A Study of a Modified-Release Tacrolimus Based Immunosuppression Regimen in Stable Pediatric Liver Transplant Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00282256
First received: January 24, 2006
Last updated: August 12, 2013
Last verified: August 2013
  Purpose

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


Condition Intervention Phase
Liver 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, Long-Term Safety and Tolerability of Tacrolimus in Stable Pediatric Liver 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, Day 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, Day 14 at pre-dose, 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 linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 and AUC 12-24 for the morning and afternoon doses.

  • Minimum Observed Concentration of Tacrolimus (Cmin) [ Time Frame: Day 7 at 12 hours post-dose (tacrolimus) and Day 14 at 24 hours post-dose (tacrolimus MR). ] [ Designated as safety issue: No ]
    The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 12 hour post-dose concentration based on the evening dose (i.e., the 8 am concentration) for tacrolimus and the 24-hour time point post-dose for tacrolimus MR, prior to receiving the next dose.

  • Patient Survival [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    Patient survival was defined as any participant known to be alive at the end of the study.

  • Graft Survival [ Time Frame: From enrollment until the end of study (up to 54 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 participant death.


Secondary Outcome Measures:
  • Maximum Observed Concentration of Tacrolimus (Cmax) [ Time Frame: For tacrolimus, Day 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, Day 14 at pre-dose, 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 the tacrolimus and tacrolimus MR at steady state, without interpolation.

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

  • Percentage of Participants With Biopsy-confirmed Acute Rejection [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte. necrosis

  • Time to Event for Patient Non-survival [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    For participants who died on study, the median number of days from first dose of study drug to death due to any cause.

  • Time to Event for Graft Non-survival [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    For participants with graft loss, the median number of days from the first dose of study drug to graft loss. Graft loss was defined as graft failure (re-transplant) or participant death.

  • Time to First Biopsy-confirmed Acute Rejection [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    For participants with a biopsy-confirmed acute rejection (BCAR), the median number of days from the first dose of study drug to the date of biopsy confirmation. BCAR is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I: Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II: Rejection infiltrate, expanding to most or all of the triads; Grade III: Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis.

  • Grade of Biopsy-confirmed Acute Rejection Episodes [ Time Frame: From enrollment until the end of study (up to 54 months). ] [ Designated as safety issue: No ]
    Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. 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 54 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.

  • Number of Participants With Multiple Rejection Episodes [ Time Frame: From enrollment until the end of study (up to 54 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 54 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 54 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 54 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 54 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 participant death.

  • Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests [ Time Frame: From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 54 months). ] [ Designated as safety issue: No ]

    An adverse event (AE) is 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: 19
Study Start Date: January 2004
Study Completion Date: October 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus MR
Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Drug: tacrolimus modified release (MR)
Oral
Other Names:
  • Advagraf,
  • FK506E,
  • MR4,
  • FKMR,
  • Astagraf XL
Drug: tacrolimus
Oral
Other Names:
  • Prograf,
  • FK506

Detailed Description:

A 1 arm study to assess the pharmacokinetics, and long-term safety and effectiveness of a modified release tacrolimus based immunosuppression regimen in stable pediatric liver transplant patients converted from a Prograf® based immunosuppression regimen.

  Eligibility

Ages Eligible for Study:   up to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient is currently receiving Prograf® based immunosuppressive therapy for liver 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 liver
  • 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: NCT00282256

Locations
United States, Georgia
Atlanta, Georgia, United States, 30322
United States, Indiana
Indianapolis, Indiana, United States, 46202
United States, Louisiana
New Orleans, Louisiana, United States, 70433
United States, New York
New York, New York, United States, 10029
United States, Wisconsin
Madison, Wisconsin, United States, 53792
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: NCT00282256     History of Changes
Other Study ID Numbers: 03-0-160
Study First Received: January 24, 2006
Results First Received: August 12, 2013
Last Updated: August 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Astellas Pharma Inc:
Child
Pharmacokinetics
Immunosuppression Drugs
Hepatic transplant
Liver Transplantation

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

ClinicalTrials.gov processed this record on July 24, 2014