A Study to Assess the Pharmacokinetics of a Modified-release Tacrolimus Based Immunosuppression Regimen in Stable Kidney Transplant Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00282568
First received: January 25, 2006
Last updated: July 25, 2013
Last verified: July 2013
  Purpose

A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.


Condition Intervention Phase
Kidney Transplantation
Drug: Tacrolimus Modified Release (MR)
Drug: tacrolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Phase 2, Open-Label, Multi-center Study to Assess the Pharmacokinetics, Safety and Tolerability of Tacrolimus in Stable Kidney Transplant Patients Converted From a Prograf® Based Immunosuppression Regimen to a Modified Release (MR) Tacrolimus Based Immunosuppression Regimen

Resource links provided by NLM:


Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus [ Time Frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. ] [ Designated as safety issue: No ]
    The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the trapezoidal rule.

  • Maximum Observed Concentration (Cmax) of Tacrolimus [ Time Frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. ] [ Designated as safety issue: No ]
    The maximum concentration was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.

  • Minimum Concentration of Tacrolimus (Cmin) [ Time Frame: Days 1 and 7 (tacrolimus) and Days 14 and 21 (tacrolimus MR), 24 hours post-dose. ] [ Designated as safety issue: No ]
    The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 24-hour time point post- dose, prior to receiving the next dose.

  • Time to Maximum Observed Concentration of Tacrolimus (Tmax) [ Time Frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. ] [ Designated as safety issue: No ]
    The time to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.

  • Patient Survival [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Patient Survival defined as any participant who did not die by the time of analysis.

  • Graft Survival [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ 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 defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participants death.


Secondary Outcome Measures:
  • Percentage of Participants With Biopsy-confirmed Acute Rejection [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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.

  • Change From Baseline in Serum Creatinine [ Time Frame: Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months). ] [ Designated as safety issue: No ]
    Renal function was assessed using serum creatinine levels over the course of the study.

  • Change From Baseline in Creatinine Clearance [ Time Frame: Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months). ] [ Designated as safety issue: No ]
    Renal function was assessed using creatinine clearance levels calculated using the Cockcroft-Gault formula, over the course of the study.

  • Time to Event for Patient Non Survival [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    For participants who died on study, the median number of days from enrollment to death due to any cause.

  • Time to Event for Graft Non Survival [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    For participants with graft loss, the median number of days from enrollment to graft loss. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participant death.

  • Time to First Biopsy-confirmed Acute Rejection [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    For participants with a biopsy-confirmed acute rejection, the median number of days from enrollment to the date of biopsy confirmation. Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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.

  • Grade of Biopsy-confirmed Acute Rejection Episodes [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]

    Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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.

    For participants with more than one biopsy-confirmed acute rejection episode, the worst case grade is reported.


  • Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Steroid-resistant rejection episodes were treated with anti-lymphocyte antibodies. If a participant had a histologically proven Banff Grade II or III rejection, they could be initiated on anti-lymphocyte antibody treatment per institutional practice. Biopsies were graded by the pathologist at the clinical site 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.

  • Number of Participants With Multiple Rejection Episodes [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ 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: From enrollment until the end of study (up to 60 months). ] [ 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 Chronic Rejection [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed.

  • Number of Participants With Treatment Failure [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed.

  • Primary Reason for Graft Loss [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis) or death. GBM = glomerular basement membrane.

  • Number of Participants Returning to Permanent Dialysis [ Time Frame: From enrollment until the end of study (up to 60 months). ] [ Designated as safety issue: No ]
    Permanent dialysis defined as dialysis for longer than 30 days.

  • Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs [ Time Frame: From the first dose of tacrolimus MR formulation through the day of last dose plus 10 days (approximately 60 months). ] [ Designated as safety issue: No ]

    An adverse event was defined as any reaction, side effect or other untoward medical occurrence, regardless of the relationship to study drug which occurred during the conduct of a clinical study. Clinically significant adverse changes in clinical status, routine laboratory studies or physical examinations were considered adverse events.

    A serious adverse event was any adverse event occurring at any dose that resulted in any of the following outcomes:

    • Death
    • Life-threatening adverse event
    • Inpatient hospitalization or prolongation of existing hospitalization
    • Persistent or significant disability or incapacity
    • Congenital abnormality or birth defect
    • Important medical event.


Enrollment: 70
Study Start Date: August 2002
Study Completion Date: October 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus Modified Release
Participants were enrolled into the study on their stable twice-daily (bid) dose of tacrolimus on Day 1 and continued to receive a stable bid dose of tacrolimus through Day 7. Participants then converted to Tacrolimus Modified Release (MR), administered once daily at an equivalent dose to the patient's previous stable total daily dose of tacrolimus. Participants who completed the 4-week pharmacokinetic treatment period with tacrolimus MR could continue receiving tacrolimus MR as part of the extended treatment period of the study. Dose adjustments were allowed in order to maintain tacrolimus trough concentrations within the target range of 5 to 15 ng/mL and for clinical reasons.
Drug: Tacrolimus Modified Release (MR)
Oral
Other Names:
  • Advagraf
  • Astagraf XL
  • FK506E
  • FKMR
  • MR4
Drug: tacrolimus
Oral
Other Names:
  • Prograf®
  • FK506

Detailed Description:

This is a Phase II open-label, multi-center conversion study in stable, adult kidney transplant recipients to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient is currently receiving Prograf ® based immunosuppressive therapy for kidney transplantation.
  • Patient has stable whole blood trough level concentrations of Prograf® and is clinically stable

Exclusion Criteria:

  • Patient has previously received an organ transplant other than a kidney
  • Patient is currently receiving sirolimus immunosuppression therapy.
  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: NCT00282568

Locations
United States, California
San Diego, California, United States
United States, Florida
Miami, Florida, United States, 33136
United States, Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Ohio
Cincinnati, Ohio, United States, 45267
United States, Oregon
Portland, Oregon, United States, 97239
United States, Wisconsin
Madison, Wisconsin, United States, 53792
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
Edmonton, Alberta, Canada, T6G 2B7
Canada, Ontario
Toronto, Ontario, Canada, M5C 2T2
Sponsors and Collaborators
Astellas Pharma Inc
Investigators
Study Director: Central Contact Astellas Pharma US, Inc.
  More Information

Publications:
Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT00282568     History of Changes
Other Study ID Numbers: 02-0-131
Study First Received: January 25, 2006
Results First Received: July 25, 2013
Last Updated: July 25, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Astellas Pharma Inc:
Pharmacokinetics
Therapy
Immunosuppression
Drugs, Investigational
Adult

Additional relevant MeSH terms:
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014