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Impact of Allo- and Autoantibodies on Chronic Cardiac Allograft Function

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ClinicalTrials.gov Identifier: NCT02752789
Recruitment Status : Active, not recruiting
First Posted : April 27, 2016
Last Update Posted : January 18, 2018
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation in Children
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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.

Condition or disease
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
Actual Enrollment : 404 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: 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)
Actual Study Start Date : July 15, 2014
Estimated Primary Completion Date : February 17, 2020
Estimated Study Completion Date : February 17, 2020

Resource links provided by the National Library of Medicine


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



Primary Outcome Measures :
  1. Pulmonary capillary wedge pressure at heart catheterization [ Time Frame: 3 years post-transplantation ]

Secondary Outcome Measures :
  1. Other invasive cardiac hemodynamic findings at cardiac catheterization [ Time Frame: 3 and 5 years post-transplantation ]
    Cardiac hemodynamic findings: right and left ventricular end diastolic pressures, right atrial pressure, pulmonary artery pressure and cardiac index

  2. Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin [ Time Frame: 3 years post-transplantation ]
  3. Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin. [ Time Frame: 3 years post-transplantation ]
  4. Frequency of first episode of late acute rejection [ Time Frame: From >1 year to 5 years post-transplantation ]
  5. Time to first episode of late acute rejection [ Time Frame: From >1 year to 5 years post-transplantation ]
    Late acute rejection is defined as occurring >1 year post-transplantation

  6. Frequency to recurrent (two or more) late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
  7. Time to recurrent late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
    Recurrent defined as two or more late acute rejection episodes

  8. Frequency to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
  9. Time to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
  10. Time to graft loss (death or retransplantation) conditional to surviving one year post-transplantation [ Time Frame: One year and up to 5 years post-transplantation ]
  11. N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Natriuretic Peptide (BNP) [ Time Frame: 3 and 5 years post-transplantation ]
  12. Systolic and diastolic graft function [ Time Frame: 3 and 5 years ]
    Graft function as assessed by echocardiography

  13. Proportion of participants with angiographic evidence of coronary artery disease [ Time Frame: 3 and 5 years post-transplantation ]
  14. Time to graft loss (death or retransplantation) after first late rejection [ Time Frame: Up to 5 years post-transplantation ]
  15. Medication Adherence Measure (MAM) after hospital discharge [ Time Frame: Up to 5 years post-transplantation ]
  16. Variability of maintenance tacrolimus levels [ Time Frame: Up to 5 years post-transplantation ]

Other Outcome Measures:
  1. Exploratory: Microvascular pathology [ Time Frame: Up to 5 years post-transplantation ]

    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)

  2. Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, ICAM, VCAM and selectins, Complement inhibitory proteins CD55, CD59, CR1, CR2 and CR3. [ Time Frame: After exposure to alloantibody (or control) (At Year 1) ]
    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).

  3. Exploratory: Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin) [ Time Frame: 24 hours prior transplantation, Months 3 and 6 post transplantation ]

    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)

  4. Exploratory: Role of Interleukin-33 (IL-33) and its Receptor (ST2) in cardioprotection against effects of DSA [ Time Frame: Month 5 post transplantation ]

    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


Biospecimen Retention:   Samples With DNA
Whole blood, plasma, PBMC and tissue


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Criteria

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.

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): NCT02752789


Locations
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30060
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
St. Louis Children's Hospital
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Children's Hospital at Montefiore
New York, New York, United States, 10467
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
United States, Tennessee
Monroe Carell Jr. Children's Hospital
Nashville, Tennessee, United States, 37232
Canada
Hospital for Sick Children
Toronto, Canada, M5G 1X8
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Trials in Organ Transplantation in Children
Investigators
Study Chair: Steven A. Webber, MBChB, MRCP Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation
Principal Investigator: Steven A. Webber, MBChB, MRCP Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02752789     History of Changes
Other Study ID Numbers: DAIT CTOTC-09
First Posted: April 27, 2016    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
alloantibodies
donor specific antibodies (DSA)-preformed, de novo
self-antigens
chronic allograft function

Additional relevant MeSH terms:
Isoantibodies
Immunologic Factors
Physiological Effects of Drugs