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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 opdateret af: 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.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

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.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

70

Fase

  • Fase 2

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

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

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 65 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

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

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Forebyggelse
  • Tildeling: Ikke-randomiseret
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: 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.
Medicin: tacrolimus
Mundtlig
Andre navne:
  • FK506
  • Prograf,
Medicin: tacrolimus modificeret frigivelse (MR)
Mundtlig
Andre navne:
  • Astagraf XL
  • Advagraf,
  • FK506E,
  • MR4,
  • FKMR,

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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).

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Antal deltagere med flere afvisningsepisoder
Tidsramme: Fra indskrivning til studiets afslutning (op til 60 måneder).
Denne analyse omfatter afstødningsepisoder, der enten blev bekræftet ved biopsi af patologen på det kliniske sted eller blev klinisk behandlet.
Fra indskrivning til studiets afslutning (op til 60 måneder).
Antal deltagere med klinisk behandlede akutte afvisningsepisoder
Tidsramme: Fra indskrivning til studiets afslutning (op til 60 måneder).
En klinisk behandlet akut afstødningsepisode var enhver biopsi-bekræftet eller mistænkt afstødningsepisode, der blev behandlet med immunsuppressiv terapi.
Fra indskrivning til studiets afslutning (op til 60 måneder).
Antal deltagere med kronisk afvisning
Tidsramme: Fra indskrivning til studiets afslutning (op til 60 måneder).
På grund af det lave antal deltagere med biopsi-bekræftede akutte afstødningsepisoder, blev kronisk afstødning ikke analyseret.
Fra indskrivning til studiets afslutning (op til 60 måneder).
Antal deltagere med behandlingssvigt
Tidsramme: Fra indskrivning til studiets afslutning (op til 60 måneder).
Behandlingssvigt blev defineret som afbrydelse af undersøgelseslægemidlet uanset årsag. På grund af sponsorens afbrydelse af undersøgelsen blev behandlingssvigt ikke analyseret.
Fra indskrivning til studiets afslutning (op til 60 måneder).
Maximum Observed Concentration of Tacrolimus (Cmax)
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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)
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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).

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Astellas Pharma Inc

Efterforskere

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

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. februar 2003

Primær færdiggørelse (Faktiske)

1. oktober 2008

Studieafslutning (Faktiske)

1. oktober 2008

Datoer for studieregistrering

Først indsendt

24. januar 2006

Først indsendt, der opfyldte QC-kriterier

24. januar 2006

Først opslået (Skøn)

26. januar 2006

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Skøn)

30. september 2013

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

1. august 2013

Sidst verificeret

1. august 2013

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 02-0-152

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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