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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00282256
First Posted: January 26, 2006
Last Update Posted: October 17, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Astellas Pharma Inc
  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
Intervention Model: Single Group Assignment
Masking: None (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. ]
    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). ]
    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). ]
    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). ]
    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. ]
    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. ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]
    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). ]

    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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   up to 12 Years   (Child)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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
First Submitted: January 24, 2006
First Posted: January 26, 2006
Results First Submitted: August 12, 2013
Results First Posted: October 17, 2013
Last Update Posted: October 17, 2013
Last Verified: August 2013

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
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action