunosuppressive therapy after 1 month from the onset of myocarditis, when the left ventricle (LV) was already dilated, as highlighted by a mean LV end-diastolic diameter (EDD) of 64 mm. It is expected that patients with FM have normal LV dimension during the acute phase despite severe LV systolic dysfunction. Based on a study from the current research group, it was observed that FM patients recover most of the LVEF in the first 2 weeks after admission, with a median absolute increase of 30%. This finding further suggests that an immunosuppressive treatment should be started as soon as possible to demonstrate effectiveness. As little has changed in the medical treatment of this condition in the last 30 years, identification of effective drugs is needed.

Patients admitted to hospital for suspected AM complicated by a reduced Left Ventricular Ejection Fraction (LVEF<50%) will be screened for randomization.

Patients will be randomized in the two arms in a 1:1 ratio (Pulsed methylprednisolone therapy vs Placebo). Randomization will be performed with stratification by country.

In the companion MYTHS trial (EudraCT identifier: 2021-000938-34) patients admitted to hospital for suspected AM complicated by acute HF/cardiogenic shock and LV systolic dysfunction will be randomized in a 1:1 ratio (pulsed methylprednisolone therapy vs Placebo).

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

Endpoints will be analyzed according to the following principles:

  • Intention-to-treat (ITT) population
  • Per Protocol (PP) population:
  • "Safety population"
  • A sensitivity analysis will also be performed on the previously defined populations after excluding patients (1) with histological diagnosis of giant cell myocarditis (GCM) or (2) who did not reach the final diagnosis of acute myocarditis based on CMRI or histology.

A pooled analysis of the efficacy and safety endpoints that are present both in the MYTHS and MYTHS-MR will be performed.

Sample size calculation: we plan to recruit a total of 184 patients, and we expect that about 5% of these patients or local physicians will refuse randomization. This would leave a total of 174 randomized patients (87 per arm).

Considering as relevant an increment in the probability to reach the primary endpoint from 45% in the placebo group on top of standard therapy to 70% in the pulsed corticosteroid arm (absolute risk difference of 25%), the planned sample size will allow to achieve a power of 0.90 with a one-sided z-test with continuity correction and an overall type I error of 0,025.

Enrollment will be 36 months. The follow-up will be 2 years with an additional 3 months to lock the database.

In parallel , a registry, called MYOCARDITIS REGISTRY will prospectively recruit all patients with acute myocarditis demonstrated by CMRI or EMB who are not eligible for randomization.

The study is supported by a grant from Fonds Wetenschappelijk Onderzoek (FWO call 2021, application nr G034622N) EuCT identifier: 2022-501547-33-01

Being tested
Methylprednisolone 125 MG, IV saline solution 0.9%

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Methylprednisolone 125 MGDrug

    Also called Solu-Medrol

    125 mg daily for 3 days diluted in saline solution 250 mL

  • IV saline solution 0.9%Other

    Also called sodium chloride

    Saline solution 0.9% 250 mL

Study groups in NCT05974462
Study groupRoleWhat they receive
Pulsed corticosteroid therapyExperimentalIV methylprednisolone 125 mg daily for 3 days diluted in saline solution 250 ml on top of standard therapy.
Receives: Drug: Methylprednisolone 125 MG
PlaceboPlacebo comparatorIV saline solution 250 mL daily for 3 days on top of standard therapy.
Receives: Other: IV saline solution 0.9%

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Left ventricular ejection fraction

    LVEF ≥55% or an absolute increase in LVEF≥10% on echocardiogram after 5 days from randomization (echocardiographic clips will be centrally reviewed in a blind fashion by readers).

    Measured: Day 5

Secondary outcomes (2)

  1. Improvement of the composite endpoint

    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)

    Measured: 6 months

  2. Composite endpoint defined as the time from randomization to the first event

    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.

    Measured: Within 6 months and 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Aug 2023
  2. Study start24 May 2024
  3. Primary completion1 Oct 2026 (estimated)
  4. Study completion1 Oct 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Single Blind, Investigator-initiated, Randomized Controlled Trial
Masking
Single blind
Who is masked
Participant
Enrolment
174 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05974462
Sponsor's protocol ID
2022-501547-33-00
Acronym
MYTHS-MR
Status last verified
Mar 2025
First submitted
26 Jul 2023
Last updated
17 Apr 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Ammirati E, Frigerio M, Adler ED, Basso C, Birnie DH, Brambatti M, Friedrich MG, Klingel K, Lehtonen J, Moslehi JJ, Pedrotti P, Rimoldi OE, Schultheiss HP, Tschope C, Cooper LT Jr, Camici PG. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. Circ Heart Fail. 2020 Nov;13(11):e007405. doi: 10.1161/CIRCHEARTFAILURE.120.007405. Epub 2020 Nov 12.

    PubMed 33176455

  • Basso C. Myocarditis. N Engl J Med. 2022 Oct 20;387(16):1488-1500. doi: 10.1056/NEJMra2114478. No abstract available.

    PubMed 36260793

  • Kociol RD, Cooper LT, Fang JC, Moslehi JJ, Pang PS, Sabe MA, Shah RV, Sims DB, Thiene G, Vardeny O; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association. Circulation. 2020 Feb 11;141(6):e69-e92. doi: 10.1161/CIR.0000000000000745. Epub 2020 Jan 6.

    PubMed 31902242

  • Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, Mafrici A, Grosu A, Briguglia D, Guglielmetto S, Perego GB, Colombo S, Caico SI, Giannattasio C, Maestroni A, Carubelli V, Metra M, Lombardi C, Campodonico J, Agostoni P, Peretto G, Scelsi L, Turco A, Di Tano G, Campana C, Belloni A, Morandi F, Mortara A, Ciro A, Senni M, Gavazzi A, Frigerio M, Oliva F, Camici PG; Registro Lombardo delle Miocarditi. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation. 2018 Sep 11;138(11):1088-1099. doi: 10.1161/CIRCULATIONAHA.118.035319.

    PubMed 29764898

  • Ammirati E, Veronese G, Brambatti M, Merlo M, Cipriani M, Potena L, Sormani P, Aoki T, Sugimura K, Sawamura A, Okumura T, Pinney S, Hong K, Shah P, Braun O, Van de Heyning CM, Montero S, Petrella D, Huang F, Schmidt M, Raineri C, Lala A, Varrenti M, Foa A, Leone O, Gentile P, Artico J, Agostini V, Patel R, Garascia A, Van Craenenbroeck EM, Hirose K, Isotani A, Murohara T, Arita Y, Sionis A, Fabris E, Hashem S, Garcia-Hernando V, Oliva F, Greenberg B, Shimokawa H, Sinagra G, Adler ED, Frigerio M, Camici PG. Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction. J Am Coll Cardiol. 2019 Jul 23;74(3):299-311. doi: 10.1016/j.jacc.2019.04.063.

    PubMed 31319912

  • Ammirati E, Bizzi E, Veronese G, Groh M, Van de Heyning CM, Lehtonen J, Pineton de Chambrun M, Cereda A, Picchi C, Trotta L, Moslehi JJ, Brucato A. Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis. Front Med (Lausanne). 2022 Mar 7;9:838564. doi: 10.3389/fmed.2022.838564. eCollection 2022.

    PubMed 35350578

  • Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2013 Oct 18;2013(10):CD004471. doi: 10.1002/14651858.CD004471.pub3.

    PubMed 24136037

  • Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995 Aug 3;333(5):269-75. doi: 10.1056/NEJM199508033330501.

    PubMed 7596370

  • McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021 Dec 21;42(48):4901. doi: 10.1093/eurheartj/ehab670. No abstract available.

    PubMed 34649282

  • Ammirati E, Cipriani M, Lilliu M, Sormani P, Varrenti M, Raineri C, Petrella D, Garascia A, Pedrotti P, Roghi A, Bonacina E, Moreo A, Bottiroli M, Gagliardone MP, Mondino M, Ghio S, Totaro R, Turazza FM, Russo CF, Oliva F, Camici PG, Frigerio M. Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis. Circulation. 2017 Aug 8;136(6):529-545. doi: 10.1161/CIRCULATIONAHA.117.026386. Epub 2017 Jun 2.

    PubMed 28576783

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Methylprednisolone 125 MG and IV saline solution 0.9% in people with Acute Myocarditis, run by University Hospital, Antwerp at 19 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 17 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 19 sites in Italy, Belgium, Slovenia, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Caroline Van De Heyning, MD PhD (+32 821 3538, caroline.vandeheyning@uza.be), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Left ventricular ejection fraction (time frame: Day 5). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05974462, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Apr 2025.

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