Multicentre, randomised placebo-controlled clinical trial (Phase III)
EudraCT 2022-001682-12 NCT05619653 |
Randomised Placebo Controlled Clinical Trial of Efficacy of MYOcardial Protection in Patients With Postacute inFLAMmatory Cardiac involvEment Due to COVID-19 |
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At the Institute of Experimental and Translational Cardiovascular Imaging, we are conducting a randomised, placebo-controlled clinical trial of cardioprotective treatment (MYOFLAME-19) in previously healthy individuals with Long COVID and recent COVID infection and cardiac symptoms (shortness of breath on exertion, chest pain, tachycardia). Patients are being actively recruited at 4 German sites (Greifswald, Frankfurt, Kiel, Ulm) and 1 Austrian site (Vienna).
If you are interested in participating, please register through the study website. In clinical trials, we test an existing or new drug in a randomised, double-blind (placebo-controlled) study. We try to find out whether treatment leads to improvement. In the Myoflame-19 study, the effect of treatment will be assessed by measurements in the heart (16 weeks) and by improved outcomes (1- and 5-year follow-up). Double-blind means that some patients will receive the treatment and others will not, but neither the patient nor the doctor knows this. All heart measurements are performed by a dedicated independent team (Core-Lab). Investigators and participants remain blinded to group allocation and imaging results. |
Overview |
Long COVID or Postacute sequelae of COVID-19 infection (PASC) are increasingly recognised complications, defined by lingering symptoms not present prior to the infection. 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., all a part of the Long COVID or PASC syndrome.
Phenotypically, post-COVID heart involvement is characterised by chronic perivascular and myopericardial inflammation. The pattern is similar to that observed in chronic systemic autoimmune conditions. We and others have shown changes using sensitive cardiac MRI imaging, as well as that the MRI findings relate to cardiac symptoms.
We hypothesise that 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).
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., all a part of the Long COVID or PASC syndrome.
Phenotypically, post-COVID heart involvement is characterised by chronic perivascular and myopericardial inflammation. The pattern is similar to that observed in chronic systemic autoimmune conditions. We and others have shown changes using sensitive cardiac MRI imaging, as well as that the MRI findings relate to cardiac symptoms.
We hypothesise that 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).
Aims of the study
The overall goal is to evaluate whether early combined immunosuppression/antiremodeling therapy in patients with PASC-CVS and signs of subclinical inflammation on cardiac MRI, leads to a reduction of symptoms and inflammatory myocardial injury and, in the long term, to reduced development of heart failure.
Who can take part
Participants with documented COVID-19 infection, experiencing new cardiac symptoms in the aftermath of COVID-19 infection, fulfilling the predefined CMR criteria for PostCOVID myocardial involvement and no previously known or demonstrable structural heart disease will be considered for inclusion. Participants have not taken ACE inhibitors or Angiotensin Receptor Blockers previously. Participants have not had any anti-inflammatory or immunosuppressive treatment or intervention within the previous 10 weeks. The list of exact inclusion and exclusion criteria is provided on the clinicaltrial.gov NCT05619653.
What happens during the study
Participants will be first asked to complete a screening questionnaire. This will be followed by a conversation about the study. If willing to proceed, the participants will sign an informed consent form and be invited to attend the baseline visit.
At the baseline visit, a cardiac MRI scan will determine whether participants fulfil the inclusion criteria for treatment. Also, blood sampling and cardiopulmonary testing will be conducted.
The participants meeting cardiac MRI criteria will be randomly allocated to either treatment (losartan and prednisolone ) or placebo. The participants will take the treatment/placebo for a total of 16 weeks of therapy. They remain closely monitored and supported throughout the 16-week period.
At the end of 16 weeks, participants attend the final visit with cardiac MRI, blood sampling and CPET. The participants are followed up after the completion of the treatment period, as well as at 1 and 5 years' time. A total of 280 patients will be enrolled.
At the baseline visit, a cardiac MRI scan will determine whether participants fulfil the inclusion criteria for treatment. Also, blood sampling and cardiopulmonary testing will be conducted.
The participants meeting cardiac MRI criteria will be randomly allocated to either treatment (losartan and prednisolone ) or placebo. The participants will take the treatment/placebo for a total of 16 weeks of therapy. They remain closely monitored and supported throughout the 16-week period.
At the end of 16 weeks, participants attend the final visit with cardiac MRI, blood sampling and CPET. The participants are followed up after the completion of the treatment period, as well as at 1 and 5 years' time. A total of 280 patients will be enrolled.
What happens with the results
All cardiac MRI imaging is conducted with fidelity to a predefined standardised imaging protocol. All images are analysed in a dedicated core laboratory to confirm the baseline eligibility for inclusion and to conduct the final assessments. To ensure the scientific validity of the study results, investigators and participants remain blinded to group allocation and imaging results. The results will be evaluated by an independent statistician at the completion of the study. The results will be submitted to a peer-reviewed journal for publication.
The organisation of the study
This is an investigator-initiated research study, supported by industrial funding (Bayer AG). Goethe University Frankfurt is the sponsor of the study (sponsor representatives/principal investigators Drs. Valentina Puntmann and Eike Nagel). The study conduct is overseen by a steering committee and data safety and monitoring committee. The study is supported and monitored by the clinical research organisation Alcedis GmbH.
