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Allograft Dysfunction in Heart Transplant

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ClinicalTrials.gov Identifier: NCT03102125
Recruitment Status : Recruiting
First Posted : April 5, 2017
Last Update Posted : November 4, 2021
Sponsor:
Information provided by (Responsible Party):
Paul Kim, University of California, San Diego

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Heart Transplant Failure and Rejection Drug: Regadenoson Phase 4

Detailed Description:

Adult heart-transplant patients, excluding those with a GFR less than 30 mL/min/1.73m2, contraindications to MRI and allergies to either regadenoson or gadolinium contrast, will be enrolled over 60 months. Patients will be recruited from UCSD. The investigators will specifically enroll all eligible heart-transplant patients.

Brief protocol:

Cardiac MRI is performed. Cine images in standard views are obtained. T1 and T2 mapping sequences are performed on short axis images pre- and post-gadolinium contrast. For stress imaging, intravenous regadenoson is given as a 0.4 mg bolus followed by a 5 mL saline flush. After 30 seconds, short-axis images are acquired for 30 consecutive heartbeats with administration of gadolinium. Rest imaging is performed 30 minutes after stress imaging. Lastly, late gadolinium enhancement images are obtained in standard views. Images are analyzed offline by a blinded independent reader. Patients will be followed for at least 1 year after enrollment for MACE.

Peripheral blood and endomyocardial biopsies will also be collected, timing as per usual clinical care as well as for-cause, for single cell RNAseq analyses.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 376 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: Defining Mechanisms for Cardiac Allograft Dysfunction to Improve Allograft Longevity and Survival in Heart-Transplant Patients
Actual Study Start Date : October 1, 2019
Estimated Primary Completion Date : April 1, 2024
Estimated Study Completion Date : April 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Regadenoson

Arms and Interventions
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Arm Intervention/treatment
Experimental: Nonspecific allograft dysfunction
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.
 Drug: Regadenoson
For use in stress myocardial perfusion imaging.
Other Name: Lexiscan
Experimental: Normal graft function
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.
 Drug: Regadenoson
For use in stress myocardial perfusion imaging.
Other Name: Lexiscan
Experimental: Cardiac allograft vasculopathy
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.
 Drug: Regadenoson
For use in stress myocardial perfusion imaging.
Other Name: Lexiscan
Experimental: ACR/AMR
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.
 Drug: Regadenoson
For use in stress myocardial perfusion imaging.
Other Name: Lexiscan


Outcome Measures
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Primary Outcome Measures :
  1. Myocardial Perfusion Reserve [ Time Frame: 60 months ]

Secondary Outcome Measures :
  1. Rest and stress myocardial blood flow [ Time Frame: 60 months ]
  2. LGE % [ Time Frame: 60 months ]
  3. LVEF [ Time Frame: 60 months ]
  4. LV end-diastolic volume index [ Time Frame: 60 months ]
  5. LV mass index [ Time Frame: 60 months ]
  6. native T1 and T2 myocardial values [ Time Frame: 60 months ]
  7. extracellular volumes [ Time Frame: 60 months ]
  8. myocardial strain rate [ Time Frame: 60 months ]

Other Outcome Measures:
  1. Major adverse cardiovascular events [ Time Frame: 60 months ]
    death, re-transplantation, percutaneous coronary intervention and HF hospitalization

  2. Percentage of different T-cell subsets by single cell RNAseq [ Time Frame: 60 months ]
  3. Number of stenotic microvasculopathy by histopathologic review of endomyocardial biopsy samples [ Time Frame: 60 months ]
    Each endomyocardial biopsy slide will be reviewed for stenotic microvasculopathy as per Hiemann et al 2007, Circulation. 1 stenotic blood vessel per view on X200 zoom is diagnostic of stenotic microvasculopathy.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age greater than or equal to 18 years old.
  • At least three months status post heart transplantation.

Exclusion Criteria:

  • Biopsy proven acute rejection episode in the past 3 months.
  • Patients with symptoms or signs of acute myocardial ischemia or recent acute coronary syndrome in the past 3 months.
  • Uncontrolled obstructive ventilatory disease including asthma and COPD.
  • History of generalized tonic-clonic seizures.
  • Second or third degree AV nodal block.
  • Sinus node dysfunction.
  • Contraindications to MRI including cardiovascular implantable electronic devices.
  • Renal dysfunction with an estimated GFR less than 30 mL/min/1.73m2.
  • Prior adverse reaction to either regadenoson or gadolinium contrast. Prior adverse reaction to adenosine or dipyridamole will be assessed on a case-by-case basis.
  • Systolic blood pressure greater than 180 or less than 85 mmHg.
  • Diastolic blood pressure greater than 120 or less than 40 mmHg.
  • Resting heart rate greater than 120 or less than 45 beats per minute. - Severe claustrophobia.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03102125


Contacts
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Contact: Paul Kim, MD 8582460638 pjk017@ucsd.edu

Locations
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United States, California
UC San Diego Recruiting
La Jolla, California, United States, 92037
Contact: Paul Kim, MD    858-246-0638    pjk017@ucsd.edu   
Sponsors and Collaborators
Paul Kim
Investigators
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Principal Investigator: Paul Kim, MD UC San Diego
More Information
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Publications of Results:
Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010 Aug;29(8):914-56. doi: 10.1016/j.healun.2010.05.034.

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Responsible Party: Paul Kim, Assistant Professor, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03102125    
Other Study ID Numbers: 160808
First Posted: April 5, 2017    Key Record Dates
Last Update Posted: November 4, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Paul Kim, University of California, San Diego:
heart transplant
acute graft rejection
chronic graft rejection
Additional relevant MeSH terms:
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Regadenoson
Adenosine A2 Receptor Agonists
Purinergic P1 Receptor Agonists
Purinergic Agonists
 Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs