Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43866   clinical trials with a EudraCT protocol, of which   7287   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase II, open-label, multi-center study to assess the pharmacokinetics, long-term safety and tolerability of Tacrolimus in stable pediatric liver transplant participants converted from a Prograf^®-based Immunosuppression regimen to a Modified Release (MR) Tacrolimus-based immunosuppression regimen.

    Summary
    EudraCT number
    		 2015-001076-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Oct 2008

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Jun 2016
    First version publication date
    18 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updates required due to non-substantial reasons.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    03-0-160
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00282256
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    Three Parkway North, Deerfield, United States, 60015
    Public contact
    Clinical Trial Disclosure , Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Oct 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2008
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine and compare the pharmacokinetics of tacrolimus in stable pediatric liver transplant patients converted from a Prograf® based immunosuppression regimen to an extended-release tacrolimus (FK506E, MR)-based immunosuppressive regimen.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.This protocol was reviewed and approved by the Institutional Review Board (IRB) of the participating institutions. The study was conducted in compliance with Good Clinical Practice (GCP) and in accordance with ethical principles that have their origin in the Declaration of Helsinki. The subject’s legal guardian read and signed an IRB-approved informed consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization prior to initiation of any study-related procedures. Subjects, 7 to 12 years of age, were fully informed and signed an IRB-approved assent form/authorization.
    Background therapy
    		 This study included a 1-week exposure to Prograf, with participants already on a stable dose of Prograf-based immunosuppressive therapy for liver transplantation. All immunosuppressants and corticosteroids used in combination with Prograf at baseline/day 1 were maintained at constant doses throughout the pharmacokinetic (PK) treatment period. Once the day 14 PK visit was completed, corticosteroid and immunosuppressant dose adjustments were permitted. Use of sirolimus, intravenous methylprednisolone, or any investigational immunosuppressant was prohibited during the PK treatment period.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 54 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Stable liver transplant recipients aged 12 years or younger receiving tacrolimus based immunosuppression regimen.

    Pre-assignment
    Screening details
    		 Pharmacokinetic (PK) treatment period was 14 days. Participants who completed the PK period were eligible to continue receiving tacrolimus MR in the extended treatment period, from Day 15 through Month 54.

    Period 1
    Period 1 title
    Pharmacokinetic Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tacrolimus (Prograf)
    Arm description
    		 Participants continued to receive their stable twice daily dose of tacrolimus (Prograf) twice daily on Day 1 through Day 7 and on Day 8 were converted to Tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Participants who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus Extended-Release Formulation
    Investigational medicinal product code
    FK506E
    Other name
    MR4,Advagraf,Astagraf XL
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    On day 8, participants were converted to tacrolimus extended release formulation on a 1:1 (mg:mg) basis for their total daily dose and received a daily oral dose of tacrolimus extended release formulation equivalent to their total twice-daily dose of Prograf. The dose was not to be altered if the trough level was within the therapeutic range of 5 to 20 ng/mL (levels below 5 ng/mL were acceptable as long as there were no clinical indications that the dose should be altered). Tacrolimus extended release formulation was administered orally once daily as 0.5, 1.0 or 5 mg capsules in the morning either 1 hour before or 2 hours after a meal, and participants were to have fasted for a minimum of 2 hours prior to being dispensed the morning dose on the day of a PK visit. The duration of the PK period was 2 weeks; 1 week of Prograf administration, followed by 1 week of tacrolimus extended release formulation administration.

    Number of subjects in period 1
    		Tacrolimus (Prograf)
    Started
    19
    Completed
    18
    Not completed
    1
         Withdrawal due to poor venous access
    1
    Period 2
    Period 2 title
    Extension Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tacrolimus MR
    Arm description
    		 Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Participants who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus Extended-Release Formulation
    Investigational medicinal product code
    FK506E
    Other name
    MR4,Advagraf,Astagraf XL
    Pharmaceutical forms
    Prolonged-release capsule
    Routes of administration
    Oral use
    Dosage and administration details
    On day 8, participants were converted to tacrolimus extended release formulation on a 1:1 (mg:mg)basis for their total daily dose and received a daily oral dose of tacrolimus extended release formulation equivalent to their total twice-daily dose of Prograf. The dose was not to be altered if the trough level was within the therapeutic range of 5 to 20 ng/mL. (Levels below 5 ng/mL were acceptable as long as there were no clinical indications that the dose should be altered.) Tacrolimus extended release formulation was administered orally once daily as 0.5, 1.0 or 5 mg capsules in the morning either 1 hour before or 2 hours after a meal, and participants were to have fasted for a minimum of 2 hours prior to being dispensed the morning dose on the day of a PK visit. The duration of the PK period was 2 weeks; 1 week of Prograf administration, followed by 1 week of tacrolimus extended release formulation administration.

    Number of subjects in period 2
    		Tacrolimus MR
    Started
    18
    Completed
    16
    Not completed
    2
         Adverse event, non-fatal
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pharmacokinetic Treatment Period
    Reporting group description
    		 The pharmacokinetic evaluable set was defined as all pharmacokinetic participants who completed both pharmacokinetic profiles: one for tacrolimus, and one for tacrolimus MR.

    Reporting group values
    		 Pharmacokinetic Treatment Period Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
    Age continuous
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: years
        arithmetic mean (standard deviation)
    		 8.5 ( 2.29 ) -
    Gender categorical
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        Male
    		 6 6
        Female
    		 13 13
    Race
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        Caucasian/White
    		 11 11
        Black
    		 8 8
    Reason for End Stage Liver Disease
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        Biliary Atresia
    		 6 6
        Unknown
    		 1 1
        Other
    		 10 10
        Metabolic disease: tyrosinemia
    		 2 2
    Type of Current Transplant
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        Whole Cadaver
    		 10 10
        Split Cadaver
    		 5 5
        Living Donor
    		 4 4
    Reason for Re-transplant
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        No Retransplant
    		 17 17
        Acute Rejection
    		 1 1
        Other
    		 1 1
    Re-Transplant
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: Subjects
        Yes
    		 2 2
        No
    		 17 17
    Gender
    Modified Safety Analysis set was used for baseline characteristics reporting. It contains all patients who took at least 1 dose of both Prograf and tacrolimus extended release formulation during the pharmacokinetic period of the study. Number of patients in the Modified Safety Analysis and the pharmacokinetic period is 18
    Units: Subjects
        Male
    		 5 5
        Female
    		 13 13
        Not Recorded
    		 1 1
    Height (cm)
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: centimeters
        arithmetic mean (standard deviation)
    		 131 ( 15.65 ) -
    Weight (kg)
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 32.9 ( 14.7 ) -
    Total Daily Dose of Prograf at Baseline
    Full analysis set was used to report baseline characteristics. It includes all patients who were enrolled in the study and received at least one dose of Prograf during the study.
    Units: milligram(s)
        arithmetic mean (standard deviation)
    		 5.3 ( 3.19 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tacrolimus (Prograf)
    Reporting group description
    		 Participants continued to receive their stable twice daily dose of tacrolimus (Prograf) twice daily on Day 1 through Day 7 and on Day 8 were converted to Tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Participants who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
    Reporting group title
    Tacrolimus MR
    Reporting group description
    		 Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Participants who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.

    Subject analysis set title
    Period 1 - Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set was defined as all participants who were enrolled in the study and received at least one dose of Prograf during the study. The full analysis set was the primary data set for all safety analyses.

    Subject analysis set title
    Period 1- Pharmacokinetic Evaluable Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The pharmacokinetic evaluable set was defined as all participants who completed both pharmacokinetic profiles: one for Prograf, and one for MR4. A complete pharmacokinetic profile was considered to be a profile that was adequate to determine AUC0-24, Cmax, and Cmin. The pharmacokinetic evaluable set was used to analyze other pharmacokinetic parameters derived from the concentration-time curve and was the primary data set for all pharmacokinetic analyses.

    Subject analysis set title
    Period 1- Trough Evaluable Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The trough evaluable set was defined as all participants with replicate whole blood trough measurements of both Prograf and MR4.

    Subject analysis set title
    Period 1- Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set was defined as all participants who completed both pharmacokinetic profiles and did not have any major protocol deviations during the pharmacokinetic treatment period (including lack of 1:1 conversion and administration of prohibited medications).

    Subject analysis set title
    Period 2- Modified Full Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Full Analysis Set included all participants who took at least 1 dose of tacrolimus extended-release formulation during the extended treatment period. This population was the primary analysis set for efficacy data obtained during the extended treatment period.

    Subject analysis set title
    Period 2- Modified Safety Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Safety Analysis Set included all participants in the Full Analysis Set who took at least 1 dose of tacrolimus extended-release formulation during the pharmacokinetic period of the study. This population was the primary analysis set for safety data obtained during the extended treatment period, except for incidence of glucose intolerance/PTDM at each extended study visit, which was evaluated in the Modified Full Analysis Set

    Primary: The primary measure of exposure for Tacrolimus (AUC0-24 - Area Under the Concentration-time Curve From Time 0 to 24 Hours)

    		 Close Top of page
    End point title
    		 The primary measure of exposure for Tacrolimus (AUC0-24 - Area Under the Concentration-time Curve From Time 0 to 24 Hours)
    End point description
    The primary measure of exposure was area under the concentration-time curve from 0 to 24 hours (AUC0-24 (ng*hr/mL)). The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 and AUC 12-24 for the morning and afternoon doses.
    End point type
    Primary
    End point timeframe
    For tacrolimus, Day 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
    End point values
    		 Tacrolimus (Prograf) Tacrolimus MR
    Number of subjects analysed
    18
    18
    Units: Number
        arithmetic mean (standard deviation)
    198.2 ( 99.2 )
    193 ( 78 )
    Statistical analysis title
    		 Statistical Analysis (AUC0-24) for Tacrolimus
    Statistical analysis description
    The method of analysis of variance was used for the comparisons of AUC0-24. Exposure at steady state was used for tacrolimus (Prograf) (defined as Day 7) and for tacrolimus MR (defined as Day 14). The natural log (ln) was used to transform AUC0-24 prior to analysis and the results were transformed back to the original scale for the presentation of results. For this statistical analysis 18 participants were analysed.
    Comparison groups
    Tacrolimus MR v Tacrolimus (Prograf)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Ratio of means
    Point estimate
    100.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.8
         upper limit
    		 112.1
    Notes
    [1] - Bioequivalence Test-If the 90% CI for AUC0-24 was found to lie entirely within the 80% to 125% range, then the exposure between the two formulations was considered to be bioequivalent.

    Primary: Patient survival (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Patient survival (Modified Full Analysis Set) [2]
    End point description
    Participant survival was defined as any participant known to be alive at the end of the study. Participants were enrolled on a stable twice-daily dose of Prograf on Day 1 and received Prograf twice daily on days 1 through 7. Participants received tacrolimus extended release formulation on a 1:1 (mg:mg) basis for their total daily dose once daily on days 8 through 14. The extended treatment period began on day 15 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study (month 54). The initial total daily dose of tacrolimus extended-release formulation was to be equivalent to the participant’s previous stable total daily dose of Prograf.
    End point type
    Primary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: percent
        number (confidence interval 95%)
    94.44 (83.86 to 100)
    No statistical analyses for this end point

    Primary: Graft Survival (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Graft Survival (Modified Full Analysis Set) [3]
    End point description
    Graft survival was defined for any participant who did not meet the definition of graft loss, where graft loss was defined as graft failure (re-transplant) or participant death. Participants were enrolled on a stable twice-daily dose of Prograf on Day 1 and received Prograf twice daily on days 1 through 7. Participants received tacrolimus extended release formulation on a 1:1 (mg:mg) basis for their total daily dose once daily on days 8 through 14. The extended treatment period began on day 15 and consisted of a single dose of tacrolimus extended release formulation once every morning through the end of the study (month 54). The initial total daily dose of tacrolimus extended-release formulation was to be equivalent to the participants previous stable total daily dose of Prograf.
    End point type
    Primary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified for this endpoint.
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: percent
        number (confidence interval 95%)
    94.44 (83.86 to 100)
    No statistical analyses for this end point

    Primary: Minimum Observed Concentration of Tacrolimus (Cmin)(Pharmacokinetic Evaluable Set)

    		 Close Top of page
    End point title
    		 Minimum Observed Concentration of Tacrolimus (Cmin)(Pharmacokinetic Evaluable Set)
    End point description
    The trough (minimum) concentration of Tacrolimus (Prograf) 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.
    End point type
    Primary
    End point timeframe
    Day 7 at 12 hours post-dose Tacrolimus (Prograf) and Day 14 at 24 hours post-dose (Tacrolimus MR).
    End point values
    		 Tacrolimus (Prograf) Tacrolimus MR
    Number of subjects analysed
    18
    18
    Units: ng/mL
        arithmetic mean (standard deviation)
    5.9 ( 2.9 )
    5.3 ( 2.6 )
    Statistical analysis title
    		 Minimum Observed Concentration of Tacrolimus -Cmin
    Statistical analysis description
    The method of analysis of variance was used for the comparisons of Cmin. Exposure at steady state was used for tacrolimus (defined as Day 7) and for tacrolimus MR (defined as Day 14). The natural log (ln) was used to transform Cmin prior to analysis and the results were transformed back to the original scale for the presentation of results.
    Comparison groups
    Tacrolimus MR v Tacrolimus (Prograf)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of means
    Point estimate
    91.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 82.6
         upper limit
    		 102.2

    Secondary: Maximum Observed Concentration of Tacrolimus (Cmax) (Pharmacokinetic evaluable set)

    		 Close Top of page
    End point title
    		 Maximum Observed Concentration of Tacrolimus (Cmax) (Pharmacokinetic evaluable set)
    End point description
    Time to reach the first observed maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.
    End point type
    Secondary
    End point timeframe
    For tacrolimus, Day 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
    End point values
    		 Tacrolimus (Prograf) Tacrolimus MR
    Number of subjects analysed
    18
    18
    Units: hours
        arithmetic mean (standard deviation)
    20.7 ( 13.3 )
    15.2 ( 5.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Biopsy-confirmed Acute Rejection (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Biopsy-confirmed Acute Rejection (Modified Full Analysis Set)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus (Prograf)
    Number of subjects analysed
    18
    Units: percent
    number (not applicable)
        Percentage with Biopsy-confirmed Acute Rejection
    16.67
    No statistical analyses for this end point

    Secondary: Time to Event for Patient Non-survival (Modified Full Analysis Set who died on study)

    		 Close Top of page
    End point title
    		 Time to Event for Patient Non-survival (Modified Full Analysis Set who died on study)
    End point description
    For participants who died on study, the median number of days from first dose of study drug to death due to any cause.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months)
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    1
    Units: Days
        median (full range (min-max))
    1204 (1204 to 1204)
    No statistical analyses for this end point

    Secondary: Time to Event for Graft Non-survival (Modified full analysis set with graft loss)

    		 Close Top of page
    End point title
    		 Time to Event for Graft Non-survival (Modified full analysis set with graft loss)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months)
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    1
    Units: Days
        median (full range (min-max))
    1203 (1203 to 1203)
    No statistical analyses for this end point

    Secondary: Time to First Biopsy-confirmed Acute Rejection (Participants in the modified full analysis set with a biopsy-confirmed acute rejection)

    		 Close Top of page
    End point title
    		 Time to First Biopsy-confirmed Acute Rejection (Participants in the modified full analysis set with a biopsy-confirmed acute rejection)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    3
    Units: Days
    median (full range (min-max))
        Time to First Biopsy-confirmed Acute Rejection
    748 (729 to 773)
    No statistical analyses for this end point

    Secondary: Grade of Biopsy-confirmed Acute Rejection Episodes (Participants in the modified full analysis set with a biopsy-confirmed acute rejection)

    		 Close Top of page
    End point title
    		 Grade of Biopsy-confirmed Acute Rejection Episodes (Participants in the modified full analysis set with a biopsy-confirmed acute rejection)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months)
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    3
    Units: Participants
    number (not applicable)
        Grade I
    2
        Grade II
    1
        Grade III
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection (Modified Full Analysis Set)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: Participants
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Multiple Rejection Episodes (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Number of Participants With Multiple Rejection Episodes (Modified Full Analysis Set)
    End point description
    This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: Participants
        number (not applicable)
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Treated Acute Rejection Episodes (Modified Full Analysis Set)

    		 Close Top of page
    End point title
    		 Number of Participants With Clinically Treated Acute Rejection Episodes (Modified Full Analysis Set)
    End point description
    A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: Participants
        number (not applicable)
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With Chronic Rejection

    		 Close Top of page
    End point title
    		 Number of Participants With Chronic Rejection
    End point description
    Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months).
    End point values
    		 Tacrolimus (Prograf)
    Number of subjects analysed
    0 [4]
    Units: Participants
        number (not applicable)
    Notes
    [4] - Due to low number of participants chronic rejection was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Failure

    		 Close Top of page
    End point title
    		 Number of Participants With Treatment Failure
    End point description
    Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months)
    End point values
    		 Tacrolimus (Prograf)
    Number of subjects analysed
    0 [5]
    Units: Participants
        number (not applicable)
    Notes
    [5] - Due to discontinuation of the study by the sponsor, treatment failure was not analyzed
    No statistical analyses for this end point

    Secondary: Primary Reason for Graft Loss

    		 Close Top of page
    End point title
    		 Primary Reason for Graft Loss
    End point description
    The primary reason for graft loss was recorded by the Investigator. It was recorded as “Other” and was reported as unknown due to inability to access participant's records and death report from Mexico. Graft loss was defined as graft failure (re-transplant) or participant death. Modified full analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    From enrollment until the end of study (up to 54 months)
    End point values
    		 Tacrolimus (Prograf)
    Number of subjects analysed
    1
    Units: Participants
    number (not applicable)
        Recurrent disease
    0
        Unknown-Unable to check participants records
    1
    No statistical analyses for this end point

    Secondary: Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests

    		 Close Top of page
    End point title
    		 Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests
    End point description
    An adverse event (AE) 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.
    End point type
    Secondary
    End point timeframe
    From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 54 months).
    End point values
    		 Tacrolimus MR
    Number of subjects analysed
    18
    Units: Participants
    number (not applicable)
        Adverse Events
    12
        Serious Adverse Event
    6
        Death
    1
        Any AE leading to a change in study drug dose
    3
        AE leading to study drug discontinuation
    1
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration of Tacrolimus (Tmax)

    		 Close Top of page
    End point title
    		 Time to Maximum Observed Concentration of Tacrolimus (Tmax)
    End point description
    Time to reach the first observed maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.
    End point type
    Secondary
    End point timeframe
    For tacrolimus, Day 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
    End point values
    		 Tacrolimus (Prograf)
    Number of subjects analysed
    18
    Units: Number
    median (full range (min-max))
        Day 7: Tacrolimus
    1 (0.5 to 19.7)
        Day 14: Tacrolimus MR
    2 (0.9 to 6)
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    6.1
    Reporting groups
    Reporting group title
    Tacrolimus MR
    Reporting group description
    		 -

    Serious adverse events
    		 Tacrolimus MR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 18 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis eosinophilic
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tacrolimus MR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Blood triglycerides increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Maxillary sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Renal and urinary disorders
    Glomerulosclerosis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cat scratch disease
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Herpes simplex
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Tinea capitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Urinary tract infection staphylococcal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Tue Apr 30 08:11:42 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA