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

1 augusti 2013 uppdaterad av: 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.

Studieöversikt

Status

Avslutad

Betingelser

Intervention / Behandling

Detaljerad beskrivning

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.

Studietyp

Interventionell

Inskrivning (Faktisk)

70

Fas

  • Fas 2

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

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

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år till 65 år (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

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.

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Förebyggande
  • Tilldelning: Icke-randomiserad
  • Interventionsmodell: Enskild gruppuppgift
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Experimentell: 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.
Läkemedel: takrolimus
Oral
Andra namn:
  • FK506
  • Prograf,
Läkemedel: takrolimus modifierad frisättning (MR)
Oral
Andra namn:
  • Astagraf XL
  • Advagraf,
  • FK506E,
  • MR4,
  • FKMR,

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus
Tidsram: 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)
Tidsram: 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
Tidsram: 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
Tidsram: 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).

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Antal deltagare med flera avslagsavsnitt
Tidsram: Från inskrivning till studieslut (upp till 60 månader).
Denna analys inkluderar avstötningsepisoder som antingen bekräftades genom biopsi av patologen på den kliniska platsen eller som behandlades kliniskt.
Från inskrivning till studieslut (upp till 60 månader).
Antal deltagare med kliniskt behandlade akuta avstötningsepisoder
Tidsram: Från inskrivning till studieslut (upp till 60 månader).
En kliniskt behandlad akut avstötningsepisod var varje biopsibekräftad eller misstänkt avstötningsepisod som behandlades med immunsuppressiv terapi.
Från inskrivning till studieslut (upp till 60 månader).
Antal deltagare med kroniskt avslag
Tidsram: Från inskrivning till studieslut (upp till 60 månader).
På grund av det låga antalet deltagare med biopsibekräftade akuta avstötningsepisoder analyserades inte kronisk avstötning.
Från inskrivning till studieslut (upp till 60 månader).
Antal deltagare med misslyckad behandling
Tidsram: Från inskrivning till studieslut (upp till 60 månader).
Behandlingsmisslyckande definierades som avbrytande av studieläkemedlet av någon anledning. På grund av att sponsorn avbröt studien analyserades inte behandlingsfel.
Från inskrivning till studieslut (upp till 60 månader).
Maximum Observed Concentration of Tacrolimus (Cmax)
Tidsram: 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)
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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)
Tidsram: 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)
Tidsram: 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
Tidsram: 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
Tidsram: 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).

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Astellas Pharma Inc

Utredare

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

Publikationer och användbara länkar

Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.

Allmänna publikationer

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 februari 2003

Primärt slutförande (Faktisk)

1 oktober 2008

Avslutad studie (Faktisk)

1 oktober 2008

Studieregistreringsdatum

Först inskickad

24 januari 2006

Först inskickad som uppfyllde QC-kriterierna

24 januari 2006

Första postat (Uppskatta)

26 januari 2006

Uppdateringar av studier

Senaste uppdatering publicerad (Uppskatta)

30 september 2013

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

1 augusti 2013

Senast verifierad

1 augusti 2013

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • 02-0-152

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