Impact of Allo- and Autoantibodies on Chronic Cardiac Allograft Function

Study Overview
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Brief Summary
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This is a multi-center, prospective, single cohort, observational study of pediatric heart transplant recipients designed to determine the impact of preformed versus de novo human leukocyte antigen (HLA) donor-specific antibodies (DSA), and antibodies to the self-antigens cardiac myosin and vimentin, on chronic allograft function. In addition, the investigators will explore mechanisms of action and predictors of DSA, rejection and altered pathophysiology.

Detailed Description
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Participants that were enrolled in the CTOTC-04 study (ClinicalTrials.gov Identifier NCT01005316) are invited to enroll in this CTOTC-09 study. Conversion from the CTOTC-04 to CTOTC-09 study will occur in such a manner as to avoid/minimize discontinuity of follow-up between the planned CTOTC-04 and CTOTC-09 study visits. In addition, subjects added to the United Network for Organ Sharing (UNOS) system-or Canadian equivalent agency-at a participating study site, who are less than 21 years of age and fulfill all study eligibility criteria, will be invited to enroll in CTOTC-09. This study focuses on the importance of antibodies against the newly transplanted heart in pediatric heart transplant recipients. The investigators aim to determine if certain antibodies lead to problems with the heart transplant. Antibodies are small proteins in the blood that the body makes to fight off infections, for example with bacteria or viruses. Since a new heart is foreign to the recipient's body, their immune system might try to attack it with antibodies, as if it were an infection. For many years it was thought that only white blood cells attacked the new heart, causing rejection. Now there is new information showing that antibodies may also cause rejection or long-term damage to the heart. At this time, very little is known about how antibodies might cause problems after heart transplantation in transplant recipients younger than 21 years at the time of transplant. This study will collect a medical history and blood samples at specified times for research. The blood samples will be used to measure antibodies in the blood, and to perform special tests to see how these antibodies might damage the heart. Participant follow-up is from the day of the heart transplant to year 5 post-transplant.

Official Title
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An Observational Cohort Study to Determine the Impact of Alloantibodies and Antibodies to Self Antigens on Chronic Graft Function up to 5 Years After Pediatric Heart Transplantation (CTOTC-09)

Conditions
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Pediatric Heart Transplantation, Pediatric Heart Transplant Recipients

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject and/or parent guardian able to understand and provide informed consent and where applicable assent Planned long-term follow-up at one of the study sites AND either: -Enrolled in the CTOTC-04 study and actively followed at one of the study sites OR -Listed at participating study sites, less than 21 years of age and not yet transplanted. The inclusion criteria for enrollment of new study patients in the CTOTC-09 Protocol will be the same as the CTOTC-04 study (refer to ClinicalTrials.gov ID NCT01005316). Exclusion Criteria: Parental withdrawal of consent from the CTOTC-04 study Past or current medical problems or findings from physical examination or laboratory testing that, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or may impact the quality or interpretation of the data obtained from the study Listed for simultaneous multiple organ transplant.

Ages Eligible for Study
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Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pediatric Heart Transplant Recipients<br>CTOTC-04 (ClinicalTrials.gov ID NCT01005316) participants who consent to long-term follow-up as part of this study as well as candidates less than 21 years of age who are listed for isolated orthotopic heart transplantation at one of the participating sites | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary capillary wedge pressure at heart catheterization |  | 3 years post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other invasive cardiac hemodynamic findings at cardiac catheterization | Cardiac hemodynamic findings: right and left ventricular end diastolic pressures, right atrial pressure, pulmonary artery pressure and cardiac index | 3 and 5 years post-transplantation | 
| Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin |  | 3 years post-transplantation | 
| Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin. |  | 3 years post-transplantation | 
| Frequency of first episode of late acute rejection |  | From >1 year to 5 years post-transplantation | 
| Time to first episode of late acute rejection | Late acute rejection is defined as occurring >1 year post-transplantation | From >1 year to 5 years post-transplantation | 
| Frequency to recurrent (two or more) late acute rejections |  | Up to 5 years post-transplantation | 
| Time to recurrent late acute rejections | Recurrent defined as two or more late acute rejection episodes | Up to 5 years post-transplantation | 
| Frequency to first episode of late acute rejection with hemodynamic compromise |  | Up to 5 years post-transplantation | 
| Time to first episode of late acute rejection with hemodynamic compromise |  | Up to 5 years post-transplantation | 
| Time to graft loss (death or retransplantation) conditional to surviving one year post-transplantation |  | One year and up to 5 years post-transplantation | 
| N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Natriuretic Peptide (BNP) |  | 3 and 5 years post-transplantation | 
| Systolic and diastolic graft function | Graft function as assessed by echocardiography | 3 and 5 years | 
| Proportion of participants with angiographic evidence of coronary artery disease |  | 3 and 5 years post-transplantation | 
| Time to graft loss (death or retransplantation) after first late rejection |  | Up to 5 years post-transplantation | 
| Medication Adherence Measure (MAM) after hospital discharge |  | Up to 5 years post-transplantation | 
| Variability of maintenance tacrolimus levels |  | Up to 5 years post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alloantibodies, donor specific antibodies (DSA)-preformed, de novo, self-antigens, chronic allograft function