Canadian Cardiology de Novo Study: A Comparison Between Tacrolimus- and Cyclosporine- Based Immunoprophylactic Regimens

Clinical and Laboratory Evaluation of Acute Rejection, Myocyte Growth, Repair, and Oxidative Stress Following de Novo Cardiac Transplant: A Comparison Between Tacrolimus- and Cyclosporine- Based Immunoprophylactic Regimens With MPA TDM

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00157014

Enrollment

111

Registered

2005-09-12

Start date

2004-05-10

Completion date

2008-07-18

Last updated

2017-06-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Diseases, Heart Transplantation

Keywords

Antirejection, Treatment Outcome, Immunosuppression, Treatment Effectiveness, Anti-rejection therapy

Brief summary

The purpose of this study is to assess the safety and efficacy of tacrolimus in de novo heart transplantation.

Detailed description

Subcellular markers will be assessed in relationship to cellular acute rejection in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine as their primary immunosuppressant Two parallel active arms.

Interventions

DRUGTacrolimus

Oral

DRUGCyclosporine

Oral

DRUGMycophenolate mofetil

Intravenous and Oral

DRUGMethylprednisolone

Intravenous

DRUGPrednisone

Oral

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

* Patients (or their legal guardians) who are capable of understanding, and who have been fully informed of the purpose of the study and the risks of participation. * Patients (or their legal guardians) who have signed and dated the Informed Consent form and are willing and able to follow the study protocol. * Patients who are primary cadaveric heart transplant recipients. * Males or females from birth. * Female patients of child-bearing potential who have a current negative pregnancy test and agree to practice effective birth control, as judged by the investigator, while participating in the study. Prepubescent pediatric patients will not require pregnancy testing. * Patients able to tolerate oral medication and who do not have a gastrointestinal condition likely to affect the absorption kinetics or metabolism of the oral study medications.

Exclusion criteria

* Previous organ transplant recipients. * Multi-organ transplant recipients. * Recipients of a heart from a donor with incompatible ABO blood type. * Patients with significant graft dysfunction and/or significant de novo infection(s) at time of randomization * Patients with known hypersensitivity to tacrolimus, cyclosporine, mycophenolate mofetil (MMF), daclizumab, prednisone, cremophor, polysorbate 80 and/or polyoxyl 60 hydrogenated castor oil (HCO-60). * Patients who are pregnant or lactating or planning to become pregnant prior to completion of the study. * Patients who have consumed an investigational product in the 30 days prior to transplantation or at any time during post-transplantation follow-up. * Patients receiving cholestyramine or colestipol. * Patients having any one of the following at enrolment: 1. History of malignancy, not chart-documented as cured or active malignancy (with exception of eradicable non-metastatic in-situ basal cell or squamous cell carcinoma). 2. Leukopenia (white cell count \< 2500/cu mm). 3. Anemia (hemoglobin \< 80 g/L). 4. Positive test for hepatitis B surface antigen and/or hepatitis C. 5. Historical positive test for human immunodeficiency virus (HIV). 6. Serum creatinine \> 230 umol/l. 7. Continual elevation of AST and/or ALT to \>= 3X the upper limit of normal. 8. Body mass index (weight in kg/height in m2) \> 30. * Undiagnosed diabetes mellitus as determined by 2 hour (2h) oral glucose tolerance test (OGTT) or fasting glucose test or uncontrolled diabetes mellitus at screening. In either case, the patient may be declared as no longer excluded by this criterion upon establishment of control of the diabetes through appropriate medical management. * Blood glucose \>= 11.1 mmol/L at pre-operative assessment. * Patients having a significant disease, substance dependency, or disability that may prevent adherence to, or understanding of, the protocol and/or the investigator's instructions.

Design outcomes

Primary

Measure	Time frame	Description
The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	2 Weeks and 52 Weeks	The markers assessed were p-ERK ½ (phosphorylated extracellular signal-regulated kinase), p-JNK (phosphorylated jun N-terminal kinase) and p-p38 MAPK (phosphorylated mitogen-activated protein kinase). The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment.
The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	2 Weeks and 52 Weeks	The markers assessed were p-ERK ½, p-JNK and p-p38 MAPK. The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment.

Secondary

Measure	Time frame	Description
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: E-selectin	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: F2 Isoprostanes	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Nitrotyrosine	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: BNP	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Troponin T	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-18	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria	52 Weeks	Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Patients may report more than one acute rejection.
Time to First Acute Rejection Episode Following de Novo Cardiac Transplant	52 Weeks	Acute Rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Time to first acute rejection is defined as: date of onset - date of transplant.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1
Number of Cardiac Rejection Episodes Requiring Treatment	52 Weeks	The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise.
Mean Cases of Acute Rejection (MCAR) Per Patient	52 Weeks	MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies. Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.
Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52	26 Weeks and 52 Weeks	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.
Number of Patients With Treatment Failure and Crossover for Treatment Failure	52 Weeks	Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first. Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.
Changes in Circulating Markers of Inflammation and Oxidation: F2 Isoprostanes (Pediatric Population)	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment
Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population)	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment
Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population)	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment
Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population)	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment
Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)	52 Weeks	Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Patients may report more than one rejection episode.
Time to First Acute Rejection Episode Following de Novo Cardiac Transplant (Pediatric Population)	52 Weeks	Acute Rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Time to first acute rejection is defined as: date of onset - date of transplant.
Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection (Pediatric Population)	52 Weeks	Severe Acute Rejection was defined as rejection with ISHLT Grade 4.
Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population)	52 Weeks	A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.
Mean Cases of Acute Rejection (MCAR) Per Patient (Pediatric Population)	52 Weeks	MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies. Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.
Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 (Pediatric Population)	26 Weeks and 52 Weeks	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.
Number of Patients With Treatment Failure and Crossover for Treatment Failure (Pediatric Population)	52 Weeks	Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first. Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.
Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection	52 Weeks	Severe Acute Rejection is defined as rejection with ISHLT Grade 4.
Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: s-ICAM	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule

Countries

Canada, United States

Participant flow

Recruitment details

* 3 patients randomized to cyclosporine actually received tacrolimus and were included in the Treatment Exposure Population for tacrolimus. * 2 patients randomized for tacrolimus were excluded from Treatment Exposure Population - 1 never received drug; 1 received incorrect drug without a waiver.

Participants by arm

Arm	Count
Tacrolimus - Adult Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	52
Cyclosporine - Adult Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	46
Tacrolimus - Pediatric Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	5
Cyclosporine - Pediatric Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	6
Total	109

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Death	4	2	1	1
Overall Study	Medications withdrawn on family request	0	1	0	0
Overall Study	Patient unable to return in nursing home	1	0	0	0
Overall Study	Patient withdrawn by investigator	1	0	0	0
Overall Study	Patient would not receive transplant	0	1	0	0
Overall Study	Physician Decision	0	1	0	0
Overall Study	Withdrawal by Subject	1	0	0	0

Baseline characteristics

Characteristic	Tacrolimus - Adult	Cyclosporine - Adult	Tacrolimus - Pediatric	Cyclosporine - Pediatric	Total
Age, Customized 0 - ˂ 2 Years	0 Participants	0 Participants	1 Participants	1 Participants	2 Participants
Age, Customized 10 - ˂ 18 Years	0 Participants	0 Participants	3 Participants	3 Participants	6 Participants
Age, Customized 18 - 49 Years	14 Participants	18 Participants	0 Participants	0 Participants	32 Participants
Age, Customized 2 - 10 Years	0 Participants	0 Participants	1 Participants	2 Participants	3 Participants
Age, Customized 50 - 59 Years	18 Participants	15 Participants	0 Participants	0 Participants	33 Participants
Age, Customized 60 - 69 Years	18 Participants	12 Participants	0 Participants	0 Participants	30 Participants
Age, Customized 70 Years and Older	2 Participants	1 Participants	0 Participants	0 Participants	3 Participants
Race/Ethnicity, Customized Aboriginal	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Black	2 Participants	4 Participants	0 Participants	1 Participants	7 Participants
Race/Ethnicity, Customized East Indian	2 Participants	0 Participants	0 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized European descent/ White	48 Participants	40 Participants	5 Participants	4 Participants	97 Participants
Race/Ethnicity, Customized Latin American	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Sex/Gender, Customized Female	9 Participants	9 Participants	5 Participants	4 Participants	27 Participants
Sex/Gender, Customized Male	43 Participants	37 Participants	0 Participants	2 Participants	82 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	52 / 52	46 / 46	5 / 5	6 / 6
serious Total, serious adverse events	21 / 52	24 / 46	3 / 5	5 / 6

Outcome results

Primary

The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies

The markers assessed were p-ERK ½ (phosphorylated extracellular signal-regulated kinase), p-JNK (phosphorylated jun N-terminal kinase) and p-p38 MAPK (phosphorylated mitogen-activated protein kinase). The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment.

Time frame: 2 Weeks and 52 Weeks

Population: The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.

Arm	Measure	Group	Value (MEAN)	Dispersion
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Change from Week 2	0.05 Densitometry / Densitometry of GAPDH	Standard Deviation 0.834
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Change from Week 2	0.03 Densitometry / Densitometry of GAPDH	Standard Deviation 1.188
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Week 52	0.87 Densitometry / Densitometry of GAPDH	Standard Deviation 0.539
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Week 2	0.48 Densitometry / Densitometry of GAPDH	Standard Deviation 0.45
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Week 2	0.70 Densitometry / Densitometry of GAPDH	Standard Deviation 0.5
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Week 52	0.63 Densitometry / Densitometry of GAPDH	Standard Deviation 0.664
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Week 52	1.33 Densitometry / Densitometry of GAPDH	Standard Deviation 0.89
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Change from Week 2	0.14 Densitometry / Densitometry of GAPDH	Standard Deviation 0.733
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Week 2	1.10 Densitometry / Densitometry of GAPDH	Standard Deviation 0.813
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Change from Week 2	0.23 Densitometry / Densitometry of GAPDH	Standard Deviation 0.828
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Week 2	0.90 Densitometry / Densitometry of GAPDH	Standard Deviation 0.641
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Week 52	0.79 Densitometry / Densitometry of GAPDH	Standard Deviation 0.674
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-ERK ½ - Change from Week 2	-0.05 Densitometry / Densitometry of GAPDH	Standard Deviation 0.662
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Week 2	1.23 Densitometry / Densitometry of GAPDH	Standard Deviation 0.722
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Week 52	1.46 Densitometry / Densitometry of GAPDH	Standard Deviation 0.792
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-JNK - Change from Week 2	0.22 Densitometry / Densitometry of GAPDH	Standard Deviation 0.957
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Week 2	0.54 Densitometry / Densitometry of GAPDH	Standard Deviation 0.556
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	p-p38 MAPK - Week 52	0.77 Densitometry / Densitometry of GAPDH	Standard Deviation 0.717

Primary

The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)

The markers assessed were p-ERK ½, p-JNK and p-p38 MAPK. The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment.

Time frame: 2 Weeks and 52 Weeks

Arm	Measure	Group	Value (MEAN)	Dispersion
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Week 52	0.93 Densitometry / Densitometry of GAPDH	Standard Deviation 0.184
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Change from Week 2	-0.21 Densitometry / Densitometry of GAPDH	Standard Deviation 0
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Week 2	1.17 Densitometry / Densitometry of GAPDH	Standard Deviation 0.42
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Week 2	0.83 Densitometry / Densitometry of GAPDH	Standard Deviation 0.467
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Change from Week 2	-0.09 Densitometry / Densitometry of GAPDH	Standard Deviation 0
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Week 52	0.24 Densitometry / Densitometry of GAPDH	Standard Deviation 0.014
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Week 52	0.57 Densitometry / Densitometry of GAPDH	Standard Deviation 0.085
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Change from Week 2	-0.04 Densitometry / Densitometry of GAPDH	Standard Deviation 0
Tacrolimus - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Week 2	1.74 Densitometry / Densitometry of GAPDH	Standard Deviation 0.972
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Change from Week 2	0.34 Densitometry / Densitometry of GAPDH	Standard Deviation 0.63
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Week 2	1.67 Densitometry / Densitometry of GAPDH	Standard Deviation 0.682
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Week 52	1.22 Densitometry / Densitometry of GAPDH	Standard Deviation 0.633
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-ERK ½ - Change from Week 2	-0.27 Densitometry / Densitometry of GAPDH	Standard Deviation 0.309
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Week 2	0.91 Densitometry / Densitometry of GAPDH	Standard Deviation 0.43
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Week 52	0.82 Densitometry / Densitometry of GAPDH	Standard Deviation 0.537
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-JNK - Change from Week 2	0.04 Densitometry / Densitometry of GAPDH	Standard Deviation 0.189
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Week 2	0.43 Densitometry / Densitometry of GAPDH	Standard Deviation 0.364
Cyclosporine - Adult	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	p-p38 MAPK - Week 52	0.58 Densitometry / Densitometry of GAPDH	Standard Deviation 0.432

Secondary