Pediatric Heart Transplantation, Pediatric Heart Transplant Recipients
Conditions
Keywords
cohort study, allo-antibodies, allosensitization
Brief 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.
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.
Interventions
Per standard of care guidelines for immunosuppression at each clinical site.
DRUGTacrolimus
Per standard of care guidelines for immunosuppression at each clinical site.
DRUGMycophenolate Mofetil
Per standard of care guidelines for immunosuppression at each clinical site.
PROCEDUREIntraoperative plasma exchange/pheresis
Per standard of care guidelines for immunosuppression at each clinical site.
PROCEDUREShort-term post-operative plasmapheresis
Per standard of care guidelines for immunosuppression at each clinical site.
Post-transplant course of intravenous immunoglobulin therapy per standard of care guidelines for immunosuppression at each clinical site.
DRUGPrednisone
Maintenance corticosteroids per standard of care guidelines for immunosuppression at each clinical site.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* All participants listed for heart transplantation at participating CTOT-C study sites.
Exclusion criteria
* 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation | Transplantation to first year post transplant (up to 12 months post transplant). | 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. |
| Percentage of Participants- Mortality While on Transplantation Wait-List | Pre-transplantation | Death that occurred while on the transplantation wait-list, and thus before receiving a heart transplant. |
| Time From Participant Listing on Organ Wait-List to Receiving Organ Transplant, Death or De-Listing | Study enrollment to transplantation | 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. |
| Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing | Pre-transplantation | Luminex SA testing was used to detect the presence of anti-HLA IgG Antibodies for all samples at a central laboratory. |
| Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | Pre-transplantation | Quantification of anti-HLA IgG antibodies is measured in mean fluorescence intensity (MFI). The maximum MFI for the given subject is provided. |
| Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay | Pre-Transplantation | 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. |
| Percentage of Participants -Overall Participant and Graft Survival | Transplantation to the end of study (up to 4 years post transplant). | This measure looks at the participants who did not die and/or did not receive a subsequent heart transplant. |
| Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies | Transplantation to first year post transplant (up to 12 months post transplant). | 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. |
| Percentage of Participants With Occurrence of Re-Hospitalization(s) | Transplantation to the end of study (up to 4 years post transplant). | Hospitalization is defined as any hospitalization lasting greater than 24 hours. |
| Percentage of Participants Positive for Severe Infection(s) | Transplantation to the end of study (up to 4 years post transplant). | Severe infections are defined as a clinical illness considered likely infectious in origin that leads to hospitalization. |
| Percentage of Participants Experiencing Acute Rejection | Transplantation to the end of study. | 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 Diagnosis of Chronic Rejection | Transplantation to the end of study (up to 4 years post transplant). | 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. |
| Time to Post-Transplantation Lymphoproliferative Disorder | Transplantation to the end of study (up to 4 years post transplant). | 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. |
| Time to New-Onset Diabetes Mellitus | Transplantation to the end of study (up to 4 years post transplant). | 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. |
| Time to Acute Rejection | Transplantation to the end of study. | 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. |
| Presence of C4d on Endomyocardial Biopsy (EMB) | Transplantation to the end of study (up to 4 years post transplant). | The biopsy of the heart stained positive for the presence of C4d, a potential marker of rejection. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Non-Sensitized Participants were enrolled into the study and received a heart transplant. Immediately prior to transplant, these participants were alloantibody negative as determined by Luminex(TM) LABScreen. All administered care was clinical site standard of care. All sites followed a similar standard of care regimen. Non-sensitized recipients received steroid-free maintenance immunosuppression: induction therapy (anti-T cell antibody induction), tacrolimus (Prograf(R)), and Mycophenolate Mofetil- MMF (CellCept(R)). | 97 |
| Cohort B: Sensitized, Crossmatch Positive Participants were enrolled into the study and received a heart transplant. Immediately prior to transplant, these participants were alloantibody positive as determined by Luminex(TM) LabScreen for Class I or Class II with specificities identified by single antigen testing. Retrospective cytotoxicity donor-specific crossmatch during their transplant procedure indicated crossmatch positivity. All administered care was clinical site standard of care. All sites followed a similar standard of care regimen. Sensitized recipients received: induction therapy (anti-T cell antibody induction), intraoperative plasma exchange/-pheresis, short-term post-operative plasmapheresis, a post-transplant course of intravenous immunoglobulin (IVIG) therapy, maintenance corticosteroids (Prednisone), tacrolimus (Prograf(R)), and Mycophenolate Mofetil- MMF (CellCept(R)). | 16 |
| Cohort B: Sensitized, Crossmatch Negative Participants were enrolled into the study and received a heart transplant. Immediately prior to transplant, these participants were alloantibody positive as determined by Luminex(TM) LabScreen for Class I or Class II with specificities identified by single antigen testing. Retrospective cytotoxicity donor-specific crossmatch during their transplant procedure indicated crossmatch negativity. All administered care was clinical site standard of care. All sites followed a similar standard of care regimen. Sensitized recipients received: induction therapy (anti-T cell antibody induction), intraoperative plasma exchange/-pheresis, short-term post-operative plasmapheresis, post-transplant course of intravenous immunoglobulin (IVIG) therapy, maintenance corticosteroids (Prednisone), tacrolimus (Prograf(R)), and Mycophenolate Mofetil- MMF (CellCept(R)). | 127 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Consented to Another Study | 2 | 0 | 0 | 0 |
| Overall Study | Death | 20 | 5 | 1 | 15 |
| Overall Study | Delisted | 8 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 | 0 | 2 |
| Overall Study | Physician Decision | 6 | 0 | 0 | 0 |
| Overall Study | Retransplanted | 0 | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 6 | 3 | 0 | 0 |
| Overall Study | Study Termination | 5 | 63 | 9 | 85 |
| Overall Study | Transferred Care | 1 | 0 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Cohort A: Non-Sensitized | Cohort B: Sensitized, Crossmatch Positive | Cohort B: Sensitized, Crossmatch Negative | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 93 Participants | 16 Participants | 124 Participants | 233 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 0 Participants | 3 Participants | 7 Participants |
| Age, Continuous | 6.9 years STANDARD_DEVIATION 6.8 | 7.8 years STANDARD_DEVIATION 6.7 | 7.4 years STANDARD_DEVIATION 6.3 | 7.2 years STANDARD_DEVIATION 6.5 |
| Region of Enrollment Canada | 12 participants | 1 participants | 18 participants | 31 participants |
| Region of Enrollment United States | 85 participants | 15 participants | 109 participants | 209 participants |
| Sex: Female, Male Female | 53 Participants | 5 Participants | 54 Participants | 112 Participants |
| Sex: Female, Male Male | 44 Participants | 11 Participants | 73 Participants | 128 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 97 | 1 / 16 | 16 / 127 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 30 / 97 | 7 / 16 | 43 / 127 |
Outcome results
Primary
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.
Time frame: 12 months post-transplantation
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation | 5.2 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation | 12.5 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants Positive for Event of Death, Graft Loss or Rejection With Hemodynamic Compromise at 12 Months Post-Transplantation | 11.8 percentage of participants |
Comparison: The p-value compares Cohort A: Non-Sensitized with Cohort B: Sensitized, Crossmatch Positive.p-value: 0.258Fisher Exact
Secondary
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).
Time frame: Transplantation to the end of study.
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants Experiencing Acute Rejection | 27.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants Experiencing Acute Rejection | 75.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants Experiencing Acute Rejection | 49.6 percentage of participants |
Secondary
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.
Time frame: Pre-transplantation
Population: Participants Enrolled, Not Transplanted
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants- Mortality While on Transplantation Wait-List | 39.2 percentage of participants |
Secondary
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.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants -Overall Participant and Graft Survival | 93.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Overall Participant and Graft Survival | 93.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Overall Participant and Graft Survival | 87.4 percentage of participants |
Secondary
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.
Time frame: Transplantation to first year post transplant (up to 12 months post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation | 22.7 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation | 50.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants Positive for de Novo Donor-Specific Alloantibody Production in the First Year Post-Transplantation | 37.8 percentage of participants |
Secondary
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.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants Positive for Severe Infection(s) | 34.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants Positive for Severe Infection(s) | 43.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants Positive for Severe Infection(s) | 30.7 percentage of participants |
Secondary
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.
Time frame: Pre-transplantation
Population: Transplanted Participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 4000-7999 | 1.0 percentage of participants |
| Cohort A: Non-Sensitized | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 1000-3999 | 20.6 percentage of participants |
| Cohort A: Non-Sensitized | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | Missing | 0 percentage of participants |
| Cohort A: Non-Sensitized | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | None | 77.3 percentage of participants |
| Cohort A: Non-Sensitized | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI ≥8000 | 1.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 1000-3999 | 6.3 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | Missing | 0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | None | 18.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 4000-7999 | 12.5 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI ≥8000 | 62.5 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI ≥8000 | 24.4 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 4000-7999 | 14.2 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | Missing | 2.4 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | MFI 1000-3999 | 29.9 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants -Quantification of Anti-HLA IgG Antibodies by Luminex SA Testing | None | 29.1 percentage of participants |
Secondary
Percentage of Participants With Occurrence of Re-Hospitalization(s)
Hospitalization is defined as any hospitalization lasting greater than 24 hours.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants With Occurrence of Re-Hospitalization(s) | 66.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants With Occurrence of Re-Hospitalization(s) | 75.0 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants With Occurrence of Re-Hospitalization(s) | 62.2 percentage of participants |
Secondary
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.
Time frame: Pre-transplantation
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing | 22.7 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing | 81.3 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants With the Presence of Anti-HLA IgG Antibodies by Luminex SA Testing | 68.5 percentage of participants |
Secondary
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.
Time frame: Pre-Transplantation
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay | 8.2 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay | 18.8 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Percentage of Participants With the Presence of Anti-MICA Antibodies by Luminex TM Assay | 11.0 percentage of participants |
Secondary
Presence of C4d on Endomyocardial Biopsy (EMB)
The biopsy of the heart stained positive for the presence of C4d, a potential marker of rejection.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Non-Sensitized | Presence of C4d on Endomyocardial Biopsy (EMB) | 18.6 percentage of participants |
| Cohort B: Sensitized, Crossmatch Positive | Presence of C4d on Endomyocardial Biopsy (EMB) | 62.5 percentage of participants |
| Cohort B: Sensitized, Crossmatch Negative | Presence of C4d on Endomyocardial Biopsy (EMB) | 34.6 percentage of participants |
Secondary
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.
Time frame: Study enrollment to transplantation
Population: Enrolled participants who died, were transplanted or de-listed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time From Participant Listing on Organ Wait-List to Receiving Organ Transplant, Death or De-Listing | 128.3 Days |
Secondary
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.
Time frame: Transplantation to the end of study.
Population: Transplanted Participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time to Acute Rejection | 151.0 Days |
| Cohort B: Sensitized, Crossmatch Positive | Time to Acute Rejection | 74.5 Days |
| Cohort B: Sensitized, Crossmatch Negative | Time to Acute Rejection | 124.7 Days |
Secondary
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.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time to Diagnosis of Chronic Rejection | 606.8 Days |
| Cohort B: Sensitized, Crossmatch Positive | Time to Diagnosis of Chronic Rejection | NA Days |
| Cohort B: Sensitized, Crossmatch Negative | Time to Diagnosis of Chronic Rejection | 398.9 Days |
Secondary
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.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants. Note to provide relevant outcome measure perspective -Of the overall number of participants analyzed, the number of new onset diabetes mellitus cases diagnosed within groups were: Cohort A: Non-Sensitized (N=1); Cohort B: Sensitized, Crossmatch Positive (N=2); and Cohort B: Sensitized, Crossmatch Negative (N=7).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time to New-Onset Diabetes Mellitus | 73 Days |
| Cohort B: Sensitized, Crossmatch Positive | Time to New-Onset Diabetes Mellitus | 48 Days |
| Cohort B: Sensitized, Crossmatch Negative | Time to New-Onset Diabetes Mellitus | 283.4 Days |
Secondary
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.
Time frame: Transplantation to the end of study (up to 4 years post transplant).
Population: Transplanted Participants. Note to provide relevant outcome measure perspective- Of the overall number of participants analyzed, the number of diagnosed PTLD cases within groups were: Cohort A: Non-Sensitized (N=1); Cohort B: Sensitized, Crossmatch Positive (N=0); and Cohort B: Sensitized, Crossmatch Negative (N=3).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time to Post-Transplantation Lymphoproliferative Disorder | 910 Days |
| Cohort B: Sensitized, Crossmatch Positive | Time to Post-Transplantation Lymphoproliferative Disorder | NA Days |
| Cohort B: Sensitized, Crossmatch Negative | Time to Post-Transplantation Lymphoproliferative Disorder | 118.7 Days |
Secondary
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.
Time frame: Transplantation to first year post transplant (up to 12 months post transplant).
Population: Transplanted Participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A: Non-Sensitized | Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies | 28.1 Days |
| Cohort B: Sensitized, Crossmatch Positive | Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies | 15.4 Days |
| Cohort B: Sensitized, Crossmatch Negative | Time to Production of Post-Transplant de Novo Donor-specific Alloantibodies | 55.1 Days |