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

1. August 2013 aktualisiert von: Astellas Pharma Inc

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

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.

Studienübersicht

Status

Abgeschlossen

Bedingungen

Intervention / Behandlung

Detaillierte Beschreibung

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.

Studientyp

Interventionell

Einschreibung (Tatsächlich)

70

Phase

  • Phase 2

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienorte

  • Vereinigte Staaten
    • California
      • Palo Alto, California, Vereinigte Staaten
    • Colorado
      • Denver, Colorado, Vereinigte Staaten, 80262
    • Maryland
      • Baltimore, Maryland, Vereinigte Staaten, 21287
    • Michigan
      • Ann Arbor, Michigan, Vereinigte Staaten, 48109
    • Minnesota
      • Minneapolis, Minnesota, Vereinigte Staaten, 55455
      • Rochester, Minnesota, Vereinigte Staaten, 55905
    • New York
      • New York, New York, Vereinigte Staaten, 10029
    • Ohio
      • Cincinnati, Ohio, Vereinigte Staaten, 45267
    • Texas
      • Dallas, Texas, Vereinigte Staaten, 75246
    • Wisconsin
      • Madison, Wisconsin, Vereinigte Staaten, 53792

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

18 Jahre bis 65 Jahre (Erwachsene, Älterer Erwachsener)

Akzeptiert gesunde Freiwillige

Nein

Studienberechtigte Geschlechter

Alle

Beschreibung

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.

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Verhütung
  • Zuteilung: Nicht randomisiert
  • Interventionsmodell: Einzelgruppenzuweisung
  • Maskierung: Keine (Offenes Etikett)

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
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.
Arzneimittel: Tacrolimus
Oral
Andere Namen:
  • FK506
  • Prograf,
Arzneimittel: Tacrolimus modifizierte Freisetzung (MR)
Oral
Andere Namen:
  • Astagraf XL
  • Advagraf,
  • FK506E,
  • MR4,
  • FKMR,

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus
Zeitfenster: 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.
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.
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.
Minimum Observed Concentration of Tacrolimus (Cmin)
Zeitfenster: Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for 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.
Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for tacrolimus MR).
Patient Survival
Zeitfenster: From enrollment until the end of study (up to 60 months).
Patient survival was defined as any participant known to be alive at the time of analysis.
From enrollment until the end of study (up to 60 months).
Graft Survival
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).

Sekundäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Anzahl der Teilnehmer mit mehreren Ablehnungsepisoden
Zeitfenster: Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Diese Analyse umfasst Abstoßungsepisoden, die entweder durch eine Biopsie des Pathologen am klinischen Standort bestätigt oder klinisch behandelt wurden.
Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Anzahl der Teilnehmer mit klinisch behandelten akuten Abstoßungsepisoden
Zeitfenster: Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Eine klinisch behandelte akute Abstoßungsepisode war jede durch eine Biopsie bestätigte oder vermutete Abstoßungsepisode, die mit einer immunsuppressiven Therapie behandelt wurde.
Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Anzahl der Teilnehmer mit chronischer Ablehnung
Zeitfenster: Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Aufgrund der geringen Anzahl von Teilnehmern mit durch Biopsie bestätigten akuten Abstoßungsepisoden wurde die chronische Abstoßung nicht analysiert.
Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Anzahl der Teilnehmer mit Behandlungsversagen
Zeitfenster: Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Als Behandlungsversagen galt das Absetzen des Studienmedikaments aus beliebigem Grund. Aufgrund des Abbruchs der Studie durch den Sponsor wurde das Therapieversagen nicht analysiert.
Von der Einschreibung bis zum Ende des Studiums (bis zu 60 Monate).
Maximum Observed Concentration of Tacrolimus (Cmax)
Zeitfenster: 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.
The maximum concentration was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state, without interpolation.
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.
Time to Maximum Observed Concentration of Tacrolimus (Tmax)
Zeitfenster: 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.
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.
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.
Percentage of Participants With Biopsy-confirmed Acute Rejection
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).
Time to Event for Patient Non-survival
Zeitfenster: From enrollment until the end of study (up to 60 months).
For participants who died on study, the median number of days from first dose of study drug to death due to any cause.
From enrollment until the end of study (up to 60 months).
Time to Event for Graft Non-survival
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).
Time to First Biopsy-confirmed Acute Rejection
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).
Grade of Biopsy-confirmed Acute Rejection Episodes
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).
Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection
Zeitfenster: From enrollment until the end of study (up to 60 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.
From enrollment until the end of study (up to 60 months).
Primary Reason for Graft Loss
Zeitfenster: From enrollment until the end of study (up to 60 months).
The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant) or participant death.
From enrollment until the end of study (up to 60 months).
Change From Baseline in Alanine Aminotransferase (ALT)
Zeitfenster: 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).
Hepatic function was assessed by measuring alanine aminotransferase levels over the course of the study.
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).
Change From Baseline in Aspartate Aminotransferase (AST)
Zeitfenster: 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).
Hepatic function was assessed by measuring aspartate aminotransferase levels over the course of the study.
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).
Change From Baseline in Total Bilirubin
Zeitfenster: 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).
Hepatic function was assessed by measuring total bilirubin over the course of the study.
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).
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs
Zeitfenster: From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months).

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.
From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months).

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

Astellas Pharma Inc

Ermittler

  • Studienleiter: Central Contact, Astellas Pharma US, Inc.

Publikationen und hilfreiche Links

Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.

Allgemeine Veröffentlichungen

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn

1. Februar 2003

Primärer Abschluss (Tatsächlich)

1. Oktober 2008

Studienabschluss (Tatsächlich)

1. Oktober 2008

Studienanmeldedaten

Zuerst eingereicht

24. Januar 2006

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

24. Januar 2006

Zuerst gepostet (Schätzen)

26. Januar 2006

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Schätzen)

30. September 2013

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

1. August 2013

Zuletzt verifiziert

1. August 2013

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Schlüsselwörter

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

  • 02-0-152

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