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

Phase 3

Completed

Conditions: Heart Transplantation
Liver Transplantation
Kidney Transplantation

Interventions: Drug: FK506E

Registration Number: NCT02118896

Lead Sponsor: Astellas Pharma Europe Ltd.

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 850

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1: FK506E (MR4)	FK506E	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.

Primary Outcome Measures

Name	Time	Method
Participant Survival	Up to 5.5 years (66 months (phase II) and 24 months (phase III)).	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) .
Graft Survival	Up to 5.5 years ((66 months (phase II) and 30 months (phase III)).	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) .

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	From first dose to duration of participation in the study (up to 6 years and 28 days after EOS).	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.
Biopsy-confirmed Acute Rejection (BCAR) Episodes	Up to 6 years.	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.
Time to First BCAR Episode	Up to 1344 days (3.75 years).	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.

Trial Locations

Locations (101): University Hospital
🇺🇸
Cincinnati, Ohio, United States
Royal Prince Alfred Hospital
🇦🇺
Camperdown, New South Wales, Australia
Princess Alexandra Hospital
🇦🇺
Brisbane, Queensland, Australia
Austin Hospital
🇦🇺
Heidelberg, Victoria, Australia
Royal Melbourne Hospital
🇦🇺
Melbourne, Victoria, Australia
Landeskrankenhaus Innsbruck
🇦🇹
Innsbruck, Austria
AKN Wien
🇦🇹
Wien, Austria
Hospital Erasme
🇧🇪
Bruxelles, Belgium
Cliniques Universitaires St. Luc
🇧🇪
Bruxelles, Belgium
Departement Heelkunde
🇧🇪
Gent, Belgium
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University Hospital
🇺🇸Cincinnati, Ohio, United States