Study to Ascertain if Prolonged Release Tacrolimus (FK506E - MR4) is Safe and Effective When Used in the Long Term and in Combination With Other Immunosuppressive Drugs in Patients Who Have Received a Transplant

A Long-term Follow up Study to Evaluate the Safety and Efficacy in Transplant Recipients Treated With Modified Release Tacrolimus, FK506E (MR4), Based Immunosuppression Regimen

The purpose of this study was to offer patients who had participated in one of the phase II PK or phase III studies on FK506E (MR4) the possibility to continue FK506E (MR4) until commercial availability of the drug and to record long term efficacy and safety data.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation; Kidney Transplantation; Heart Transplantation
• Intervention / Treatment: Drug: FK506E

Detailed Description

The objective of this study was to asses the safety and efficacy of FK506E (MR4) as a long-term treatment in transplant recipients. Only patients who had participated in one of the phase II PK or phase III studies on FK506E (MR4) and had received at least one dose of study medication were enrolled.

• Study Type: Interventional
• Enrollment (Actual): 850
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Austria
  • Innsbruck, Austria, 6020
    • Landeskrankenhaus Innsbruck
  • Wien, Austria, 1090
    • AKN Wien
• Belgium
  • Bruxelles, Belgium, 1070
    • Hospital Erasme
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires St. Luc
  • Gent, Belgium, 9000
    • Departement Heelkunde
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Gasthuisberg
  • Liege, Belgium, 4000
    • Domaine Universitaire du Sart Tillman
• Brazil
  • Campinas, Brazil, 13083-888
    • Hospital da Clínicas da UNICAMP
  • Porto Alegre, Brazil, 90020-090
    • Hospital São Francisco
  • Porto Alegre, Brazil, 90020-090
    • Irmandade Da Santa Casa de Misericordia de Porto Alegre
  • Rio de Janeiro, Brazil, 21041-030
    • Hospital Geral de Bonsucesso
• Canada
  • Vancouver, Canada, V5Z 1L7
    • Vancouver Hospital & Health Sciences Centre
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital
    • Montreal, Quebec, Canada, H2X 3J4
      • Centre hospitalier de l'Universite de Montreal (CHUM)
    • Montréal, Quebec, Canada, H1T 1C8
      • Institut de Cardiologie de Montreal
• Czechia
  • Praha 4, Czechia, 14021
    • IKEM
• Denmark
  • Århus N, Denmark, 8200
    • Skejby University Hospital
• Finland
  • Helsinki, Finland, 00130
    • Helsinki University Central Hospital
• France
  • Clichy, France, 92118
    • Hopital Beaujon
  • Creteil, France, 94010
    • Hôpital Henri Mondor
  • Créteil, France, 94000
    • Hôpital Henri Mondor
  • Grenoble, France, 38043
    • CHU Nord
  • St Etienne, France, 42055
    • CHU Saint-Etienne
  • Strasbourg, France, 67098
    • Hôpital Hautepierre
  • Villejuif, France, 94804
    • Hopital Paul Brousse
  • Bicetre Cedex
    • Le Kremlin-Bicêtre, Bicetre Cedex, France, 94275
      • Hôpital Bicêtre
  • Cedex
    • Lille, Cedex, France, 59037
      • Hopital Calmette
    • Rennes, Cedex, France, 35033
      • Hôpital Pontchaillou
  • Cedex 05
    • Montpellier, Cedex 05, France, 34295
      • Hôpital Saint-Eloi
  • Cedex 1
    • Nantes, Cedex 1, France, 44093
      • Hôpital Laënnec
    • Nantes, Cedex 1, France, 44093
      • Hotel Dieu
    • Nice, Cedex 1, France, 06002
      • Service de néphrologie
  • Cedex 3
    • Lyon, Cedex 3, France, 69437
      • Hôpital Edouard Herriot
  • Cedex 5
    • Montpellier, Cedex 5, France, 34295
      • Hopital Lapeyronie
  • Cedex 9
    • Toulouse, Cedex 9, France, 31059
      • Hopital Rangueil
• Germany
  • Bad Oeynhausen, Germany, 32545
    • Herz- und Diabeteszentrum NRW
  • Berlin, Germany, 13353
    • Charite Campus Virchow Klinikum
  • Berlin, Germany, 10117
    • Universitätsklinik Charité
  • Bochum, Germany, 44892
    • Knappschaftskrankenhaus Bochum-Langendreer
  • Erlangen, Germany, 91504
    • Medizinische Klink IV
  • Essen, Germany, 45122
    • Universitatklinikum Essen
  • Frankfurt/Main, Germany, 60590
    • Funktionsbereich Nephrologie
  • Halle, Germany, 06120
    • Univ. Klinik und Poliklinik fuer Urologie
  • Hamburg, Germany, 20246
    • Universitats-Krankenhaus Eppendorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany, 69120
    • Leiter Viszerale Organtransplantation
  • Koeln, Germany, 51109
    • DR MED Wolfgang Arns
  • Munchen, Germany, 81675
    • Klinikum rechts der Isar
  • Regensburg, Germany, 93053
    • Klinikum der Universität Regensburg
  • Regensburg, Germany, 93042
    • Klinik und Poliklinik fuer Chirurgie
• Hungary
  • Budapest, Hungary, 1082
    • Semmelweis University of Medicine
• Ireland
  • Dublin, Ireland, 4
    • National Liver Transplantation Unit
  • Dublin, Ireland, 9
    • Beaumont Private Clinic
• Italy
  • Bergamo, Italy, 24122
    • Ospedali Riuniti di Bergamo
  • Bologna, Italy, 40138
    • Unita Operativa Trapianto di Fegato e Multiorgano
  • Genova, Italy, 16132
    • DISCAT - Centro Trapianti
  • Milano, Italy, 20122
    • Azienda Ospedaliera Ospedale Maggiore di Milano
  • Modena, Italy, 41100
    • Azienda Ospedaliera Policlinico di Modena
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Palermo, Italy, 90134
    • Ismett
  • Roma, Italy, 00168
    • Policlinico Universitario Agostino Gemelli
  • Siena, Italy, 53100
    • Unita Operativa Complessa di Chirurgia dei Trapianti
  • Udine, Italy, 33100
    • Clinica Chirurgica Universitaria
• Mexico
  • Morelos, Mexico, 62448
    • Instituto Mexicano de Transplantes Cuernava
  • Tlalpan, Mexico, 14000
    • Instituto Nacional de Ciencias Médicas y Nutricion "Salvador Zubiran"
• Netherlands
  • Maastricht, Netherlands, 6229
    • Akademisch Ziekenhuis Maastricht
• New Zealand
  • Auckland, New Zealand
    • New Zealand Liver Transplant Unit
• Poland
  • Bydgoszcz, Poland, 85-094
    • Samodzielny Publiczny Szpital Kliniczny
  • Szczecin, Poland, 70-111
    • Samodzielny Publiczny Szpital Kliniczny
• South Africa
  • Cape Town, South Africa, 8001
    • Christiaan Barnard Memorial Hospital
  • Cape Town, South Africa, 7925
    • Groote Schuur Hospital
  • Durban, South Africa, 4001
    • St Augustine's Hospital
  • Pretoria, South Africa, 0181
    • Jacaranda Hospital
  • Tygerberg, South Africa, 7505
    • University of Stellenbosch, Tygerberg Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 08036
    • Hospital Clinic I Provincial
  • Barcelona, Spain, 08025
    • Servicio de Nefrologia
  • Barcelona, Spain, 08035
    • Servicio de Nefrologia
  • Barcelona, Spain, 08036
    • Unidad de Trasplante Hepatico
  • Barcelona, Spain, 08916
    • Servicio de Nefrologia
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain, 28041
    • Consultas de Trasplante Renal
  • Oviedo, Spain, 33006
    • Hospital Central de Asturias
  • Pamplona, Spain, 31008
    • Clínica de Navarra
  • Santiago de Compostela, Spain, 15706
    • Hospital Clinico Universitario de Santiago
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces
• Sweden
  • Gothenburg, Sweden, 41345
    • SU/Sahlgrenska University Hospital
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital Huddinge
• Switzerland
  • Zurich, Switzerland, 8091
    • Universitätsspital Zürich
• United Kingdom
  • Coventry, United Kingdom, CV2 2DX
    • Walsgrove Hospital
  • Edgbaston, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • Glasgow, United Kingdom, G11 6NT
    • Western Infirmary
  • London, United Kingdom, SE5 9RS
    • Kings College Hospital
  • Manchester, United Kingdom, M13 9WL
    • Department of Renal Medicine
  • Manchester, United Kingdom, M23 9LT
    • Wythenshaw Hospital
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • The Freeman Hospital
• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0542
      • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who had already participated in the previous phase II pharmacokinetic or phase III studies with FK506E (MR4).
• Patients capable of understanding the purpose and risks of the study, who had been fully informed and given written informed consent to participate in the study.

Exclusion Criteria:

• Pregnant women or nursing mothers.
• Women unwilling or unable to use adequate contraception during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1: FK506E (MR4); Single open arm of FK506E (MR4). Since this was an extension study for many studies, generally the dose given at enrollment was to be continued. The investigator was permitted to adjust the subject's dose and modify the MR4 dose regimen as deemed necessary to minimize Adverse Events (AEs) and maintain effective immunosuppression. MR4 capsules were taken orally, once daily in the morning. MR4 capsules were to be swallowed with fluid (preferably water) on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal. MR4 was supplied as 0.5 mg, 1 mg and 5 mg capsules in amber glass bottles or in blister packs.

Drug: FK506E; oral; Other Names: Advagraf; Astagraf XL; MR4; Graceptor; Prograf XL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant Survival	Participant survival was analyzed using Kaplan-Meier (KM) method procedures at 66 months (phase 2) and 24 months (phase III). The two-sided 95% confidence intervals (CI) for the estimated rates of patients alive at end of study (EOS) was calculated using Greenwood's formula. Start, event and censor times for the Kaplan-Meier analyses of participant survival were (Event time: day of death, Censor Time: day of last follow-up (for participants prematurely withdrawn from the study), and day of last visit (for participants completing the study) .	Up to 5.5 years (66 months (phase II) and 24 months (phase III)).
Graft Survival	Graft survival was analyzed using Kaplan-Meier Method procedures at 66 months (phase II) and 30 months (phase III). The two-sided 95% confidence intervals for the estimated rates of patients free from graft loss at EOS was calculated using Greenwood's formula. Graft loss was defined as re-transplantation or death. For kidney transplantation graft loss was also defined as nephrectomy or return to long-term dialysis. The date of graft loss is the earliest date of either of these events. Start, event and censor times for the Kaplan-Meier analyses of graft survival were (Event time: day of death, Censor Time: day of last follow-up (for participants prematurely withdrawn from the study), and day of last visit (for participants completing the study) .	Up to 5.5 years ((66 months (phase II) and 30 months (phase III)).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biopsy-confirmed Acute Rejection (BCAR) Episodes	FAS population. Evaluation of biopsy specimens performed by local histopathologist following "Histological Grading of Biopsies for Rejection" using grading relevant to type of organ allograft. Spontaneously resolving AR defined as episode not treated with new/increased corticosteroid medication, antibodies/any other medication and resolved irrespective of any MR4/MMF/azathioprine dose changes; corticosteroid sensitive AR was an episode which was treated with new/increased corticosteroid medication only and resolved, irrespective of any MR4, MMF or azathioprine dose changes; corticosteroid resistant AR was an episode which did not resolve following treatment with corticosteroids, if it was not treated with corticosteroids first but only with antibodies, it was included in this category; corticosteroid resistant AR episodes were further classified into episodes which resolved with further treatment and those which did not respond to further treatment/were ongoing at EOS/withdrawal.	Up to 6 years.
Time to First BCAR Episode	The time to first acute rejection episode was defined as the number of days from day 1 (defined as the day of study enrollment) to the first clinical, laboratory or histological signs that were considered to be related to the first acute rejection episode.	Up to 1344 days (3.75 years).
Number of Participants With Adverse Events	An AE was defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have a causal relationship with treatment. An AE was, therefore, any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use the study drug, whether or not related to the study drug. Causally-related is defined as a highly probably, probably, possible, not assessable or missing relationship as assessed by the investigator. An SAE was any untoward medical occurrence that at any dose: Resulted in death, was life threatening: did not refer to event which hypothetically might have caused death if more severe); resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect; required inpatient hospitalization/led to prolongation of hospitalization (treatment/observation/examination caused by AE was considered serious); other medically important events.	From first dose to duration of participation in the study (up to 6 years and 28 days after EOS).

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe Ltd.
• Investigators: Study Chair: Central Contact, Astellas Pharma Europe Ltd.

Publications and helpful links

Helpful Links

• Link to Results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2003
• Primary Completion (Actual): October 7, 2009
• Study Completion (Actual): October 7, 2009

Study Registration Dates

• First Submitted: April 17, 2014
• First Submitted That Met QC Criteria: April 17, 2014
• First Posted (Estimate): April 21, 2014

Study Record Updates

• Last Update Posted (Actual): February 21, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Renal Transplantation; Heart Transplantation; Tacrolimus; FK506E; MR4; Kidney Transplantation; Advagraf
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: F506-CL-0857; 2005-005714-20 (EudraCT Number); FG-506-14-02 (Other Identifier: Sponsor Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."