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Pediatric Heart TransplantationNCT01005316

Alloantibodies in Pediatric Heart Transplantation

An observational study of Pediatric Heart Transplantation and Pediatric Heart Transplant Recipients, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity crossmatch and to compare this group with outcomes in nonsensitized heart transplant recipients. Read more about this study

Who is it for?
Ages Up to 21 years
What is being tested?
Induction Therapy, Tacrolimus and Mycophenolate Mofetil
How many people
290 participants
Where
8 sitesin 2 countries
Study dates
Jan 2010to Dec 2014
Phase
Observational
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Study population: Pediatric heart transplantation candidates

Who may be able to join

  • All participants listed for heart transplantation at participating CTOT-C study sites.

Who cannot join

  • Listed for multiple organ transplant
  • Inability or unwillingness of the participant or parent/guardian to give written informed consent or comply with the study protocol
  • Condition or characteristic which in the opinion of the investigator makes the participant unlikely to complete at least one year of follow-up
  • Current participation in other research studies that would, or might, interfere with the scientific integrity or safety of current study (e.g. by interference with immunosuppression management guidelines, study endpoints, excessive blood draws or SAE evaluation).

Trial locations and contacts

8 sites in 2 countries.

8 sites in 2 countries

United States7 sites
  • Children's Hospital Boston, Harvard Medical School

    Boston, Massachusetts, 02115

  • Vanderbilt University

    Nashville, Tennessee, 37232

  • Children's Hospital of New York, Columbia University Medical Center

    New York, New York, 10032

  • Children's Hospital of Philadelphia, University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15213

  • St. Louis Children's Hospital, Washington University

    St Louis, Missouri, 63110

  • Children's Hospital at Montefiore

    The Bronx, New York, 10467

Other trials in United States

Canada1 site
  • Hospital for Sick Children, Labatt Family Heart Centre

    Toronto, Ontario, M5G 1X8

Other trials in Canada

About this study

The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity crossmatch and to compare this group with outcomes in nonsensitized heart transplant recipients.

Read the detailed description

There is currently a renewed interest in alloantibodies in transplantation. In 1966, Kissmeyer and colleagues reported that pre-existing antibodies directed against donor cells could cause hyperacute rejection of the renal allograft. Three years later, in a landmark study, Patel and Terasaki showed that a lymphocytotoxic assay to identify donor-specific antibodies was highly predictive of acute graft failure. These observations led to the practice of performing prospective, donor-specific crossmatches by lymphocytotoxicity assay for all kidney transplants and for heart and lung transplants when the candidate has a positive panel reactive antibody (PRA) assay. A concept evolved that transplantations should not be performed across a positive cytotoxicity crossmatch. The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity crossmatch and to compare this group with outcomes in nonsensitized heart transplant recipients.

This study plans to enroll 370 pediatric heart transplant recipients over a period of 3 years. The follow-up period will last up to 3 years. All participants will be enrolled pretransplant. In the pretransplant phase, visits will occur every 6 months. These routine visits will continue until transplant or the end of the study. They will coincide with routine pretransplant status visits. At the time of transplant, the participants will be assigned to one of two groups. Group A will include participants who are allo-antibody negative (less than 10% by AHG CDC-PRA and ELISA in all DTT-treated serum samples). Cohort B will include participants who have the presence of a DTT-treated AHG CDC-PRA of greater than or equal to 10% and/or an ELISA-PRA greater than or equal to 10% in any pretransplant sample.

Both cohorts will receive standard transplantation care. This study has no interventions. All participants will undergo regular blood tests, and, those in the sensitized group will have additional blood testing performed after the transplant and lasting until the end of the study. Post-transplant visits will occur while participants are recovering in the hospital; at Months 1, 3, and 6; and annually until the study closes.

The information collected for the study include data from a physical exam, routine testing, adverse (AEs) and serious adverse (SAEs) events assessments, and blood collection. Each time a biopsy is done, the study will ask to review the biopsy tissue and to collect a sample. If stored tissue is not available, none will be collected.

Being tested
Induction Therapy, Tacrolimus, Mycophenolate Mofetil, Intraoperative plasma exchange/pheresis, Short-term post-operative plasmapheresis
Keywords
cohort study, allo-antibodies, allosensitization

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Induction TherapyDrug

    Also called anti-T cell antibody induction

    Per standard of care guidelines for immunosuppression at each clinical site.

  • TacrolimusDrug

    Also called Prograf®

    Per standard of care guidelines for immunosuppression at each clinical site.

  • Mycophenolate MofetilDrug

    Also called CellCept®, MMF

    Per standard of care guidelines for immunosuppression at each clinical site.

  • Intraoperative plasma exchange/pheresisProcedure or surgery

    Also called plasmapheresis

    Per standard of care guidelines for immunosuppression at each clinical site.

  • Short-term post-operative plasmapheresisProcedure or surgery

    Also called pheresis

    Per standard of care guidelines for immunosuppression at each clinical site.

  • Immunoglobulins, IntravenousDrug

    Also called IVIG

    Post-transplant course of intravenous immunoglobulin therapy per standard of care guidelines for immunosuppression at each clinical site.

  • PrednisoneDrug

    Also called corticosteroid

    Maintenance corticosteroids per standard of care guidelines for immunosuppression at each clinical site.

Study groups in NCT01005316
Study groupRoleWhat they receive
Cohort A: Non-SensitizedCohort A will include participants who are alloantibody Luminex(TM) LABScreen. There is no study mandated care or treatment. All care given is clinical site standard of care. All sites follow a similar standard of care regimen. Non-sensitized recipients receive steroid-free maintenance immunosuppression: 1. Induction Therapy (anti-T cell antibody induction) 2. Tacrolimus (Prograf®) 3. Mycophenolate Mofetil- MMF (CellCept®).
Receives: Drug: Induction Therapy; Drug: Tacrolimus; Drug: Mycophenolate Mofetil
Cohort B: SensitizedCohort B will include participants who are alloantibody positive (Sensitized) as determined by Luminex LabScreen for Class I or Class II with specificities identified by single antigen testing. There is no study mandated care or treatment. All care given is clinical site standard of care. All sites follow a similar standard of care regimen. Sensitized recipients receive: 1. Induction Therapy (anti-T cell antibody induction) 2. Intraoperative plasma exchange/pheresis 3. Short-term post-operative plasmapheresis 4. Post-transplant course of intravenous immunoglobulin (IVIG) therapy 5. Maintenance corticosteroids (Prednisone) 6. Tacrolimus (Prograf®) 7. Mycophenolate Mofetil-MMF (CellCept®).
Receives: Drug: Induction Therapy; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Procedure: Intraoperative plasma exchange/pheresis; Procedure: Short-term post-operative plasmapheresis; Drug: Immunoglobulins, Intravenous; Drug: Prednisone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation

    This is a composite outcome of death, graft loss or rejection with hemodynamic compromise.

    Rejection was considered to be with hemodynamic compromise if the rejection event had new onset echocardiographically measured from fractional shortening <26% with ≥5% fall from last echocardiogram or the rejection event had new onset of heart failure.

    Measured: 12 months post-transplantation

Secondary outcomes (16)
  1. Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies

    Time (in days) from transplant to development of de novo donor-specific alloantibodies (DSA). This measure is calculated as time from transplant until the earliest time of development of any de novo DSA. The DSA is a newly developed alloantibody that is against the donor organ. Alloantibodies are important mediators of acute and chronic rejection.

    Measured: Transplantation to first year post transplant (up to 12 months post transplant).

  2. Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation

    A de novo donor-specific alloantibody (DSA) is a newly developed alloantibody that is against the donor organ. This measure includes all de novo DSA (≥1000 MFI) regardless of is persistence or timing within the first year post-transplant. Alloantibodies are important mediators of acute and chronic rejection.

    Measured: Transplantation to first year post transplant (up to 12 months post transplant).

  3. Percentage of Participants- Mortality While on Transplantation Wait-List

    Death that occurred while on the transplantation wait-list, and thus before receiving a heart transplant.

    Measured: Pre-transplantation

  4. Time From Participant Listing on Organ Wait-List to Receiving Organ Transplant, Death or De-Listing

    Time (in days) from listing on the organ wait-list to receiving an organ transplant, death or de-listing. This measure is calculated as time from listing on the organ wait-list until the earliest time among transplantation, death and de-listing.

    Measured: Study enrollment to transplantation

  5. Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing

    Luminex SA testing was used to detect the presence of anti-HLA IgG Antibodies for all samples at a central laboratory.

    Measured: Pre-transplantation

  6. Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing

    Quantification of anti-HLA IgG antibodies is measured in mean fluorescence intensity (MFI). The maximum MFI for the given subject is provided.

    Measured: Pre-transplantation

  7. Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay

    Major histocompatibility complex class I chain-related gene A (MICA) is an antigen that is a potential marker of rejection. Luminex TM assay was used to detect its presence.

    Measured: Pre-Transplantation

  8. Percentage of Participants -Overall Participant and Graft Survival

    This measure looks at the participants who did not die and/or did not receive a subsequent heart transplant.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  9. Presence of C4d on Endomyocardial Biopsy (EMB)

    The biopsy of the heart stained positive for the presence of C4d, a potential marker of rejection.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  10. Percentage of Participants With Occurrence of Re-Hospitalization(s)

    Hospitalization is defined as any hospitalization lasting greater than 24 hours.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  11. Percentage of Participants Positive for Severe Infection(s)

    Severe infections are defined as a clinical illness considered likely infectious in origin that leads to hospitalization.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  12. Time to Diagnosis of Chronic Rejection

    Time (in days) to the diagnosis of chronic rejection. Chronic rejection is defined as stenosis, irregularity, or ectasia of the epicardial vessels, or severe peripheral pruning of the distal coronary artery tree. Time to diagnosis is time from transplantation until the first diagnosis of chronic rejection.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  13. Time to Post-Transplantation Lymphoproliferative Disorder

    Time (in days) post-transplant lymphoproliferative disorder (PTLD). PTLD is defined as histopathological evidence of lymphoid proliferation (nodal or extranodal) fulfilling the criteria of the revised classification of the WHO 2008 (Swerdlow 2008). Time to PTLD is time from transplantation until the diagnosis of PTLD.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  14. Time to New-Onset Diabetes Mellitus

    Time (in days) to new-onset diabetes mellitus. New-onset diabetes mellitus is defined as the new onset of insulin dependency or the need for oral hypoglycemic agents lasting more than 30 days post-transplant. Time to new-onset diabetes is time from transplantation until the diagnosis of new-onset diabetes.

    Measured: Transplantation to the end of study (up to 4 years post transplant).

  15. Percentage of Participants Experiencing Acute Rejection

    Acute rejection is defined as any one of the following types of rejection: acute cellular rejection (International Society for Heart and Lung Transplant (ISHLT)) system for grading rejection grade 2R or greater), acute refractory cellular rejection (acute cellular rejection unresponsive to two sequential courses of corticosteroids), acute antibody mediated rejection (histological evidence of unequivocal acute capillary injury, with complement deposition and margination of macrophages with or without neutrophils), acute mixed rejection (evidence of acute antibody mediated rejection with ISHLT grade 1R or greater), or acute clinical rejection (clinically-based acute rejection, no matter the ISHLT grade, leading to an acute augmentation of immunosuppression).

    Measured: Transplantation to the end of study.

  16. Time to Acute Rejection

    Time (in days) to acute rejection. Acute rejection is defined as any one of the following types of rejection: acute cellular rejection (International Society for Heart and Lung Transplant (ISHLT) system for grading rejection grade 2R or greater), acute refractory cellular rejection (acute cellular rejection unresponsive to two sequential courses of corticosteroids), acute antibody mediated rejection (histological evidence of unequivocal acute capillary injury, with complement deposition and margination of macrophages with or without neutrophils), acute mixed rejection (evidence of acute antibody mediated rejection with ISHLT grade 1R or greater), or acute clinical rejection (clinically-based acute rejection, no matter the ISHLT grade, leading to an acute augmentation of immunosuppression). Time to acute rejection is time from transplantation to first acute rejection date.

    Measured: Transplantation to the end of study.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Oct 2009 (estimated)
  2. Study startJan 2010
  3. Primary completionDec 2014
  4. Study completionDec 2014

Why it stopped: Inability to meet accrual goals within the funding period.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
290 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01005316
Sponsor's protocol ID
DAIT CTOTC-04
Other IDs
7U01AI077867-02
Status last verified
Mar 2017
First submitted
27 Oct 2009
Last updated
20 Apr 2017
Data monitoring committee
Yes

Publications

  • Rose ML, Smith JD. Clinical relevance of complement-fixing antibodies in cardiac transplantation. Hum Immunol. 2009 Aug;70(8):605-9. doi: 10.1016/j.humimm.2009.04.016. Epub 2009 Apr 16.

    PubMed 19375471
  • Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med. 1969 Apr 3;280(14):735-9. doi: 10.1056/NEJM196904032801401. No abstract available.

    PubMed 4886455
  • Lamour JM, Mason KL, Hsu DT, Feingold B, Blume ED, Canter CE, Dipchand AI, Shaddy RE, Mahle WT, Zuckerman WA, Bentlejewski C, Armstrong BD, Morrison Y, Diop H, Ikle DN, Odim J, Zeevi A, Webber SA; CTOTC-04 investigators. Early outcomes for low-risk pediatric heart transplant recipients and steroid avoidance: A multicenter cohort study (Clinical Trials in Organ Transplantation in Children - CTOTC-04). J Heart Lung Transplant. 2019 Sep;38(9):972-981. doi: 10.1016/j.healun.2019.06.006. Epub 2019 Jun 20.

    PubMed 31324444

Questions about this trial

What is this clinical trial studying?

An observational study of Pediatric Heart Transplantation and Pediatric Heart Transplant Recipients, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 20 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation (time frame: 12 months post-transplantation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01005316, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2017.

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