Clinical trial NCT05150704: MYTHS - MYocarditis THerapy With Steroids
Official title: Single Blind Randomized Controlled Trial to Assess the Safety and Efficacy of High Dose Pulse Intravenous Corticosteroid Therapy to Treat Patients With Complicated/Fulminant Acute Myocarditis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Myocarditis Acute
Keywords: Acute Myocarditis
Corticosteroid therapy
Myocarditis
Trial
Immunosuppression
Acute heart failure
Fulminant acute myocarditis
Lead sponsor: Niguarda Hospital
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
name: Istituto Di Ricerche Farmacologiche Mario Negri
name: University of Milano Bicocca
name: Regione Lombardia
First posted: 2021-12-09
Enrollment: 288
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single blind randomized controlled trial
Primary purpose: TREATMENT

Brief summary: This is a phase III, multi-center international, single blind randomized controlled trial to test the efficacy of pulsed intravenous (IV) methylprednisolone versus standard therapy on top of maximal support in patients with Acute myocarditis (AM).

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 PI 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 acute HF/cardiogenic shock and LV systolic dysfunction 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.

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.

Sample size calculation: we plan to recruit a total of 360 patients, and we expect that about 20% of these patients or local physicians will refuse randomization. This would leave a total of 288 randomized patients (144 per arm).

Considering as relevant a reduction in the probability to reach the primary endpoint at 6 months from 25% in the standard therapy on top of maximal supportive care arm to 12% in the pulsed corticosteroid therapy arm (absolute risk reduction of 13% in absolute corresponding to a hazard ratio (HR) pulsed corticosteroid therapy vs. standard therapy of 0.44), the planned sample size will allow achieving a power of 0.80 with a one-sided log-rank test and an overall type I error of 0.025. The 25% figure considered for the standard therapy derives from a retrospective analysis of the patient's cohort spanning over 20 years. The calculation includes an interim analysis planned at 50% recruitment (O\&#39;Brien-Fleming method). This interim analysis is accounted for in the sample size calculation with an alpha level of 0.001525 (final analysis 0.023475 alpha level) and is planned on the primary endpoint to assess a possible early treatment effect. No specific stopping rules are planned, given the multiplicity of aspects involved, but the report on safety will be reviewed by the Data and Safety Monitoring Committee (DSMC) will advise on possible aspects of the trial that need reconsideration.

Sample size adaptation: We will consider, based on the DSMC advise an adaptive approach to sample size in two regards:

1. At the interim analysis, if the baseline incidence is lower than the expected 25%, the sample size calculation may be re-evaluated keeping the same HR of 0.44. For instance, if the observed incidence is 20%, maintaining the same HR of 0.44 (corresponding to an incidence of 9% in the pulsed corticosteroid therapy group, i.e. 11% in absolute risk reduction) the effective sample size needed to achieve 80% power should be increased to 360 patients. If the baseline incidence is higher than 25%, the planned actual sample size will achieve a power greater than 80% to detect a HR of 0.44 and no action will be taken.
2. Based on the conditional power method, and on the DSMC advise, we may reconsider if a less promising result than HR=0.4444 is worth pursuing, given the current observed estimate. This case would require an increase in sample size that will be discussed in terms of relevance and feasibility. For example, if at the planned interim analysis, the estimated absolute risk reduction is at least 10% (HR=0.56) with 25% baseline, and the conditional power of meeting this 10% target (instead of the planned 13%) would be at least 60%, the sample size may be increased to reach the 80% desired power. In this case, the final effective sample size should be increased to 254 patients per arm to preserve an 80% power of demonstrating the less marked difference. The flexibility allowed in the sample size estimate will be considered based on the evaluation of the interim report by the DSMC and no data will be disclosed on interim treatment estimates to the study coordinator and steering committee.

The overall duration of the study from first patient first visit to last patient last visit will be 39 months. The follow-up will be up to 6 months and with additional 3 months to lock the database. Enrollment will last 30 months.

In parallel, there will be a prospective registry of patients that are eligible for the trial, but they are not randomized.

A second registry, called MYOCARDITIS REGISTRY will prospectively recruit all patients with acute myocarditis demonstrated by CMRI or EMB who are not eligible for randomization (not all centers will take part in this registry).

The study is supported by a grant from Italian Ministry of Health (GR-2019-12368506) and Lombardy Region.

Exemption from the investigational new drug (IND) regulations by FDA on August 2nd, 2021 (PIND: 15727)

EudraCT identifier: 2021-000938-34

Eligibility criteria: Inclusion Criteria:

* Patients admitted to hospital for suspected AM
* Age 18 years or older and below 70 years (18-69 years)
* 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;
* Left ventricular ejection fraction (LVEF)\<41% and left ventricular end diastolic diameter (LV-EDD)\<56 mm (parasternal long-axis view) on echocardiogram;
* Increased troponin (3x upper reference limit \[URL\]) 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.

Exclusion Criteria:

* 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 giant cell myocarditis (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 of a systemic autoimmune disorder, or cardiac sarcoidosis or GCM;
* 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 endomyocardial biopsy (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 disease (i.e., previous cardiomyopathy) that does NOT include previous myocarditis if there is a functional recovery at the time of screening);
* 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;
* t-MCS instituted more than 48 hours before randomization;
* Patients clinically judged too sick to initiate t-MCS (i.e., irreversible multiorgan failure);
* 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.

Primary outcomes:
measure: Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, need for an upgrading of the t-MCS, VT/VF treated with DC shock, first rehospitalization due to HF or ventricular arrhythmias, or AV block.
timeFrame: 6 months from patients enrollment
Secondary outcomes:
measure: Time from randomization to the first event among: all-cause death, HTx, long-term LVAD implant, first rehospitalization due to HF or ventricular arrhythmias, or advanced AV block.
timeFrame: 6 months from patients enrollment
measure: Mortality
timeFrame: 6 months from patients enrollment
measure: 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
timeFrame: 6 months from patients enrollment
measure: Number of days on t-MCS from randomization
timeFrame: 6 months from patients enrollment
measure: Number of days in ICU from randomization
timeFrame: 6 months from patients enrollment
measure: Change in LVEF on echocardiogram after 5 days from randomization
timeFrame: 5 days from randomization
measure: Change of troponin levels after 5 days from randomization
timeFrame: 5 days from randomization
measure: Change in heart rate (HR) on ECG after 3 days from randomization
timeFrame: 3 days from randomization
measure: Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month cardiac magnetic resonance imaging (CMRI)
timeFrame: 6 months from patients enrollment
measure: Proportion of patients with LVEF<55% on 6-month CMRI
timeFrame: 6 months from patients enrollment
measure: Proportion of patients with LV dilation on 6-month CMRI
timeFrame: 6 months from patients enrollment
Other outcomes:
measure: Safety endpoints
timeFrame: 6 months from patients enrollment
Locations:
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Houston
country: United States
facility: University of Texas
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Graz
country: Austria
facility: Medical University of Graz
city: Innsbruck
country: Austria
facility: Medical University Innsbruck
city: Wien
country: Austria
facility: Medical University of Wien
city: Aalst
country: Belgium
facility: Onze Lieve Vrouwziekenhuis
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Hasselt
country: Belgium
facility: Jessa Hospital Hasselt
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Brno
country: Czechia
facility: Masaryk University and St. Anne's University Hospital
city: Prague
country: Czechia
facility: Charles University in Prague and General University Hospital
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine - IKEM
city: Copenhagen
country: Denmark
facility: Rigshospitalet and University of Copenhagen
city: Helsinki
country: Finland
facility: Heart and Lung Center, Helsinki University Hospital
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti Umberto I°-Lancisi-Salesi di Ancona
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Policlinico S.Orsola-Malpighi
city: Brescia
country: Italy
facility: ASST Spedali Civili
city: Cagliari
country: Italy
facility: Azienda Ospedaliera "G.Brotzu"
city: Chieti
country: Italy
facility: P.O. SS. Annunziata Chieti -ASL 2 Abruzzo
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino, IRCCS
city: Lecco
country: Italy
facility: Azienda Socio-Sanitaria Territoriale (ASST) di Lecco
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Milano
country: Italy
facility: Centro Cardiologico Monzino
city: Monza
country: Italy
facility: ASST Monza, Ospedale San Gerardo
city: Napoli
country: Italy
facility: Azienda Ospedaliera Specialistica dei Colli - Ospedale Monaldi
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pisa
country: Italy
facility: Fondazione Toscana Gabriele Monasterio
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini di Roma
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese, Policlinico Santa Maria alle Scotte
city: Torino
country: Italy
facility: Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
city: Udine
country: Italy
facility: Presidio Ospedaliero Universitario "Santa Maria della Misericordia"
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: A Coruña
country: Spain
facility: Complexo Hospitalario Universitario A Coruña (CHUAC)
city: Barcelona
country: Spain
facility: Barcelona
city: Barcelona
country: Spain
facility: Bellvitge University Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón in Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Göthenburg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Lund
country: Sweden
facility: Lund University and Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
Study officials:
References:
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citation: 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.
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citation: 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.
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citation: 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.
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