Impact of Allo- and Autoantibodies on Chronic Cardiac Allograft Function

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)

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.

Study Overview

• Status: Completed
• Conditions: Pediatric Heart Transplantation; Pediatric Heart Transplant Recipients

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 407

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada, M5G 1X8
    • Hospital for Sick Children
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30060
      • Emory University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10467
      • Children's Hospital at Montefiore
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carell Jr. Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Participants that were enrolled in CTOTC-04 (ClinicalTrials.gov ID NCT01005316) who consent to long-term follow-up and new participants at the nine designated sites who are listed for isolated orthotopic heart transplantation

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Pediatric Heart Transplant Recipients; 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?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Microvascular pathology	Microvascular pathology as defined by: cytoprotective intracellular signaling (bcl2, Heme Oxygenase-1(HO-1)); interstitial capillary network; endothelial cell progenitor influx and premature senescence; obliterative microvasculopathy (arteriolopathy)	Up to 5 years post-transplantation
Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, ICAM, VCAM and selectins, Complement inhibitory proteins CD55, CD59, CR1, CR2 and CR3.	Endothelial Cell (EC) Culture Model is used to study factors that will predict and contribute to the protection of the graft following transplantation across sub-threshold concentrations of DSA. Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, Intercellular adhesion molecules (ICAM), Vascular Cell Adhesion Molecule (VCAM) and selectins, Complement inhibitory proteins (cluster of differentiation antigen 55 (CD55), cluster of differentiation antigen 59 (CD59), Complement Receptor 1 (CR1), (CR2) and (CR3).	After exposure to alloantibody (or control) (At Year 1)
Exploratory: Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin)	Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin) will be measured by: ELISPOT for Interleukin 17 (IL17) and Interleukin 10 (IL10) producing T cells; Plasma cytokines by Luminex (IL-6, IL-1beta, IL-17, Cxcl12, IL-10 and Transforming Growth Factor-beta (TGF-beta)	24 hours prior transplantation, Months 3 and 6 post transplantation
Exploratory: Role of Interleukin-33 (IL-33) and its Receptor (ST2) in cardioprotection against effects of DSA	Role of IL-33 and its Receptor (ST2) in cardioprotection against effects of DSA will be measured by: IL33 and ST2 expression in graft biopsies; Soluble ST2 in serum	Month 5 post transplantation

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Clinical Trials in Organ Transplantation in Children
• Investigators: Principal Investigator: Steven A. Webber, MBChB, MRCP, Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation; Study Chair: Steven A. Webber, MBChB, MRCP, Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Clinical Trials in Organ Transplantation in Children (CTOT-C)

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2014
• Primary Completion (Actual): November 1, 2019
• Study Completion (Actual): November 1, 2019

Study Registration Dates

• First Submitted: April 22, 2016
• First Submitted That Met QC Criteria: April 22, 2016
• First Posted (Estimate): April 27, 2016

Study Record Updates

• Last Update Posted (Actual): November 29, 2019
• Last Update Submitted That Met QC Criteria: November 27, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: alloantibodies; donor specific antibodies (DSA)-preformed, de novo; self-antigens; chronic allograft function
• Other Study ID Numbers: DAIT CTOTC-09