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

NCT05974462 | Recruiting Phase 3 DMC

• 1 other identifier: 2022-501547-33-00
• Study Type: interventional
• Target: 174
• Locations: 4 countries
• Sites: 19

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

• 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.

Conditions

Acute Myocarditis

Outcome Measures

Primary Outcomes (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).

  Day 5

Secondary Outcomes (2)

• Improvement of the composite endpoint

  6 months

• Composite endpoint defined as the time from randomization to the first event

  Within 6 months and 2 years

Study Arms (2)

Pulsed corticosteroid therapy

EXPERIMENTAL

IV methylprednisolone 125 mg daily for 3 days diluted in saline solution 250 ml on top of standard therapy.

Drug: Methylprednisolone 125 MG

Placebo

PLACEBO COMPARATOR

IV saline solution 250 mL daily for 3 days on top of standard therapy.

Other: IV saline solution 0.9%

Interventions

Methylprednisolone 125 MG DRUG

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

Also known as: Solu-Medrol

Pulsed corticosteroid therapy

IV saline solution 0.9% OTHER

Saline solution 0.9% 250 mL

Also known as: sodium chloride

Placebo

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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);
• 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).

Sponsors & Collaborators

• University Hospital, Antwerp: lead
• Niguarda Hospital: collaborator

Study Sites (19)

Antwerp University Hospital

Edegem, Antwerp, Belgium

RECRUITING

Onze-Lieve-Vrouwziekenhuis (OLV ziekenhuis)

Aalst, Belgium

RECRUITING

Middelheim Ziekenhuis

Antwerp, Belgium

RECRUITING

Jessa ziekenhuis

Hasselt, Belgium

RECRUITING

Universitair ziekenhuis Leuven

Leuven, Belgium

RECRUITING

Niguarda Hospital

Milan, Milan, 20125, Italy

RECRUITING

Azienda USL Toscane SUD Est

Arezzo, Italy

NOT YET RECRUITING

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, Italy

NOT YET RECRUITING

ASST Spedali Civili di Brescia

Brescia, 25123, Italy

NOT YET RECRUITING

Careggi University Hospital

Florence, Italy

NOT YET RECRUITING

Alessandro Manzoni hospital

Lecco, 23900, Italy

NOT YET RECRUITING

San Raffaele Hospital

Milan, 20132, Italy

NOT YET RECRUITING

Ospedale Maggiore di Milano

Milan, Italy

NOT YET RECRUITING

Fondazione IRCCS Policlinico San Matteo

Pavia, Italy

NOT YET RECRUITING

Fondazione Toscana Gabriele Monasterio

Pisa, Italy

NOT YET RECRUITING

Policlinico Universitario Agostino Gemelli

Roma, Italy

NOT YET RECRUITING

Azienda Sanitaria Universitaria Friuli Centrale

Udine, Italy

NOT YET RECRUITING

University Medical Centre of Ljubljana

Ljubljana, Slovenia

RECRUITING

Hospital Universitario A Coruña (CHUAC)

A Coruña, 15006, Spain

NOT YET RECRUITING

Related Publications (10)

• 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.

  PMID: 33176455 BACKGROUND

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

  PMID: 36260793 BACKGROUND

• 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.

  PMID: 31902242 BACKGROUND

• 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.

  PMID: 29764898 BACKGROUND

• 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.

  PMID: 31319912 BACKGROUND

• 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.

  PMID: 35350578 BACKGROUND

• 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.

  PMID: 24136037 BACKGROUND

• 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.

  PMID: 7596370 BACKGROUND

• 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.

  PMID: 34649282 BACKGROUND

• 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.

  PMID: 28576783 BACKGROUND

MeSH Terms

Interventions

Methylprednisolone; Methylprednisolone Hemisuccinate; Sodium Chloride

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Caroline Van de Heyning

  University Hospital, Antwerp

  PRINCIPAL INVESTIGATOR

• Enrico Ammirati

  Niguarda Hospital Milano

  STUDY CHAIR

• Nicole Sturkenboom

  University Hospital, Antwerp

  STUDY CHAIR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single Blind, Investigator-initiated, Randomized Controlled Trial

Study Record Dates

• First Submitted: July 26, 2023
• First Posted: August 3, 2023
• Study Start: May 24, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2028
• Last Updated: April 17, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

BE (5); SL (1); IT (12); ES (1)