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

Phase 3

Completed

Conditions: Heart Diseases
Heart Transplantation

Interventions: Drug: Tacrolimus
Drug: Cyclosporine
Drug: Mycophenolate mofetil
Drug: Methylprednisolone
Drug: Prednisone

Registration Number: NCT00157014

Lead Sponsor: Astellas Pharma Inc

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus - Pediatric	Methylprednisolone	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Tacrolimus - Adult	Tacrolimus	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Tacrolimus - Adult	Mycophenolate mofetil	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Tacrolimus - Adult	Methylprednisolone	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Tacrolimus - Adult	Prednisone	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Cyclosporine - Adult	Cyclosporine	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Cyclosporine - Adult	Mycophenolate mofetil	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Cyclosporine - Adult	Prednisone	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Tacrolimus - Pediatric	Mycophenolate mofetil	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Tacrolimus - Pediatric	Tacrolimus	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Cyclosporine - Pediatric	Cyclosporine	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Cyclosporine - Pediatric	Mycophenolate mofetil	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Tacrolimus - Pediatric	Prednisone	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Cyclosporine - Pediatric	Prednisone	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Cyclosporine - Pediatric	Methylprednisolone	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Cyclosporine - Adult	Methylprednisolone	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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: 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: 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: MCP-1	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1
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
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: 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: 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: 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: 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.
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: hsCRP (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.
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: 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: IL-6	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin
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.
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.
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.
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.
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.
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 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.
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: IL-18	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment.
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: Nitrotyrosine (Pediatric Population)	Pre-Transplant and 52 Weeks	Change is defined as Week 52 assessment - Pre-Transplant assessment
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 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 (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.
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 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.