Cell Free DNA Testing for Myocarditis

(cfDNA in CS Trial)

Overseen By Brenda Werner, RN

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Nabeel Hamzeh

Must not be taking: Immunosuppressive therapy

Disqualifiers: Cardiac disease, Smoker, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

120 Participants Needed

Trial Summary

What is the purpose of this trial?

Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect any organ in the body, including the heart. Granulomatous myocarditis can lead to ventricular dysfunction and ventricular arrhythmias causing significant morbidity and mortality. Immunosuppressive therapy (IST) has been shown to reverse active myocarditis and preserve left ventricular (LV) function and in some cases improve LV function. In addition, IST can suppress arrhythmias that develop due to active myocarditis and prevent the formation of scar. The potential role of cardiac biomarkers, including brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and cardiac troponins, in detecting active myocarditis is limited and studies have been disappointing. At present, there are no biomarkers to detect active myocarditis and the use of advanced imaging modalities (FDG-PET) for assessing and monitoring active myocarditis is not feasible or practical and is associate with high radiation exposure. As such, a biomarker that is reflective of active myocarditis and that is cardiac specific will assist physicians in assessing the presence of active myocarditis to guide therapeutic decisions and to assess response to therapy which can limit further cardiac damage. Cell free DNA (cfDNA) are fragments of genomic DNA that are released into the circulation from dying or damaged cells. It is a powerful diagnostic tool in cancer, transplant rejection and fetal medicine especially when the genomic source differs from the host. A novel technique that relies on tissue unique CpG methylation patterns can identify the tissue source of cell free DNA in an individual reflecting potential tissue injury. We will be conducting a pilot study to explore the utility of this diagnostic tool to identify granulomatous myocarditis in patients with sarcoidosis.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on immunosuppressive therapy to participate.

What data supports the effectiveness of the drug Cell free DNA, Prednisone, Corticosteroids for myocarditis?

Corticosteroids, a part of the treatment, have been studied for viral myocarditis, showing some improvement in heart function but not in survival rates. A scoring system suggests that steroids may help certain patients with active myocarditis, but overall evidence does not strongly support their routine use. ^{1 2 3 4 5}

Is Cell Free DNA Testing for Myocarditis safe for humans?

Research on corticosteroids, like prednisone, used in treating myocarditis shows they are generally safe, with no significant side effects reported in children and adults. However, the effectiveness of these treatments for myocarditis varies, and they are not routinely recommended for viral myocarditis. ^{4 5 6 7 8}

How does cell-free DNA testing differ from other treatments for myocarditis?

Cell-free DNA testing for myocarditis is unique because it focuses on detecting DNA fragments in the blood to diagnose and monitor the condition, rather than directly treating it. This approach is different from traditional treatments like immunosuppressive therapy, which aim to reduce inflammation in the heart. ^{4 5 7 9 10}

Research Team

Nabeel Hamzeh, MD

Principal Investigator

University of Iowa

Eligibility Criteria

This trial is for non-smokers with sarcoidosis diagnosed by ATS/ERS criteria, experiencing active myocarditis confirmed by cMRI or cFDG-PET. It includes those undergoing cardiac intervention for acute coronary syndrome (STEMI) and healthy controls without cardiovascular risks or known cardiac disease. Excluded are smokers, those on immunosuppressive therapy, hemodynamically unstable patients, and anyone with other known cardiac diseases.

Inclusion Criteria

I have no known heart diseases.

I am receiving treatment for a sudden heart problem.

I have been diagnosed with sarcoidosis but do not have active heart inflammation.

Exclusion Criteria

I had a severe heart attack and am currently unstable.

I have sarcoidosis without heart inflammation and I currently smoke.

I am currently a smoker and have had a recent heart attack.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Initial blood draw to measure cfDNA levels in all participant groups

1 day

1 visit (in-person)

Follow-up Assessment

Additional blood draws for sarcoidosis patients with active myocarditis and STEMI patients to monitor cfDNA levels

2 months

2 visits (in-person) for sarcoidosis with myocarditis, 2 visits (in-person) for STEMI

Follow-up

Participants are monitored for safety and effectiveness after the main assessments

4 weeks

Treatment Details

Interventions

• Cell free DNA

Trial Overview The study tests the use of cell free DNA (cfDNA) as a diagnostic tool to identify granulomatous myocarditis in sarcoidosis patients. The goal is to find a specific biomarker that can guide treatment decisions and monitor response to therapy without the need for high-radiation imaging techniques like FDG-PET.

Participant Groups

Group I: Sarcoidosis patients with evidence of active myocarditis Experimental Treatment 1 Intervention

Two blood draws 2 months apart.

Group II: Sarcoidosis patients without evidence of active myocarditis Active Control 1 Intervention

A single blood draw.

Group III: Acute ST elevation myocardial infarction (STEMI) Active Control 1 Intervention

Three blood draws, baseline, 6 hours and 24 hours.

Group IV: Healthy controls Placebo Group 1 Intervention

A single blood draw

Who Is Running the Clinical Trial?

Nabeel Hamzeh

Lead Sponsor

Trials

2

Recruited

140+

Findings from Research

In a study of 11 patients with immune checkpoint inhibitor (ICI) myocarditis, 4 were treated with infliximab, suggesting it may be a safe option for those who do not respond to corticosteroids, despite its black box warning for heart failure.

While infliximab did not significantly shorten the time to troponin normalization compared to corticosteroids alone, all patients survived their initial hospital admission, indicating potential efficacy in managing this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series. Zhang, RS., Padegimas, A., Murphy, KM., et al.[2021]

In a study of 40 children under 21 diagnosed with myocarditis, treatment with high-dose steroids and IVIG resulted in a 92.5% transplant-free survival rate and significant recovery of heart function, with 70% regaining normal left ventricular function by 3 months.

The treatment was found to be safe, as there were no serious secondary bacterial infections reported after starting steroids, indicating that this combination therapy may be a viable option for managing acute myocarditis in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Pediatric Myocarditis with High Dose Steroids and Immunoglobulin. Schauer, J., Newland, D., Hong, B., et al.[2023]

A new scoring system based on six clinical parameters can help predict the efficacy of steroid therapy in patients with active myocarditis, as demonstrated in a retrospective analysis of 21 patients.

In this study, non-steroid treatments were effective for patients with lower scores (-5 to -4), while steroid therapy showed better outcomes for those with higher scores (0 to +6), suggesting that the scoring system can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new scoring system to predict the efficacy of steroid therapy for patients with active myocarditis--a retrospective study. Kodama, M., Okura, Y., Hirono, S., et al.[2019]

The Myocarditis Treatment Trial involved 66 patients receiving immunosuppressive therapy plus conventional treatment and 45 patients receiving only conventional treatment for 24 weeks, aiming to improve heart function in those with biopsy-confirmed myocarditis.

Results showed that the trial focused on measuring the improvement in left ventricular ejection fraction (LVEF) at week 28, with additional analyses planned for survival rates and immunological markers, highlighting the potential role of immunosuppressive therapy in treating myocarditis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Myocarditis Treatment Trial: design, methods and patients enrollment. Hahn, EA., Hartz, VL., Moon, TE., et al.[2019]

A systematic review of 8 randomized controlled trials involving 719 patients found that corticosteroid therapy did not significantly reduce mortality in patients with viral myocarditis.

However, patients receiving corticosteroids showed improved left ventricular ejection fraction post-treatment, indicating some potential benefit in heart function, though the overall evidence does not support routine corticosteroid use for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cochrane Corner: Corticosteroids for viral myocarditis. Caldeira, D., Lopes, LR., Vaz-Carneiro, A., et al.[2018]

In a study of 53 patients with idiopathic dysrhythmias, myocarditis was found in 36% of cases through histologic examination, highlighting its prevalence in this population.

Steroid therapy was effective in 77.8% of patients with biopsy-proven myocarditis, but only 29.4% in those with clinically suspected myocarditis but negative biopsies, indicating that steroid treatment may be more beneficial for confirmed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of myocarditis in idiopathic dysrhythmias: role of endomyocardial biopsy and efficacy of steroid therapy. Thongtang, V., Chiathiraphan, S., Ratanarapee, S., et al.[2013]

In a study of 13 children with biopsy-proven myocarditis, steroid therapy (prednisone) led to significant clinical improvements, including normalization of ECG changes and heart function, with no significant side effects reported.

Repeat biopsies showed improvement in all patients, with six out of eight showing elimination of inflammatory infiltrate, suggesting that immunosuppressive therapy can effectively enhance recovery in pediatric myocarditis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive therapy in the management of acute myocarditis in children: a clinical trial. Chan, KY., Iwahara, M., Benson, LN., et al.[2021]

Scintigraphy using (99m)Tc-Anti-Granulocyte antibody was tested on 14 patients with confirmed myocarditis and successfully identified inflammation in 13 of them, suggesting it could be a valuable non-invasive diagnostic tool for myocarditis.

The study showed a strong agreement between scintigraphy results and myocardial biopsy findings, indicating that this imaging method may help in diagnosing myocarditis without the need for invasive procedures, although more research is needed to confirm its accuracy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Screening for acute myocarditis--is scintigraphy with (99m)Tc-Anti-Granulocyte BW 250/183 an answer? Hubalewska, A., Dudek, D., Dubiel, J., et al.[2016]

In a study of 20 patients with myocarditis treated with prednisone and azathioprine, histologic improvement was observed in all patients, with 15 achieving complete resolution of inflammation, indicating the treatment's efficacy.

While overall left ventricular ejection fraction improved from 0.37 to 0.46, the direct impact of treatment on heart function recovery was unclear; however, some patients did show a correlation between histological improvement and enhanced ejection fraction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive treatment in myocarditis. Salvi, A., Di Lenarda, A., Dreas, L., et al.[2019]

In a study of 30 patients with unexplained congestive heart failure, only 10% were found to have biopsy-proven myocarditis, indicating a low incidence of this condition in the sample.

The immunosuppressive treatment with prednisone and azathioprine in two patients showed clinical improvement, but their heart function did not improve as expected, suggesting that more research is needed to confirm the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myocarditis and cardiomyopathy: diagnosis by endomyocardial biopsy. Arbustini, E., Gavazzi, A., Pucci, A., et al.[2014]

References

1. England pubmed.ncbi.nlm.nih.gov

Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Treating Pediatric Myocarditis with High Dose Steroids and Immunoglobulin. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

A new scoring system to predict the efficacy of steroid therapy for patients with active myocarditis--a retrospective study. [2019]

4. England pubmed.ncbi.nlm.nih.gov

The Myocarditis Treatment Trial: design, methods and patients enrollment. [2019]

5. Portugal pubmed.ncbi.nlm.nih.gov

Cochrane Corner: Corticosteroids for viral myocarditis. [2018]

6. Thailand pubmed.ncbi.nlm.nih.gov

Prevalence of myocarditis in idiopathic dysrhythmias: role of endomyocardial biopsy and efficacy of steroid therapy. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Immunosuppressive therapy in the management of acute myocarditis in children: a clinical trial. [2021]

8. Poland pubmed.ncbi.nlm.nih.gov

Screening for acute myocarditis--is scintigraphy with (99m)Tc-Anti-Granulocyte BW 250/183 an answer? [2016]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Immunosuppressive treatment in myocarditis. [2019]

10. Italy pubmed.ncbi.nlm.nih.gov

Myocarditis and cardiomyopathy: diagnosis by endomyocardial biopsy. [2014]