Comparative Study of Modified Release (MR) Tacrolimus/Mycophenolate Mofetil (MMF) in de Novo Kidney Transplant Recipients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00064701
First received: July 10, 2003
Last updated: November 12, 2013
Last verified: November 2013
  Purpose

The purpose of this study is to compare the safety and efficacy of tacrolimus/mycophenolate mofetil (MMF), cyclosporine/MMF and tacrolimus modified release/MMF in de novo kidney transplant recipients.


Condition Intervention Phase
Kidney Transplantation
Drug: Tacrolimus Modified Release (MR)
Drug: Tacrolimus
Drug: cyclosporine microemulsion
Drug: mycophenolate mofetil
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: A Phase III, Randomized, Open-Label, Comparative, Multi-Center Study to Assess the Safety and Efficacy of Prograf (Tacrolimus)/MMF, Modified Release (MR) Tacrolimus/MMF and Neoral (Cyclosporine)/MMF in de Novo Kidney Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • Percentage of Participants With Efficacy Failure [ Time Frame: one year ] [ Designated as safety issue: No ]

    Efficacy failure is defined as any participant who died, experienced a graft failure (permanent return to dialysis [> 30 days] or retransplant), had a biopsy-confirmed (Banff Grade ≥ I) acute rejection (BCAR), or was lost to follow-up.

    Biopsies were graded according to the 1997 Banff criteria:

    Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.



Secondary Outcome Measures:
  • Patient Survival at One Year [ Time Frame: One year ] [ Designated as safety issue: No ]
    Patient survival is defined as any participant who is known to be alive one year after the skin closure date. Participants who died or whose outcome was unknown at one year were considered to be non-survivors.

  • Graft Survival at One Year [ Time Frame: One year ] [ Designated as safety issue: No ]

    Graft survival defined as any participant who did not meet the criteria for graft loss, where graft loss is defined as any re-transplant, permanent return to dialysis (> 30 days), patient death, or participant whose outcome at one year was unknown.

    Participants were only counted once regardless of how many criteria were met.


  • Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months [ Time Frame: Six months and 12 months ] [ Designated as safety issue: No ]

    Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria:

    Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.

    Acute rejection is defined as a grade ≥ I.


  • Time to First Biopsy-confirmed Acute Rejection Episode [ Time Frame: one year ] [ Designated as safety issue: No ]

    Time to first biopsy-confirmed acute rejection episode defined as the number of days from skin closure (Day 0) to the date of biopsy. Rejection episodes were confirmed by biopsy by the clinical site pathologist and graded according to the 1997 Banff criteria:

    Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.

    Acute rejection is defined as a grade ≥ I.


  • Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection [ Time Frame: one year ] [ Designated as safety issue: No ]

    Rejection episodes were confirmed by biopsy by the clinical site pathologist. Participants with histologically-proven Banff Grade II or III rejection or participants with steroid-resistant rejection were treated with anti-lymphocyte antibody treatment according to institutional practice.

    Biopsies were graded according to the 1997 Banff criteria:

    Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.


  • Severity of Acute Rejection [ Time Frame: one year ] [ Designated as safety issue: No ]

    Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria:

    Borderline: No intimal arteritis present but foci of mild tubulitis; Grade IA: Significant interstitial infiltration and foci of moderate tubulitis; Grade IB: Significant interstitial infiltration and foci of severe tubulitis; Grade IIA: Mild to moderate intimal arteritis in at least 1 arterial cross section Grade IIB: Severe intimal arteritis comprising >25% of the luminal area lost in at least 1 arterial cross section; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.


  • Number of Participants Experiencing Multiple Rejection Episodes [ Time Frame: one year ] [ Designated as safety issue: No ]
    This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.

  • Number of Participants With Clinically Treated Acute Rejection Episodes [ Time Frame: one year ] [ Designated as safety issue: No ]
    A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.

  • Number of Participants With Treatment Failure [ Time Frame: one year ] [ Designated as safety issue: No ]
    Treatment failure was defined as the discontinuation of randomized study drug for any reason. Participants who met the definition of treatment failure were to be followed throughout the 12-month treatment period.

  • Number of Participants Who Crossed Over Due to Treatment Failure [ Time Frame: one year ] [ Designated as safety issue: No ]
    Participants were allowed to cross over to an alternative primary immunosuppressive regimen (either to the tacrolimus or cyclosporine treatment arms) to address an adverse event which led to randomized study drug discontinuation or in the case of severe or refractory rejection. Crossover to the modified release tacrolimus treatment arm was not permitted.

  • Change From Month 1 in Serum Creatinine at Month 6 and Month 12 [ Time Frame: Month 1, Month 6, and Month 12 ] [ Designated as safety issue: No ]
    Renal function was assessed by the change from Month 1 in serum creatinine six months and 12 months after transplant.

  • Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 [ Time Frame: Month 1, Month 6, and Month 12 ] [ Designated as safety issue: No ]
    Renal function was assessed by creatinine clearance, calculated using the Cockcroft-Gault formula.

  • Kaplan-Meier Estimate of Patient Survival at the End of the Study [ Time Frame: End of study (maximum time on study was 1,941 days). ] [ Designated as safety issue: No ]
    Patient survival was defined as any participant who was alive at the end of the study. Patient survival was censored at the time of last follow-up contact.

  • Kaplan-Meier Estimate of Graft Survival at the End of the Study [ Time Frame: End of study (maximum time on study was 1,941 days). ] [ Designated as safety issue: No ]

    Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was any retransplant or the permanent return to dialysis (more than 30 days) or patient death.

    Graft survival was censored at the time of last follow-up contact.



Enrollment: 668
Study Start Date: June 2003
Study Completion Date: March 2009
Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus
Participants received a first dose of tacrolimus between 0.075 and 0.10 mg/kg twice daily, orally prior to or within 48 hours of the completion of the transplant procedure, and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.
Drug: Tacrolimus
The target range for whole blood tacrolimus trough concentrations was the recommended trough concentration range for Prograf: 7 to 16 ng/mL for days 0 through 90 and 5 to 15 ng/mL thereafter.
Other Name: Prograf, FK506
Drug: mycophenolate mofetil
Oral
Other Name: CellCept, MMF
Active Comparator: Tacrolimus Modified Release
Participants received a first dose of tacrolimus modified release between 0.15 and 0.20 mg/kg/day, given as a single oral dose in the morning, prior to or within 48 hours following the completion of the transplant procedure, and subsequently as once daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.
Drug: Tacrolimus Modified Release (MR)
The target range for whole blood tacrolimus trough concentrations was 7 to 16 ng/mL for days 0 through 90, and 5 to 15 ng/mL thereafter.
Other Name: Advagraf, FK506, FKMR, MR4, Astagraf XL
Drug: mycophenolate mofetil
Oral
Other Name: CellCept, MMF
Active Comparator: Cyclosporine
Participants received a first dose of cyclosporine between 4 to 5 mg/kg orally prior to or within 48 hours following the completion of the transplant procedure and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study.
Drug: cyclosporine microemulsion
The target range for whole blood cyclosporine trough concentrations was 125 to 400 ng/mL for days 0 through 90, and 100 to 300 ng/mL thereafter.
Other Name: Neoral, CsA
Drug: mycophenolate mofetil
Oral
Other Name: CellCept, MMF

Detailed Description:

This was a 3 arm randomized, open-label, comparative, multi-center study in de novo kidney transplant recipients at 60 centers in the U.S., Canada and Brazil.

The study consisted of a 1-year post-transplant efficacy and safety study with a clinical continuation phase of a minimum of 2 years or until commercial availability of tacrolimus modified release, unless the Data Safety Monitoring Board or sponsor specified otherwise.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipient of a primary or retransplanted non-human leukocyte antigen (HLA)-identical living or non-HLA-identical cadaveric kidney transplant
  • Age greater or equal to 12 years

Exclusion Criteria:

  • Recipient or donor is known seropositive for human immunodeficiency virus (HIV)
  • Has current malignancy or history of malignancy
  • Has significant liver disease
  • Has uncontrolled concomitant infection or any other unstable medical condition
  • Is receiving everolimus or enteric coated mycophenolic acid at any time during the study
  • Received kidney with a cold ischemia time of equal or more than 36 hours
  • Received kidney transplant from a cadaveric donor equal or more than 60 years of age
  • Received intravenous immunoglobulin (IVIG) therapy prior to randomization
  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: NCT00064701

  Show 57 Study Locations
Sponsors and Collaborators
Astellas Pharma Inc
Investigators
Study Director: Use Central Contact Astellas Pharma Global Development
  More Information

Publications:
Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT00064701     History of Changes
Other Study ID Numbers: 02-0-158
Study First Received: July 10, 2003
Results First Received: July 25, 2013
Last Updated: November 12, 2013
Health Authority: United States: Food and Drug Administration
Brazil: Ministry of Health
Canada: Health Canada

Keywords provided by Astellas Pharma Inc:
De Novo Kidney Transplant
cyclosporine
Prograf®
mycophenolate mofetil
tacrolimus

Additional relevant MeSH terms:
Tacrolimus
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 02, 2014