Clinical trial NCT02752789: Impact of Allo- and Autoantibodies on Chronic Cardiac Allograft Function
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)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pediatric Heart Transplantation
Pediatric Heart Transplant Recipients
Keywords: alloantibodies
donor specific antibodies (DSA)-preformed, de novo
self-antigens
chronic allograft function
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation in Children
First posted: 2016-04-27
Enrollment: 407
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

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.

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.

Eligibility 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.

Primary outcomes:
measure: Pulmonary capillary wedge pressure at heart catheterization
timeFrame: 3 years post-transplantation
Secondary outcomes:
measure: Other invasive cardiac hemodynamic findings at cardiac catheterization
timeFrame: 3 and 5 years post-transplantation
measure: Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin
timeFrame: 3 years post-transplantation
measure: Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin.
timeFrame: 3 years post-transplantation
measure: Frequency of first episode of late acute rejection
timeFrame: From >1 year to 5 years post-transplantation
measure: Time to first episode of late acute rejection
timeFrame: From >1 year to 5 years post-transplantation
measure: Frequency to recurrent (two or more) late acute rejections
timeFrame: Up to 5 years post-transplantation
measure: Time to recurrent late acute rejections
timeFrame: Up to 5 years post-transplantation
measure: Frequency to first episode of late acute rejection with hemodynamic compromise
timeFrame: Up to 5 years post-transplantation
measure: Time to first episode of late acute rejection with hemodynamic compromise
timeFrame: Up to 5 years post-transplantation
measure: Time to graft loss (death or retransplantation) conditional to surviving one year post-transplantation
timeFrame: One year and up to 5 years post-transplantation
measure: N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Natriuretic Peptide (BNP)
timeFrame: 3 and 5 years post-transplantation
measure: Systolic and diastolic graft function
timeFrame: 3 and 5 years
measure: Proportion of participants with angiographic evidence of coronary artery disease
timeFrame: 3 and 5 years post-transplantation
measure: Time to graft loss (death or retransplantation) after first late rejection
timeFrame: Up to 5 years post-transplantation
measure: Medication Adherence Measure (MAM) after hospital discharge
timeFrame: Up to 5 years post-transplantation
measure: Variability of maintenance tacrolimus levels
timeFrame: Up to 5 years post-transplantation
Other outcomes:
measure: Exploratory: Microvascular pathology
timeFrame: Up to 5 years post-transplantation
measure: Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, ICAM, VCAM and selectins, Complement inhibitory proteins CD55, CD59, CR1, CR2 and CR3.
timeFrame: After exposure to alloantibody (or control) (At Year 1)
measure: Exploratory: Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin)
timeFrame: 24 hours prior transplantation, Months 3 and 6 post transplantation
measure: Exploratory: Role of Interleukin-33 (IL-33) and its Receptor (ST2) in cardioprotection against effects of DSA
timeFrame: Month 5 post transplantation
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital
state: Tennessee
city: Toronto
country: Canada
facility: Hospital for Sick Children
Study officials:
affiliation: Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation
name: Steven A. Webber, MBChB, MRCP
role: STUDY_CHAIR
affiliation: Monroe Carell Jr. Children's Hospital at Vanderbilt: Pediatric Transplantation
name: Steven A. Webber, MBChB, MRCP
role: PRINCIPAL_INVESTIGATOR
References: