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

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

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Heart Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: Cyclosporine; Drug: Mycophenolate mofetil; Drug: Methylprednisolone; Drug: Prednisone

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.

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
    • Edmonton, Alberta, Canada, T6G 2B7
    • Edmonton, Alberta, Canada, T6G 2E1
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
  • Ontario
    • London, Ontario, Canada, N6A 5A5
    • Ottawa, Ontario, Canada, K1Y 4W7
    • Toronto, Ontario, Canada, M5G 1X8
    • Toronto, Ontario, Canada, M5G 2N2
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
    • Montreal, Quebec, Canada, H1T 1C8
    • Sainte-Foy, Quebec, Canada, G1V 4G5
• United States
  • California
    • Los Angeles, California, United States, 90095

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tacrolimus - Adult; Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Drug: Tacrolimus; Oral; Other Names: Prograf; FK506; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
ACTIVE_COMPARATOR: Cyclosporine - Adult; Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Drug: Cyclosporine; Oral; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
EXPERIMENTAL: Tacrolimus - Pediatric; Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Drug: Tacrolimus; Oral; Other Names: Prograf; FK506; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
ACTIVE_COMPARATOR: Cyclosporine - Pediatric; Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Drug: Cyclosporine; Oral; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Astellas Pharma Canada, Inc.
• Investigators: Study Director: Medical Monitor, Astellas Pharma Canada, Inc.

Publications and helpful links

Helpful Links

• Link to Prescribing Information

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 10, 2004
• Primary Completion (ACTUAL): July 18, 2008
• Study Completion (ACTUAL): July 18, 2008

Study Registration Dates

• First Submitted: September 8, 2005
• First Submitted That Met QC Criteria: September 8, 2005
• First Posted (ESTIMATE): September 12, 2005

Study Record Updates

• Last Update Posted (ACTUAL): June 5, 2017
• Last Update Submitted That Met QC Criteria: May 4, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Immunosuppression; Treatment Effectiveness; Treatment Outcome; Anti-rejection therapy; Antirejection
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone; Prednisone; Tacrolimus; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: FKC-009