Clinical trial NCT05619653: Myocardial Protection in Patients With Post-acute Inflammatory Cardiac Involvement Due to COVID-19
Official title: Randomised Placebo Controlled Clinical Trial of Efficacy of MYOcardial Protection in Patients With Postacute inFLAMmatory Cardiac involvEment Due to COVID-19
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: COVID-19 Associated Cardiac Involvement
Remodeling, Left Ventricle
Remodeling, Vascular
Left Ventricular Dysfunction
Exercise Intolerance
Vascular Inflammation
Microvascular Angina
Lead sponsor: Johann Wolfgang Goethe University Hospital
Sponsor class: OTHER
Collaborators: name: Bayer
name: Alcedis GmbH
First posted: 2022-11-17
Enrollment: 279
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicentre randomised double-blind, placebo-controlled clinical trial 1:1 randomisation
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Left ventricular ejection fraction
timeFrame: 16 weeks
Secondary outcomes:
measure: Scar burden by late gadolinium enhancement (LGE)
timeFrame: 16 weeks
measure: Cardiopulmonary exercise testing (CPET)
timeFrame: 16 weeks
measure: Mean T1 and T2 mapping
timeFrame: 16 Weeks
measure: LV mass (g/m2)
timeFrame: 16 Weeks
measure: LV strain %
timeFrame: 16 Weeks
measure: Aortic stiffness (PWV)
timeFrame: 16 Weeks
measure: Aortic wall imaging (LGE)
timeFrame: 16 Weeks
measure: Average Symptom Score (RAND 36)
timeFrame: 16 Weeks
measure: HF and MACE Endpoints
timeFrame: 1 and 5 years
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: University Medical Centre Vienna
city: Frankfurt Am Main
country: Germany
facility: Institute for experimental and translational cardiovascular imaging
state: Hessen
city: Greifswald
country: Germany
facility: University Hospital Greifswald
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein, Campus KIEL
city: Ulm
country: Germany
facility: University Hospital Ulm
Study officials:
affiliation: Goethe University
name: Valentina Puntmann, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Goethe University
name: Eike Nagel, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
citation: Puntmann VO, Beitzke D, Kammerlander A, Voges I, Gabbert DD, Doerr M, Chamling B, Bozkurt B, Kaski JC, Spatz E, Herrmann E, Rohde G, DeLeuw P, Taylor L, Windemuth-Kieselbach C, Harz C, Santiuste M, Schoeckel L, Hirayama J, Taylor PC, Berry C, Nagel E. Design and rationale of MYOFLAME-19 randomised controlled trial: MYOcardial protection to reduce post-COVID inFLAMmatory heart disease using cardiovascular magnetic resonance Endpoints. J Cardiovasc Magn Reson. 2024 Oct 29;27(1):101121. doi: 10.1016/j.jocmr.2024.101121. Online ahead of print.