Cardiac Allograft Vasculopathy, Chronic Kidney Diseases, Heart Transplant Failure and Rejection, Heart Transplant Infection, Immunosuppression, Pediatric Heart Transplantation, Post-transplant Lymphoproliferative Disorder
Conditions
Keywords
heart transplantation, children, everolimus, tacrolimus, mycophenolate mofetil, randomized clinical trial
Brief summary
The TEAMMATE Trial will enroll 210 pediatric heart transplant patients from 25 centers at 6 months post-transplant and follow each patient for 2.5 years. Half of the participants will receive everolimus and low-dose tacrolimus and the other half will receive tacrolimus and mycophenolate mofetil. The trial will determine which treatment is better at reducing the cumulative risk of coronary artery vasculopathy, chronic kidney disease and biopsy proven-acute cellular rejection without an increase in graft loss due to all causes (e.g. infection, PTLD, antibody mediated rejection).
Detailed description
Median survival after pediatric heart transplantation (HT) is 15 years in the current era. This means that a substantial fraction of patients transplanted during childhood fail to survive to adulthood, or require heart re-transplantation, because of complications related to heart transplant. These complications include heart transplant rejection, infection, coronary artery disease, post-transplant lymphoproliferative disorder (PTLD; a form of lymphoma seen in transplant recipients), and kidney failure. Most complications stem not from the heart transplant itself, but from the drugs commonly used to suppress the immune system in order to prevent rejection. In the US, tacrolimus (TAC) and mycophenolate mofetil (MMF), have emerged over the past decade as the standard of care for pediatric heart transplant immunosuppression. While pediatric survival has improved significantly in the era of TAC and MMF, post-HT complications remain a major problem that limits median survival to 15 years. Recently, everolimus (EVL) has emerged as a potential alternative immunosuppressant that may prevent rejection, coronary artery disease and kidney failure more effectively than TAC/MMF when administered in combination with low-dose tacrolimus (LDTAC). Preliminary studies suggest that EVL, and its first-generation analog sirolimus, are well tolerated in children after HT, regardless of whether it is started in response to coronary artery disease, in response to chronic kidney disease, or empirically 4-6 months after transplant in an effort to prevent the development of these complications1. However, studies are generally limited to single-center experiences using historical controls and have inadequate statistical power to demonstrate treatment differences. This will be the first multicenter randomized clinical trial of maintenance immunosuppression in pediatric heart transplantation to systematically evaluate the safety and efficacy of EVL with LDTAC vs. TAC/MMF to prevent long-term complications which lead to death/graft loss. The major adverse transplant event (MATE) score will serve as the primary endpoint to power the trial. Because no Food & Drug Administration (FDA)-approved immunosuppressants currently exist for children after heart transplant (all prescriptions are off-label) and market incentives to support a trial are limited, the investigators have funded the trial through a Fiscal Year 2016 Peer Reviewed Medical Research Program Clinical Trial Award sponsored by the Department of Defense office of the Congressionally Directed Medical Research Programs. It is worth noting that in contrast to adults, children have a substantially longer potential life expectancy if post-transplant complications can be minimized, making the prevention of late complications an urgent priority for the pediatric heart transplant community.
Interventions
DRUGEverolimus
Everolimus tablet
DRUGTacrolimus
Tacrolimus capsule or liquid suspension
DRUGMycophenolate Mofetil
Mycophenolate Mofetil capsule or liquid suspension
Sponsors
Boston Children's Hospital
Stanford University
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The Coronary Angiography Core Laboratory readers will be blinded to treatment assignment and time point (study visit). The Adjudication Committee members will be blinded to treatment assignment.
Intervention model description
Multicenter open-label randomized clinical trial with randomization within 4 strata, defined by donor-specific antibody status and center annual transplant volume. There are 2 parallel groups of equal sizes for randomization: everolimus/low-dose tacrolimus and tacrolimus/mycophenolate mofetil.
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Orthotopic heart transplantation 2. Age \< 21 years at time of transplant 3. Stable immunosuppression at the time of randomization with no contraindication to everolimus, tacrolimus, or mycophenolate mofetil 4. Planned follow-up at a study site for the 30 month duration of the study. 5. Subject or legal adult representative capable of providing informed consent (in general, assent will be sought for children aged 12 years or older).
Exclusion criteria
1. Multi-organ transplant (e.g. heart-lung or heart-liver). 2. Known hypersensitivity to everolimus, sirolimus, tacrolimus or mycophenolate mofetil (MMF), or to components of the drug products. 3. Patients on maintenance corticosteroid therapy exceeding a dose equivalent of prednisone 0.1 mg/kg/day at randomization. 4. High-risk for rejection defined as active rejection, recurrent (≥ 2 episodes of grade 2R rejection) cellular rejection, recurrent rejection (≥ 2 episodes of any grade) with hemodynamic compromise, steroid-resistant rejection or unresolved antibody-mediated rejection during the first 6 months post-heart transplant 5. Graft dysfunction (LVEF \<40% or wedge pressure \>22 mmHg or cardiac index \<2.2 L/min/m2) 6. Stage 4 or 5 CKD (eGFR \<30 ml/min/1.73 m2) 7. Moderate or severe proteinuria 8. Active infection requiring hospitalization or treatment dose medical therapy. 9. Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the Site Principal Investigator. 10. Fasting Serum Cholesterol ≥300 mg/dL OR greater than or equal to 7.75 mmol/L, AND fasting triglycerides ≥2.5x the upper limit of normal (ULN). Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication, and reduction of serum cholesterol and triglyceride levels to below exclusion ranges is confirmed. 11. Uncontrolled diabetes mellitus. 12. Diagnosis of post-transplant lymphoproliferative disorder (PTLD) during the first 6 months post-heart transplant. 13. History of non-adherence to medical regimens. 14. Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and cannot discontinue the treatment 15. Patients who are pregnant or breast-feeding or intend to get pregnant during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| EFFICACY: MATE-3 Score | 30 months post-randomization | MATE-3 is a validated score ranging from 0 to 12. The score adds together each subscore so that it represents the cumulative burden of three major adverse transplant events: Cardiac Allograft Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR). Complete details of the score can be found in the study protocol. A higher score represents a worse outcome. |
| SAFETY: MATE-6 Score | 30 months post-randomization | MATE-6 is a validated score ranging from 0 to 24. The score adds together each subscore so that it represents the cumulative burden of all six major adverse transplant events: Coronary Artery Vasculopathy (CAV), Chronic Kidney Disease (CKD), Biopsy-proven Acute Cellular Rejection (ACR), pathologic diagnosis of Antibody-Mediated Rejection (AMR), Infection, and Post-Transplant Lymphoproliferative Disorder (PTLD). Complete details of the score can be found in the study protocol. A higher score represents a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Overall Patient Survival | Up to 30 months post-randomization | Number of participants who experienced death from any cause |
| Efficacy: Overall Allograft Survival | Up to 30 months post-randomization | Number of participants who experienced death or heart re-transplantation |
| Efficacy: Change in Kidney Function | 0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization | Change in estimated glomerular filtration rate (eGFR) using the modified Schwartz equation. A positive number indicates improved kidney function, a negative number indicates worsened kidney function. |
| Efficacy: Freedom From CKD Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a chronic kidney disease MATE. A chronic kidney disease MATE was defined as an eGFR \< 60 ml/min/1.73 m\^2 during follow-up or worsening by at least one MATE score if \< 60 ml/min/1.73 m\^2 at baseline. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: Freedom From CAV Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) cardiac allograft vasculopathy (CAV) during follow up as graded by the angiography core laboratory. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: Freedom From BP-ACR Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) biopsy-proven Acute Cellular Rejection (ACR) MATE event during follow-up. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: Freedom From Composite Failure | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) the composite of death, graft loss, 2R/3R acute cellular rejection or rejection with hemodynamic compromise. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: EuroQOL EQ-5D Y (Youth Version) | 30 months post-randomization | The EuroQOL EQ-5D Y uses a visual-analog scale and asks the participant to mark an X on the line to show how good or bad your is health TODAY. The scale ranges from 0 to 100. |
| Safety: Freedom From AMR | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a pathologic diagnosis of Antibody-Mediated Rejection (AMR) MATE Event. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Infection | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a serious infection MATE during follow-up. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From PTLD | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a Post-Transplant Lymphoproliferative Disorder (PTLD) MATE event during follow-up. A higher number of participants on this measure indicates a better outcome. |
| Safety: Number of Participants Experiencing Adverse Events | From enrollment to 30 months after enrollment | Adverse events reported throughout the study. Adverse events are classified by CTCAE classification. Serious adverse events include CTCAE classes 3, 4, and 5. |
| Safety: Freedom From Major Transplant Events (Composite) | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) any MATE event, this includes chronic kidney disease, cardiac allograft vasculopathy, acute cellular rejection, antibody mediated rejection, serious infection, and post-transplant lymphoproliferative disease. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity CKD Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a chronic kidney disease MATE of Grade 2 or greater (eGFR \<45 ml/min/1.73 m\^2 or on dialysis) or death due to chronic kidney disease. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity CAV Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a cardiac allograft vasculopathy MATE of Grade 2 or greater. Grade 2 or greater is the same as having International Society of Heart and Lung Transplantation cardiac allograft vasculopathy Grade 2 or 3 or death due to cardiac allograft vasculopathy. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity ACR Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) an acute cellular rejection MATE of Grade 2 or greater. Grade 2 or greater is the equivalent of treated rejection with an assigned International Society of Heart \& Lung Transplantation acute cellular rejection grade 2 or grade 3 or rejection with hemodynamic compromise (decreased ejection fraction, need for IV medicine to support heart, need for mechanical circulatory support) or death due to acute cellular rejection. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity AMR Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) an antibody mediated rejection MATE of Grade 2 or greater. Grade 2 or greater is the equivalent of treated rejection with an assigned International Society of Heart \& Lung Transplantation antibody mediated rejection grade 2 or grade 3 or antibody mediated rejection with hemodynamic compromise (decreased ejection fraction, need for IV medicine to support heart, need for mechanical circulatory support) or death due to antibody mediated rejection. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity Infection Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a serious infection MATE of Grade 2 or greater. Grade 2 infections require treatment with intravenous antibiotics or antivirals for 5 or more days. Grade 3 includes treatment of sepsis, endocarditis, invasive infection, or infection leading to respiratory failure. Grade 4 is death due to infection. A higher number of participants on this measure indicates a better outcome. |
| Safety: Freedom From Grade 2 or Greater Severity PTLD Event | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) a post-transplant lymphoproliferative disease MATE of Grade 2 or greater. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: Freedom From Composite of CAV, CKD, BP-ACR, or Any CMV Infection | From enrollment to 30 months after enrollment | Number of participants who are "free from" (have NOT experienced) at least one of cardiac allograft vasculopathy, chronic kidney disease with estimated glomerular filtration rate less than or equal to 60 ml/min/1.73m2, treated acute cellular rejection, or any cytomegalovirus infection. A higher number of participants on this measure indicates a better outcome. |
| Efficacy: Change in CKD Stage | Baseline visit through 30 months post-randomization | Change in chronic kidney disease stage where improvements in CKD stage can take on a negative value. |
| Efficacy: MATE-3 Score Where CKD Score is Calculated by Change From Baseline Visit | Baseline visit through 30 months post-randomization | MATE-3 is a validated score ranging from 0 to 12. The score adds together each subscore so that it represents the cumulative burden of three major adverse transplant events: Cardiac Allograft Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR). For this version of the score, the chronic kidney disease score is replaced by the change in MATE-CKD score from baseline visit through 30 months post-randomization. CKD change score can assume a negative value. This modified score can range from -2 to 12. A higher score represents a worse outcome. |
| Efficacy: MATE-3 Score Where CKD Score is Replaced by Change in CKD Stage | Baseline visit through 30 months post-randomization | MATE-3 is a validated score ranging from 0 to 12. The score adds together each subscore so that it represents the cumulative burden of three major adverse transplant events: Cardiac Allograft Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR). For this version of the score, the chronic kidney disease score is replaced by the change in chronic kidney disease stage from the baseline visit through 30 months post-randomization. Chronic kidney disease stage change score can assume a negative value. This modified score can range from -2 to 12. A higher score represents a worse outcome. |
| Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, MATE CKD Score, and Any CMV Infection. | Baseline visit through 30 months post-randomization | Composite score ranging from 0 to 16. The score adds each subscore to represent the cumulative burden of three major adverse transplant events plus CMV infection. The three major adverse transplant events are Cardiac Allograft Vasculopathy (CAV), Chronic Kidney Disease (CKD), and Biopsy-proven Acute Cellular Rejection (ACR). Any CMV infection is assigned a score of 1 with additional points using the MATE infection scoring criteria. Full details of the score can be found in the protocol. A higher score represents a worse outcome. |
| Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, Change in CKD Stage, and Any CMV Infection. | Baseline visit through 30 months post-randomization | Composite score ranging from -2 to 16. The score adds each subscore to represent the cumulative burden of Cardiac Allograft Vasculopathy (CAV), chronic kidney disease, and Biopsy-proven Acute Cellular Rejection (ACR). Any CMV infection is assigned a score of 1 with additional points using the MATE infection scoring criteria. The chronic kidney disease MATE score is replaced by change in CKD stage. A higher score represents a worse outcome. |
| Efficacy: Lansky Scores | Baseline | Validated functional performance score, assigned by clinician assessment: Lansky score is assigned if \< 16 years old at randomization. Each score is on a 10-100 point scale and is assigned in 10-point increments (i.e. 10, 20, 30, etc.). A higher score represents a better outcome. |
| Efficacy: Karnofsky Scores | Baseline | Validated functional performance score, assigned by clinician assessment: Karnofsky score is assigned if \>=16 years at randomization. Each score is on a 10-100 point scale and is assigned in 10-point increments (i.e. 10, 20, 30, etc.). A higher score represents a better outcome. |
Countries
United States
Contacts
STUDY_CHAIRChristopher S Almond, MD, MPH
Stanford University
STUDY_CHAIRKevin P Daly, MD
Boston Children's Hospital
PRINCIPAL_INVESTIGATORLynn A Sleeper, ScD
Boston Children's Hospital
Participant flow
Recruitment details
Heart transplant recipients who were alive 6 months after their heart transplant procedure were recruited at 25 pediatric heart transplant hospitals in the United States from January 2018 to August 2020.
Pre-assignment details
Participants were assessed for eligibility according to inclusion and exclusion criteria and asked to provide informed consent. All eligible participants were randomized.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 12 to < 18 years of age | 70 Participants |
| Age, Customized 1 to < 6 years of age | 57 Participants |
| Age, Customized < 1 year of age | 35 Participants |
| Age, Customized 6 to < 12 years of age | 41 Participants |
| Age, Customized Greater than or equal to 18 years of age | 8 Participants |
| Chronic kidney disease stage Stage 1/2 | 106 Participants |
| Chronic kidney disease stage Stage 3A | 1 Participants |
| Chronic kidney disease stage Stage 3B | 0 Participants |
| Chronic kidney disease stage Stage 4/5 | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 84 Participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 107 | 3 / 104 |
| other Total, other adverse events | 101 / 107 | 100 / 104 |
| serious Total, serious adverse events | 76 / 107 | 60 / 104 |
Outcome results
None listed