Impact of Allo- and Autoantibodies on Chronic Cardiac Allograft Function

• ClinicalTrials.gov Identifier: NCT02752789
• Recruitment Status: Completed
• First Posted: April 27, 2016
• Last Update Posted: November 29, 2019
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Clinical Trials in Organ Transplantation in Children
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: April 22, 2016
• First Posted Date: April 27, 2016
• Last Update Posted Date: November 29, 2019
• Actual Study Start Date: July 15, 2014
• Actual Primary Completion Date: November 1, 2019 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 22, 2016): Pulmonary capillary wedge pressure at heart catheterization [ Time Frame: 3 years post-transplantation ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 30, 2016)

• 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
• Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin [ Time Frame: 3 years post-transplantation ]
• Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin. [ Time Frame: 3 years post-transplantation ]
• Frequency of first episode of late acute rejection [ Time Frame: From >1 year to 5 years post-transplantation ]
• 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
• Frequency to recurrent (two or more) late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
• Time to recurrent late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
  Recurrent defined as two or more late acute rejection episodes
• Frequency to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
• Time to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
• 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 ]
• N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Natriuretic Peptide (BNP) [ Time Frame: 3 and 5 years post-transplantation ]
• Systolic and diastolic graft function [ Time Frame: 3 and 5 years ]
  Graft function as assessed by echocardiography
• Proportion of participants with angiographic evidence of coronary artery disease [ Time Frame: 3 and 5 years post-transplantation ]
• Time to graft loss (death or retransplantation) after first late rejection [ Time Frame: Up to 5 years post-transplantation ]
• Medication Adherence Measure (MAM) after hospital discharge [ Time Frame: Up to 5 years post-transplantation ]
• Variability of maintenance tacrolimus levels [ Time Frame: Up to 5 years post-transplantation ]

Original Secondary Outcome Measures (submitted: April 22, 2016)

• 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
• Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin [ Time Frame: 3 years post-transplantation ]
• Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin. [ Time Frame: 3 years post-transplantation ]
• Frequency of first episode of late acute rejection [ Time Frame: From >1 year to 5 years post-transplantation ]
• 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
• Frequency to recurrent (two or more) late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
• Time to recurrent late acute rejections [ Time Frame: Up to 5 years post-transplantation ]
  Recurrent defined as two or more late acute rejection episodes
• Frequency to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
• Time to first episode of late acute rejection with hemodynamic compromise [ Time Frame: Up to 5 years post-transplantation ]
• 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 ]
• N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Nautriuretic Peptide (BNP) [ Time Frame: 3 and 5 years post-transplantation ]
• Systolic and diastolic graft function [ Time Frame: 3 and 5 years ]
  Graft function as assessed by echocardiography
• Proportion of participants with angiographic evidence of coronary artery disease [ Time Frame: 3 and 5 years post-transplantation ]
• Time to graft loss (death or retransplantation) after first late rejection [ Time Frame: Up to 5 years post-transplantation ]
• Medication Adherence Measure (MAM) after hospital discharge [ Time Frame: Up to 5 years post-transplantation ]
• Variability of maintenance tacrolimus levels [ Time Frame: Up to 5 years post-transplantation ]

Current Other Pre-specified Outcome Measures (submitted: November 30, 2016)

• 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)
• 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).
• 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)
• 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

Original Other Pre-specified Outcome Measures (submitted: April 22, 2016)

• Exploratory: Microvascular pathology [ Time Frame: Up to 5 years post-transplantation ]
  Microvascular pathology as defined by:

  • cytoprotective intracellular signaling (bcl2, HO-1)
  • interstitial capillary network
  • endothelial cell progenitor influx and premature senescence
  • obliterative microvasculopathy (arteriolopathy)
• Exploratory: Expression of cytoprotective genes Bcl2 and HO-1 adhesion molecules 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: 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 IL17 and 1L10 producing T cells
  • Plasma cytokines by Luminex (IL-6, IL-1beta, IL-17, Cxcl12, IL-10 and Transforming Growth Factor-beta (TGF-beta)
• Exploratory: Role of 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 ST2L expression in graft biopsies
  • Soluble ST2 in serum

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Whole blood, plasma, PBMC and tissue

• 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

Condition

• Pediatric Heart Transplantation
• Pediatric Heart Transplant Recipients

• Intervention: Not Provided

Study Groups/Cohorts

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 26, 2018): 407
• Original Estimated Enrollment (submitted: April 22, 2016): 320
• Actual Study Completion Date: November 1, 2019
• Actual Primary Completion Date: November 1, 2019 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 20 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT02752789
• Other Study ID Numbers: DAIT CTOTC-09
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: 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

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: November 2019