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).
Brief Title
Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score
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.
Completion Date
Completion Date Type
Actual
Conditions
PEDIATRIC HEART TRANSPLANTATION
IMMUNOSUPPRESSION
CHRONIC KIDNEY DISEASES
CARDIAC ALLOGRAFT VASCULOPATHY
HEART TRANSPLANT FAILURE AND REJECTION
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
HEART TRANSPLANT INFECTION
Eligibility Criteria
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.
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.
Inclusion Criteria
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).
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).
Gender
All
Gender Based
false
Keywords
heart transplantation
children
everolimus
tacrolimus
mycophenolate mofetil
randomized clinical trial
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
21 Years
NCT Id
NCT03386539
Org Class
Other
Org Full Name
Boston Children's Hospital
Org Study Id
P00025970
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Phase III Multicenter Open-label Randomized Clinical Trial Comparing Everolimus and Low Dose Tacrolimus to Tacrolimus and Mycophenolate Mofetil at 6 mo Post-Transplant to Prevent Long-term Complications After Pediatric Heart Transplantation
Primary Outcomes
Outcome Description
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.
Outcome Measure
EFFICACY: MATE-3 Score
Outcome Time Frame
30 months post-randomization
Outcome Description
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.
Outcome Measure
SAFETY: MATE-6 Score
Outcome Time Frame
30 months post-randomization
Secondary Ids
Secondary Id
PR160574
Secondary Id
IND 127980
Secondary Outcomes
Outcome Description
Number of participants who experienced death from any cause
Outcome Time Frame
Up to 30 months post-randomization
Outcome Measure
Efficacy: Overall Patient Survival
Outcome Description
Number of participants who experienced death or heart re-transplantation
Outcome Time Frame
Up to 30 months post-randomization
Outcome Measure
Efficacy: Overall Allograft Survival
Outcome Description
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.
Outcome Time Frame
0 to 6 months, 0 to 12 months, 0 to 30 months post-randomization
Outcome Measure
Efficacy: Change in Kidney Function
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Efficacy: Freedom From CKD Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Efficacy: Freedom From CAV Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Efficacy: Freedom From BP-ACR Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Efficacy: Freedom From Composite Failure
Outcome Description
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.
Outcome Time Frame
30 months post-randomization
Outcome Measure
Efficacy: EuroQOL EQ-5D Y (Youth Version)
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From AMR
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Infection
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From PTLD
Outcome Description
Adverse events reported throughout the study. Adverse events are classified by CTCAE classification. Serious adverse events include CTCAE classes 3, 4, and 5.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Number of Participants Experiencing Adverse Events
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Major Transplant Events (Composite)
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity CKD Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity CAV Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity ACR Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity AMR Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity Infection Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Safety: Freedom From Grade 2 or Greater Severity PTLD Event
Outcome Description
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.
Outcome Time Frame
From enrollment to 30 months after enrollment
Outcome Measure
Efficacy: Freedom From Composite of CAV, CKD, BP-ACR, or Any CMV Infection
Outcome Description
Change in chronic kidney disease stage where improvements in CKD stage can take on a negative value.
Outcome Time Frame
Baseline visit through 30 months post-randomization
Outcome Measure
Efficacy: Change in CKD Stage
Outcome Description
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.
Outcome Time Frame
Baseline visit through 30 months post-randomization
Outcome Measure
Efficacy: MATE-3 Score Where CKD Score is Calculated by Change From Baseline Visit
Outcome Description
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.
Outcome Time Frame
Baseline visit through 30 months post-randomization
Outcome Measure
Efficacy: MATE-3 Score Where CKD Score is Replaced by Change in CKD Stage
Outcome Description
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.
Outcome Time Frame
Baseline visit through 30 months post-randomization
Outcome Measure
Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, MATE CKD Score, and Any CMV Infection.
Outcome Description
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.
Outcome Time Frame
Baseline visit through 30 months post-randomization
Outcome Measure
Efficacy: Composite Score Consisting of MATE CAV, MATE BP-ACR, Change in CKD Stage, and Any CMV Infection.
Outcome Description
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.
Outcome Time Frame
Baseline
Outcome Measure
Efficacy: Lansky Scores
Outcome Description
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.
Outcome Time Frame
18 months post-randomization
Outcome Measure
Efficacy: Lansky Scores
Outcome Description
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.
Outcome Time Frame
30 months post-randomization
Outcome Measure
Efficacy: Lansky Scores
Outcome Description
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.
Outcome Time Frame
Baseline
Outcome Measure
Efficacy: Karnofsky Scores
Outcome Description
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.
Outcome Time Frame
18 months post-randomization
Outcome Measure
Efficacy: Karnofsky Scores
Outcome Description
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.
Outcome Time Frame
30 months post-randomization
Outcome Measure
Efficacy: Karnofsky Scores
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
21
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Daphne Hsu
Investigator Email
dhsu@montefiore.org
Investigator Phone
718-741-2538
Categories Mesh Debug
Kidney & Urinary Tract --- RENAL INSUFFICIENCY, CHRONIC
Kidney & Urinary Tract --- KIDNEY DISEASES
Kidney & Urinary Tract --- UROLOGIC DISEASES
MeSH Terms
RENAL INSUFFICIENCY, CHRONIC
REJECTION, PSYCHOLOGY
RENAL INSUFFICIENCY
KIDNEY DISEASES
UROLOGIC DISEASES
FEMALE UROGENITAL DISEASES
FEMALE UROGENITAL DISEASES AND PREGNANCY COMPLICATIONS
UROGENITAL DISEASES
MALE UROGENITAL DISEASES
CHRONIC DISEASE
DISEASE ATTRIBUTES
PATHOLOGIC PROCESSES
PATHOLOGICAL CONDITIONS, SIGNS AND SYMPTOMS
SOCIAL BEHAVIOR
BEHAVIOR
EVEROLIMUS
TACROLIMUS
MYCOPHENOLIC ACID
SIROLIMUS
MACROLIDES
LACTONES
ORGANIC CHEMICALS
CAPROATES
ACIDS, ACYCLIC
CARBOXYLIC ACIDS
FATTY ACIDS
LIPIDS