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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00282243
First received: January 24, 2006
Last updated: August 1, 2013
Last verified: August 2013
  Purpose

A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable liver transplant patients converted from a tacrolimus (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 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: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 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 the tacrolimus and tacrolimus MR treatment periods at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 for the morning (0-12 hour) and afternoon (12-24 hour) doses.

  • Minimum Observed Concentration of Tacrolimus (Cmin) [ Time Frame: Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for 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 60 months). ] [ Designated as safety issue: No ]
    Patient survival was defined as any participant known to be alive at 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 participant death.


Secondary Outcome Measures:
  • Maximum Observed Concentration of Tacrolimus (Cmax) [ Time Frame: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 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 treatment periods at steady state, without interpolation.

  • Time to Maximum Observed Concentration of Tacrolimus (Tmax) [ Time Frame: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose. ] [ Designated as safety issue: No ]
    Time to the first occurrence to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state, without interpolation.

  • 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 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 60 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 60 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 60 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 60 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 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.

  • 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 participant death.

  • Change From Baseline in Alanine Aminotransferase (ALT) [ Time Frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (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 ]
    Hepatic function was assessed by measuring alanine aminotransferase levels over the course of the study.

  • Change From Baseline in Aspartate Aminotransferase (AST) [ Time Frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (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 ]
    Hepatic function was assessed by measuring aspartate aminotransferase levels over the course of the study.

  • Change From Baseline in Total Bilirubin [ Time Frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (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 ]
    Hepatic function was assessed by measuring total bilirubin over the course of the study.

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

    An adverse event 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: 70
Study Start Date: February 2003
Study Completion Date: October 2008
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus MR

After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study.

Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.

Drug: tacrolimus modified release (MR)
Oral
Other Names:
  • Advagraf,
  • FK506E,
  • MR4,
  • FKMR,
  • Astagraf XL
Drug: tacrolimus
Oral
Other Names:
  • Prograf,
  • FK506

Detailed Description:

A one arm study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable liver transplant patients converted from a tacrolimus (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 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: NCT00282243

Locations
United States, California
Palo Alto, California, United States
United States, Colorado
Denver, Colorado, United States, 80262
United States, Maryland
Baltimore, Maryland, United States, 21287
United States, Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Minneapolis, Minnesota, United States, 55455
Rochester, Minnesota, United States, 55905
United States, New York
New York, New York, United States, 10029
United States, Ohio
Cincinnati, Ohio, United States, 45267
United States, Texas
Dallas, Texas, United States, 75246
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: NCT00282243     History of Changes
Other Study ID Numbers: 02-0-152
Study First Received: January 24, 2006
Results First Received: August 1, 2013
Last Updated: August 1, 2013
Health Authority: United States: Food and Drug Administration

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 28, 2014