Myocardial Protection in Patients With Post-acute Inflammatory Cardiac Involvement Due to COVID-19

Left Ventricular Dysfunction Clinical Trial

— MYOFLAME-19  

Official title:

Randomised Placebo Controlled Clinical Trial of Efficacy of MYOcardial Protection in Patients With Postacute inFLAMmatory Cardiac involvEment Due to COVID-19

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05619653
• Other study ID #: MYOFLAME-19
• Secondary ID: 2022-001682-12
• Status: Recruiting
• Phase: Phase 3
• Start date: December 12, 2022
• Est. completion date: December 31, 2028

Study information

• Verified date: September 2023
• Source: Johann Wolfgang Goethe University Hospital
• Contact: Valentina Puntmann, MD, PhD
• Phone: ?+4969630189441?
• Email: CVI-Myoflame[@]kgu.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Long COVID or Postacute sequelae of COVID-19 infection (PASC) are increasingly recognised complications, defined by lingering symptoms, not present prior to the infection, typically persisting for more than 4 weeks. Cardiac symptoms due to post-acute inflammatory cardiac involvement affect a broad segment of people, who were previously well and may have had only mild acute illness (PASC-cardiovascular syndrome, PASC-CVS). Symptoms may be contiguous with the acute illness, however, more commonly they occur after a delay. Symptoms related to the cardiovascular system include exertional dyspnoea, exercise intolerance chest tightness, pulling or burning chest pain, and palpitations (POTS, exertional tachycardia). Pathophysiologically, Long COVID relates to small vessel disease (endothelial dysfunction) vascular dysfunction and consequent tissue organ hypoperfusion due to ongoing immune dysregulation. Active organs with high oxygen dependency are most affected (heart, brain, kidneys, muscles, etc.). Thus, cardiac symptoms are often accompanied by manifestations of other organ systems, including fatigue, brain fog, kidney problems, myalgias, skin and joint manifestations, etc, now commonly referred to as the Long COVID or PASC syndrome. Phenotypically, PostCOVID Heart involvement is characterised by chronic perivascular and myopericardial inflammation. We and others have shown changes using sensitive cardiac MRI imaging that relate to cardiac symptoms (Puntmann et al, Nature Medicine 2022; Puntmann et al, JAMA Cardiol 2020; Summary of studies included in 2022 ACC PostCOVID Expert Consensus Taskforce Development Statement, JACC 2022, references below). Early intervention with immunosuppression and antiremodelling therapy may reduce symptoms and development of myocardial impairment, by minimising the disease activity and inducing disease remission. Low-dose maintenance therapy may help to maintain the disease activity at the lowest possible level. The benefits of early initiations of antiremodelling therapy to reduce symptoms of exercise intolerance are well recognised, but not commonly employed outside the classical cardiology contexts, such as heart failure or hypertension. As most patients with inflammatory heart disease only have mild or no structural abnormalities, they are left untreated (standard of care). The aim of this study is to examine the efficacy of a combined immunosuppressive / antiremodelling therapy in patients with PASC symptoms and inflammatory cardiac involvement determined by CMR, to reduce the symptoms and inflammatory myocardial injury and thereby stop the progression to reduced LVEF, HF and death. References: https://www.nature.com/articles/s41591-022-02000-0 https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916 https://www.jacc.org/doi/abs/10.1016/j.jacc.2022.02.003

Description:

Patients with documented COVID-19 infection, experiencing new cardiac symptoms in the aftermath of COVID-19 infection, fulfilling predefined CMR criteria for PostCOVID myocardial involvement and no previously known or demonstrable cardiovascular disease will be randomised to 16-week treatment with Losartan/Prednisolon or placebo. All imaging is conducted with fidelity to standardised imaging protocol. All images are analysed in a dedicated core-lab to confirm eligibility for inclusion. Investigators and participants remain blinded to group allocation and imaging results. The primary outcome is a change in LVEF from the baseline to 16 weeks measured by MRI. Secondary outcomes include changes in clinical symptom scores, imaging parameters, CPET (VO2max), as well as outcomes after 1 and 5 years time.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 280
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patients = 18 years
• Patients with documented recent COVID19 infection (>4 weeks)
• PASC Syndrome, defined by persistence or new symptoms, not present prior to the infection.
• CMR evidence of inflammatory cardiac involvement at BL by any of the following

criteria:

• Increased native T1= 1130 ms at 3.0 Tesla (or 1030 ms at 1.5 Tesla) and/or;
• Increased native T2 =39.5 ms at 3.0 Tesla (or 49.5 at 1.5 Tesla) and/or
• present non-ischaemic myopericardial LGE and/or;
• LVEF =45 - =50%.
• Willingness to comply with the study procedures and study protocol

Exclusion Criteria:

• Severe acute COVID illness requiring hospitalisation
• Known allergy to or intolerance of the study medications
• Symptomatic hypotension (systolic blood pressure less than 90 mm Hg), not reversible with oral hydration
• Any previous or current use of ACE inhibitors, AR Blockers
• Any previous oral prednisolone, or any other immunosuppressive or biological treatment (within prior 10 weeks)
• History or CMR evidence of pre-existing significant heart disease, including:

1. Known cardiac impairment with LVEF =44%

2. Congestive heart failure (NYHA III-IV)

3. Active heart failure treatment

4. Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease

5. Persistent or permanent atrial fibrillation or significant heart rhythm abnormalities

6. Congenital or clinically relevant valvular heart disease (moderate or severe)

7. Specific cardiomyopathy (hypertrophic, hypertensive heart disease, amyloidosis, previous myocarditis, non-ischaemic dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, non-compaction cardiomyopathy, etc).

• Known significant concomitant diseases that are likely to interfere with the evaluation of the patient's safety and of the study outcome (e.g. diabetes, lung or hepatic disease, epilepsy, psychiatric disorders, renal disease with a current estimated GFR <30 mL/min/1.73 m² using MDRD formula, chronic systemic infection or immunocompromise)
• Exceeding scanner bore and table-holding capacity: Weight >125 kg, BMI > 35 kg/m2
• Contraindications to contrast-enhanced CMR imaging, e.g.

1. MR-unsafe implantable device

2. known allergy to gadolinium-based contrast agent (CBGA)

• For female participants:

1. Pregnant or breastfeeding women

2. Persons of childbearing potential not willing to use effective contraception (defined as PEARL index <1 - e.g. contraceptive pill, IUD)

• Known alcohol, drug or chemical abuse
• Patients currently participating in an investigational study or for whom participation is planned.
• Unable to provide written informed consent Patients with CMR evidence of structural heart disease or incidental heart rhythm abnormalities will be advised to see their own doctor for further investigation.

Related Conditions & MeSH terms

• COVID-19
• Exercise Intolerance
• Inflammation
• Left Ventricular Dysfunction
• Microvascular Angina
• Remodeling, Left Ventricle
• Vascular Inflammation
• Vascular Remodeling
• Ventricular Dysfunction
• Ventricular Dysfunction, Left
• Ventricular Remodeling

Intervention

Drug:
• Prednisolone
randomised double-blind, placebo-controlled clinical trial 1:1 randomisation
• Losartan
randomised double-blind, placebo-controlled clinical trial 1:1 randomisation

Locations

Country	Name	City	State
Austria	University Medical Centre Vienna	Vienna
Germany	Institute for experimental and translational cardiovascular imaging	Frankfurt Am Main	Hessen
Germany	University Hospital Greifswald	Greifswald
Germany	University Hospital Schleswig-Holstein, Campus KIEL	Kiel
Germany	University Hospital Ulm	Ulm

Sponsors (3)

Lead Sponsor	Collaborator
Valentina Puentmann	Alcedis GmbH, Bayer

Countries where clinical trial is conducted

Austria,  Germany, 

References & Publications (3)

Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, Shchendrygina A, Escher F, Vasa-Nicotera M, Zeiher AM, Vehreschild M, Nagel E. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Nov 1;5(11):1265-1273. doi: 10.1001/jamacardio.2020.3557. Erratum In: JAMA Cardiol. 2020 Nov 1;5(11):1308. — View Citation

Puntmann VO, Martin S, Shchendrygina A, Hoffmann J, Ka MM, Giokoglu E, Vanchin B, Holm N, Karyou A, Laux GS, Arendt C, De Leuw P, Zacharowski K, Khodamoradi Y, Vehreschild MJGT, Rohde G, Zeiher AM, Vogl TJ, Schwenke C, Nagel E. Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nat Med. 2022 Oct;28(10):2117-2123. doi: 10.1038/s41591-022-02000-0. Epub 2022 Sep 5. — View Citation

Writing Committee; Gluckman TJ, Bhave NM, Allen LA, Chung EH, Spatz ES, Ammirati E, Baggish AL, Bozkurt B, Cornwell WK 3rd, Harmon KG, Kim JH, Lala A, Levine BD, Martinez MW, Onuma O, Phelan D, Puntmann VO, Rajpal S, Taub PR, Verma AK. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022 May 3;79(17):1717-1756. doi: 10.1016/j.jacc.2022.02.003. Epub 2022 Mar 16. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left ventricular ejection fraction	absolute change of LVEF from baseline	16 weeks
Secondary	Scar burden by late gadolinium enhancement (LGE)	absolute change of LGE from baseline	16 weeks
Secondary	Cardiopulmonary exercise testing (CPET)	absolute change of achieved VO2max from baseline	16 weeks
Secondary	Mean T1 and T2 mapping	absolute change in T1 and T2 mapping values (ms) from baseline	16 Weeks
Secondary	LV mass (g/m2)	absolute change of measures from baseline	16 Weeks
Secondary	LV strain %	absolute change of measures from baseline	16 Weeks
Secondary	Aortic stiffness (PWV)	absolute change of measures from baseline	16 Weeks
Secondary	Aortic wall imaging (LGE)	absolute change of measures from baseline	16 Weeks
Secondary	Average Symptom Score (RAND 36)	change thereof compared to baseline	16 Weeks
Secondary	HF and MACE Endpoints	proportion of patients with endpoints	1 and 5 years

External Links

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