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

This study has been completed.
Sponsor:
Collaborator:
Astellas Pharma Canada, Inc.
Information provided by:
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00157014
First received: September 8, 2005
Last updated: January 24, 2011
Last verified: January 2011
  Purpose

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


Condition Intervention Phase
Heart Transplantation
Heart Diseases
Drug: Tacrolimus
Drug: Cyclosporine
Drug: Mycophenolate mofetil
Drug: Methylprednisolone
Drug: Prednisone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies [ Time Frame: 2 Weeks and 52 Weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: 2 Weeks and 52 Weeks ] [ Designated as safety issue: No ]

    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:
  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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: E-selectin [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment.

  • Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Severe Acute Rejection is defined as rejection with ISHLT Grade 4.

  • Number of Cardiac Rejection Episodes Requiring Treatment [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 26 Weeks and 52 Weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment

  • Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population) [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment

  • Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population) [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    Change is defined as Week 52 assessment - Pre-Transplant assessment

  • Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population) [ Time Frame: Pre-Transplant and 52 Weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Severe Acute Rejection was defined as rejection with ISHLT Grade 4.

  • Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: 26 Weeks and 52 Weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

    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.



Enrollment: 111
Study Start Date: July 2004
Study Completion Date: July 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Prograf, FK506
Drug: Mycophenolate mofetil
Intravenous and Oral
Other Name: 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 Name: 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 Name: Prograf, FK506
Drug: Mycophenolate mofetil
Intravenous and Oral
Other Name: 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 Name: CellCept
Drug: Methylprednisolone
Intravenous
Drug: Prednisone
Oral

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00157014

Locations
United States, California
Los Angeles, California, United States, 90095
Canada, Alberta
Calgary, Alberta, Canada, T2N 2T9
Edmonton, Alberta, Canada, T6G 2B7
Edmonton, Alberta, Canada, T6G 2E1
Canada, British Columbia
Vancouver, British Columbia, Canada, V6Z 1Y6
Canada, Nova Scotia
Halifax, Nova Scotia, Canada, B3H 3A7
Canada, Ontario
London, Ontario, Canada, N6A 5A5
Ottawa, Ontario, Canada, K1Y 4W7
Toronto, Ontario, Canada, M5G 2N2
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Montreal, Quebec, Canada, H1T 1C8
Montreal, Quebec, Canada, H3A 1A1
Sainte-Foy, Quebec, Canada, G1V 4G5
Sponsors and Collaborators
Astellas Pharma Inc
Astellas Pharma Canada, Inc.
Investigators
Study Director: Medical Monitor Astellas Pharma Canada, Inc.
  More Information

Additional Information:
No publications provided

Responsible Party: Sr Manager Clinical Trial Registry, Astellas Pharma US, Inc.
ClinicalTrials.gov Identifier: NCT00157014     History of Changes
Other Study ID Numbers: FKC-009
Study First Received: September 8, 2005
Results First Received: October 28, 2010
Last Updated: January 24, 2011
Health Authority: Canada: Health Canada

Keywords provided by Astellas Pharma Inc:
Treatment Outcome
Treatment Effectiveness
Anti-rejection therapy
Immunosuppression
Antirejection

Additional relevant MeSH terms:
Heart Diseases
Cardiovascular Diseases
Cyclosporine
Cyclosporins
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Mycophenolate mofetil
Mycophenolic Acid
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Tacrolimus
Anti-Infective Agents
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Antirheumatic Agents
Autonomic Agents
Central Nervous System Agents
Dermatologic Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on October 23, 2014