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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Heart Diseases, Heart Transplantation

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Cyclosporine
* Drug: Mycophenolate mofetil
* Drug: Methylprednisolone
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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: 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). Leukopenia (white cell count < 2500/cu mm). Anemia (hemoglobin < 80 g/L). Positive test for hepatitis B surface antigen and/or hepatitis C. Historical positive test for human immunodeficiency virus (HIV). Serum creatinine > 230 umol/l. Continual elevation of AST and/or ALT to >= 3X the upper limit of normal. 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus - Adult<br>Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant | Drug: Tacrolimus<br>* Oral<br>* Other names: FK506;Drug: Mycophenolate mofetil<br>* Intravenous and Oral<br>* Other names: CellCept;Drug: Methylprednisolone<br>* Intravenous<br>Drug: Prednisone<br>* Oral<br>|
| Active Comparator: Cyclosporine - Adult<br>Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant | Drug: Cyclosporine<br>* Oral<br>Drug: Mycophenolate mofetil<br>* Intravenous and Oral<br>* Other names: CellCept;Drug: Methylprednisolone<br>* Intravenous<br>Drug: Prednisone<br>* Oral<br>|
| Experimental: Tacrolimus - Pediatric<br>Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant | Drug: Tacrolimus<br>* Oral<br>* Other names: FK506;Drug: Mycophenolate mofetil<br>* Intravenous and Oral<br>* Other names: CellCept;Drug: Methylprednisolone<br>* Intravenous<br>Drug: Prednisone<br>* Oral<br>|
| Active Comparator: Cyclosporine - Pediatric<br>Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant | Drug: Cyclosporine<br>* Oral<br>Drug: Mycophenolate mofetil<br>* Intravenous and Oral<br>* Other names: CellCept;Drug: Methylprednisolone<br>* Intravenous<br>Drug: Prednisone<br>* Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 Weeks and 52 Weeks | 
| 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. | 2 Weeks and 52 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1 | Change is defined as Week 52 assessment - Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1 | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: s-ICAM | Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: E-selectin | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP | Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: F2 Isoprostanes | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars | Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Nitrotyrosine | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG | Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: BNP | Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Troponin T | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6 | Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-18 | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C | Change is defined as Week 52 assessment - Pre-Transplant assessment. | Pre-Transplant and 52 Weeks | 
| Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria | 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. | 52 Weeks | 
| Time to First Acute Rejection Episode Following de Novo Cardiac Transplant | 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. | 52 Weeks | 
| Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection | Severe Acute Rejection is defined as rejection with ISHLT Grade 4. | 52 Weeks | 
| Number of Cardiac Rejection Episodes Requiring Treatment | The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise. | 52 Weeks | 
| Mean Cases of Acute Rejection (MCAR) Per Patient | 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. | 52 Weeks | 
| Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 | A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26. | 26 Weeks and 52 Weeks | 
| Number of Patients With Treatment Failure and Crossover for Treatment Failure | 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. | 52 Weeks | 
| Changes in Circulating Markers of Inflammation and Oxidation: F2 Isoprostanes (Pediatric Population) | Change is defined as Week 52 assessment - Pre-Transplant assessment | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population) | Change is defined as Week 52 assessment - Pre-Transplant assessment | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population) | Change is defined as Week 52 assessment - Pre-Transplant assessment | Pre-Transplant and 52 Weeks | 
| Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population) | Change is defined as Week 52 assessment - Pre-Transplant assessment | Pre-Transplant and 52 Weeks | 
| Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population) | 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. | 52 Weeks | 
| Time to First Acute Rejection Episode Following de Novo Cardiac Transplant (Pediatric Population) | 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. | 52 Weeks | 
| Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection (Pediatric Population) | Severe Acute Rejection was defined as rejection with ISHLT Grade 4. | 52 Weeks | 
| Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population) | A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise. | 52 Weeks | 
| Mean Cases of Acute Rejection (MCAR) Per Patient (Pediatric Population) | 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. | 52 Weeks | 
| Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 (Pediatric Population) | A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26. | 26 Weeks and 52 Weeks | 
| Number of Patients With Treatment Failure and Crossover for Treatment Failure (Pediatric Population) | 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. | 52 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antirejection, Treatment Outcome, Immunosuppression, Treatment Effectiveness, Anti-rejection therapy