Regadenoson for Heart Transplant Rejection

Overseen By Paul Kim, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Paul Kim

Disqualifiers: Acute rejection, Ischemia, Seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

376 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators will evaluate for early evidence of cardiac allograft dysfunction by cardiac MRI and single cell sequencing to determine underlying molecular and macroscopic causes.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

Is Regadenoson generally safe for humans?

The research does not provide specific safety data for Regadenoson, but it highlights that cardiac adverse effects are common with many drugs, especially those affecting cardiovascular functions. It's important to consult with healthcare professionals for personalized safety information. ^{1 2 3 4 5}

How does the drug Regadenoson differ from other treatments for heart transplant rejection?

Regadenoson is unique because it is primarily used as a stress agent in cardiac imaging, and its application for heart transplant rejection is novel. Unlike traditional immunosuppressive drugs like cyclosporine or prednisone, Regadenoson works by affecting blood flow and heart rate, which may offer a different approach to managing rejection. ^{6 7 8 9 10}

Research Team

Paul Kim, MD

Principal Investigator

UC San Diego

Eligibility Criteria

This trial is for adults over 18 who had a heart transplant at least three months ago. It's not for those with recent heart issues, uncontrolled lung diseases like asthma or COPD, seizure history, recent organ rejection, certain heart rhythm problems, MRI contraindications (like pacemakers), severe kidney issues, past bad reactions to regadenoson or gadolinium contrast agents, extreme blood pressure or pulse rates.

Inclusion Criteria

I am 18 years old or older.

I had a heart transplant more than three months ago.

Exclusion Criteria

I have uncontrolled asthma or COPD.

I have had seizures that affect my whole body.

Resting heart rate greater than 120 or less than 45 beats per minute

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Cardiac MRI and single cell sequencing are performed to evaluate cardiac allograft function

1-2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for major adverse cardiovascular events (MACE) and other outcomes

12 months

Regular visits as per clinical care

Long-term Follow-up

Participants are monitored for long-term outcomes including stenotic microvasculopathy and MACE

60 months

Treatment Details

Interventions

• Regadenoson

Trial Overview The study tests if the drug Regadenoson can help detect early signs of heart transplant rejection using advanced imaging (cardiac MRI) and detailed cell analysis. The goal is to understand the molecular and physical changes that indicate graft dysfunction.

Participant Groups

Group I: Normal graft function Experimental Treatment 1 Intervention

Patients with normal graft function will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. Peripheral blood and endomycardial biopsies will also be obtained for single cell RNAseq analyses.

Group II: Nonspecific allograft dysfunction Experimental Treatment 1 Intervention

Patients with nonspecific allograft dysfunction will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. Peripheral blood and endomycardial biopsies will also be obtained for single cell RNAseq analyses.

Group III: Cardiac allograft vasculopathy Experimental Treatment 1 Intervention

Patients with allograft dysfunction from known cardiac allograft dysfunction will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. Peripheral blood and endomycardial biopsies will also be obtained for single cell RNAseq analyses.

Group IV: ACR/AMR Experimental Treatment 1 Intervention

Patients with allograft dysfunction from prior episodes of acute cellular or antibody mediated rejection will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. Peripheral blood and endomycardial biopsies will also be obtained for single cell RNAseq analyses.

Who Is Running the Clinical Trial?

Paul Kim

Lead Sponsor

Trials

2

Recruited

390+

Findings from Research

A comprehensive database of 396,985 drug-related cardiac adverse effects (AEs) linked to 1,632 approved drugs was created, revealing significant clusters of AEs affecting heart function, such as arrhythmias and heart failure.

The study identified that cardiac AEs are highly correlated with drugs targeting cardiovascular functions and specific mechanisms of action, including interactions with various receptors like alpha- and beta-adrenergic receptors, which may help predict and understand these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of drug-related cardiac adverse effects in humans--A: creation of a database of effects and identification of factors affecting their occurrence. Matthews, EJ., Frid, AA.[2013]

In 2011, the MedWatch system received 600,000 adverse event reports, highlighting its role in improving drug and device safety awareness, but it also faces challenges with reporting bias and data accuracy.

A study analyzing 10.2 million reports found that while patient information was mostly accurate, suspect product data was often incomplete or incorrect, with significant gaps in key details like dosage and product lot numbers, which could lead to incorrect conclusions about drug safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the completeness and accuracy of MedWatch data. Getz, KA., Stergiopoulos, S., Kaitin, KI.[2017]

In a review of 306 cardiovascular adverse events associated with sipuleucel-T from a large pharmacovigilance database, significant risks were identified, including myocardial ischemia, congestive heart failure, and supraventricular tachycardia, particularly in patients with cardiovascular risk factors.

Among patients experiencing congestive heart failure, 26% of cases were fatal, indicating a serious risk associated with sipuleucel-T, suggesting the need for close monitoring of cardiac function during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database. Moey, MYY., Jiwani, RA., Takeda, K., et al.[2021]

A comprehensive analysis of 15 clinical studies involving 6638 patients showed that liraglutide, a GLP-1 receptor agonist, had a lower incidence of major adverse cardiovascular events (MACE) compared to other diabetes treatments, with an incidence ratio of 0.73.

The study confirmed that liraglutide's cardiovascular safety profile is within the limits set by the FDA for diabetes therapies, indicating it is a safe option for patients at risk of cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Marso, SP., Lindsey, JB., Stolker, JM., et al.[2022]

Between 2010 and 2016, 164 safety advisories regarding cardiac-related adverse events were issued by regulators in Australia, Canada, the UK, and the US, highlighting the prevalence of risks associated with 61 different drugs, primarily involving cardiac arrhythmias and coronary artery disorders.

While monitoring patients was the most common recommendation in these advisories, only 41.2% provided detailed guidance on how to conduct this monitoring, indicating a need for more consistent and comprehensive information for healthcare professionals and consumers regarding rare but serious medication harms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies. Hooimeyer, A., Bhasale, A., Perry, L., et al.[2023]

In a study of 37 cardiac transplant recipients, treating acute rejection episodes with only oral prednisone (increased to 100 mg/day) resulted in a 90% histologic resolution of myocyte necrosis, indicating effective management of rejection without high-dose intravenous steroids.

The protocol showed low rates of complications, with only 3.5% of episodes requiring additional treatments, and it was associated with low infectious morbidity and mortality, suggesting that oral steroids can be a safe and effective alternative for managing acute rejection in heart transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of cardiac transplant rejection without massive immunosuppression. Michler, RE., Smith, CR., Drusin, RE., et al.[2013]

In a study of 112 heart transplant patients followed for an average of 25 months, those on a steroid-free immunosuppression regimen experienced a high incidence of acute rejection (1.7 episodes per patient), but maintained excellent survival rates of 95% at 12 months and 94% at 48 months.

Despite the increased risk of acute rejection, the low rates of infection (85% freedom from infectious episodes at 48 months) and chronic rejection suggest that steroid-free immunosuppression could be a viable option for heart transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical results of steroid-free induction immunosuppression after heart transplantation. Livi, U., Luciani, GB., Boffa, GM., et al.[2021]

A 3-day course of 100 mg oral prednisone without tapering effectively treated 75% of asymptomatic ISHLT Grade 3A cardiac allograft rejection episodes in a study of 100 patients, indicating its efficacy as a treatment option.

The treatment was particularly successful for rejections occurring more than 60 days post-transplant, with an 84% response rate, making it a cost-effective alternative to traditional intravenous steroid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection. Park, MH., Starling, RC., Ratliff, NB., et al.[2019]

Sirolimus, a macrolide antibiotic with immunosuppressant properties, was successfully used to treat chronic rejection in two heart transplant patients who did not respond to standard antirejection medications.

Both patients remained free of rejection for 10 months while significantly reducing their doses of other immunosuppressants, suggesting sirolimus may be an effective alternative for managing graft rejection in heart transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus, a new potent immunosuppressant agent for refractory cardiac transplantation rejection: two case reports. Haddad, H., MacNeil, DM., Howlett, J., et al.[2013]

Early rejection prophylaxis in cardiac transplantation typically involves a combination of cyclosporine, azathioprine, and corticosteroids, with the option to include anti-T cell agents, to prevent immediate rejection after surgery.

Chronic maintenance therapy usually consists of triple therapy (cyclosporine, azathioprine, and prednisone), although there is potential for corticosteroid-free regimens, and treatment for acute rejection may require dose adjustments and additional medications based on the severity of the rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppression following cardiac transplantation. Woodley, SL., Renlund, DG., O'Connell, JB., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Prediction of drug-related cardiac adverse effects in humans--A: creation of a database of effects and identification of factors affecting their occurrence. [2013]

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

Evaluating the completeness and accuracy of MedWatch data. [2017]

3. England pubmed.ncbi.nlm.nih.gov

Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database. [2021]

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

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. [2022]

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

Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies. [2023]

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

Reversal of cardiac transplant rejection without massive immunosuppression. [2013]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical results of steroid-free induction immunosuppression after heart transplantation. [2021]

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

Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Sirolimus, a new potent immunosuppressant agent for refractory cardiac transplantation rejection: two case reports. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Immunosuppression following cardiac transplantation. [2021]