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 are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   35510   clinical trials with a EudraCT protocol, of which   5839   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).
     
    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 2, Parallel Group, Randomized, Multicenter, Open-label Study to Compare the Pharmacokinetics of Tacrolimus in De Novo Pediatric Allograft Recipients Treated with an Advagraf® or Prograf® Based Immunosuppressive Regimen, Including a Long-term Follow-up

    Summary
    EudraCT number
    2011-000078-80
    Trial protocol
    AT   CZ   GB   BE   PL   IT   FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Nov 2017
    First version publication date
    13 Nov 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    PMR-EC-1207
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01614665
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe, Ltd
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey, United Kingdom, KT16 0RS
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe, Ltd, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe, Ltd, 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
    Interim
    Date of interim/final analysis
    11 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the systemic exposure (area under the plasma concentration-time curve from time 0 to time 24 hours [AUC24]) of tacrolimus for tacrolimus prolonged release (Advagraf) vs tacrolimus (Prograf) after the first dose and following repeated administration in pediatric patients undergoing primary heart, kidney or liver transplantation.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (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.
    Background therapy
    This study is composed of 3 parts: Part A (pharmacokinetics), Part B (long-term follow-up) and Part C (continuation of long-term follow-up until participants discontinued treatment or received the approved treatment). Basiliximab, mycophenolate mofetil (MMF) and corticosteroids could have been administered as concomitant immunosuppressive treatment. Basiliximab and MMF were administered according to current accepted local and institutional clinical practice. Corticosteroids were administered following a predetermined schedule in Part A, and then in Part B or C followed the routine practice of the center.
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    24
    Adolescents (12-17 years)
    20
    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
    Children aged < 16 years of age were enrolled in sites in 5 countries: Czech Republic, France, Italy, Poland and UK for this 3-part study. Results reported in this disclosure include data from Part A and Part B of the study.

    Pre-assignment
    Screening details
    Pediatric participants undergoing primary heart, kidney or liver transplantation (de novo allograft) meeting the eligibility criteria were enrolled. Participants were randomized to treatment with either tacrolimus and tacrolimus prolonged release on a 1:1 basis stratified by organ and center.

    Period 1
    Period 1 title
    Part A: Pharmacokinetics
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tacrolimus (Part A)
    Arm description
    Participants received an initial dose of tacrolimus orally or via nasogastric tube on day 1, and subsequently twice daily for up to 4 weeks in Part A of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Prograf
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Participants received an initial total daily dose of tacrolimus depending on the type of organ transplant (heart = 0.075 mg/kg; liver/kidney = 0.3 mg/kg), given orally (or via nasogastric tube for liver transplant recipients) in 2 doses in the morning and the evening. The first dose was administered in the morning within days of skin closure (heart = 4 days; liver = 2 days; kidney = within 24 hours following reperfusion). Subsequent tacrolimus doses were taken orally twice a day in the morning and evening and were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and observing the recommended whole blood trough level ranges (Day 1 through 21 = 10 to 20 ng/mL; Day 22 through 365 = 5 to 15 ng/mL).

    Arm title
    Tacrolimus Prolonged Release (Part A)
    Arm description
    Participants received an initial dose of tacrolimus prolonged release orally or via nasogastric tube on day 1, and subsequently once daily for up to 4 weeks in Part A of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus prolonged release
    Investigational medicinal product code
    Other name
    Advagraf, Astagraf XL, Graceptor, Prograf XL
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Participants received an initial total daily dose of tacrolimus prolonged release depending on the type of organ transplant (heart = 0.075 mg/kg; liver/kidney = 0.3 mg/kg), given orally (or via nasogastric tube for liver transplant recipients) in 1 dose. The first dose was administered in the morning within days of skin closure (heart = 4 days; liver = 2 days; kidney = within 24 hours following reperfusion). Subsequent tacrolimus prolonged release doses were taken orally once a day in the morning and were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and observing the recommended whole blood trough level ranges (Day 1 through 21 = 10 to 20 ng/mL; Day 22 through 365 = 5 to 15 ng/mL).

    Number of subjects in period 1
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Started
    24
    20
    Treated with Study Drug
    24
    20
    Completed
    23
    20
    Not completed
    1
    0
         Withdrawal of Consent
    1
    -
    Period 2
    Period 2 title
    Part B: Long-Term Follow-up
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tacrolimus (Part A)
    Arm description
    After Part A, participants continued to receive tacrolimus twice daily for up to 48 weeks in Part B of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Prograf
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Participants received an initial total daily dose of tacrolimus depending on the type of organ transplant (heart = 0.075 mg/kg; liver/kidney = 0.3 mg/kg), given orally (or via nasogastric tube for liver transplant recipients) in 2 doses in the morning and the evening. The first dose was administered in the morning within days of skin closure (heart = 4 days; liver = 2 days; kidney = within 24 hours following reperfusion). Subsequent tacrolimus doses were taken orally twice a day in the morning and evening and were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and observing the recommended whole blood trough level ranges (Day 1 through 21 = 10 to 20 ng/mL; Day 22 through 365 = 5 to 15 ng/mL).

    Arm title
    Tacrolimus Prolonged Release (Part B)
    Arm description
    After Part A, participants continued to receive tacrolimus prolonged release once daily for up to 48 weeks in Part B of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus prolonged release
    Investigational medicinal product code
    Other name
    Advagraf, Astagraf XL, Graceptor, Prograf XL
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Participants received an initial total daily dose of tacrolimus prolonged release depending on the type of organ transplant (heart = 0.075 mg/kg; liver/kidney = 0.3 mg/kg), given orally (or via nasogastric tube for liver transplant recipients) in 1 dose. The first dose was administered in the morning within days of skin closure (heart = 4 days; liver = 2 days; kidney = within 24 hours following reperfusion). Subsequent tacrolimus prolonged release doses were taken orally once a day in the morning and were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and observing the recommended whole blood trough level ranges (Day 1 through 21 = 10 to 20 ng/mL; Day 22 through 365 = 5 to 15 ng/mL).

    Number of subjects in period 2
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part B)
    Started
    23
    20
    Treated with Study Drug
    23
    20
    Completed
    21
    20
    Not completed
    2
    0
         Noncompliance with scheduled visits
    1
    -
         Adverse Event
    1
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus (Part A)
    Reporting group description
    Participants received an initial dose of tacrolimus orally or via nasogastric tube on day 1, and subsequently twice daily for up to 4 weeks in Part A of the study.

    Reporting group title
    Tacrolimus Prolonged Release (Part A)
    Reporting group description
    Participants received an initial dose of tacrolimus prolonged release orally or via nasogastric tube on day 1, and subsequently once daily for up to 4 weeks in Part A of the study.

    Reporting group values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A) Total
    Number of subjects
    24 20 44
    Age categorical
    Units: Subjects
        ≥ 0 days to ≤ 27 days (newborn)
    0 0 0
        ≥ 28 days to ≤ 23 months (infants and toddlers)
    0 0 0
        ≥ 2 years to ≤ 11 years (children)
    13 11 24
        ≥ 12 years to ≤ 17 years (adolescents)
    11 9 20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.25 ± 3.21 11.10 ± 3.02 -
    Gender categorical
    Units:
        Male
    17 16 33
        Female
    7 4 11
    Type of Organ Transplant
    Units: Subjects
        Heart
    4 3 7
        Kidney
    12 13 25
        Liver
    8 4 12

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Tacrolimus (Part A)
    Reporting group description
    Participants received an initial dose of tacrolimus orally or via nasogastric tube on day 1, and subsequently twice daily for up to 4 weeks in Part A of the study.

    Reporting group title
    Tacrolimus Prolonged Release (Part A)
    Reporting group description
    Participants received an initial dose of tacrolimus prolonged release orally or via nasogastric tube on day 1, and subsequently once daily for up to 4 weeks in Part A of the study.
    Reporting group title
    Tacrolimus (Part A)
    Reporting group description
    After Part A, participants continued to receive tacrolimus twice daily for up to 48 weeks in Part B of the study.

    Reporting group title
    Tacrolimus Prolonged Release (Part B)
    Reporting group description
    After Part A, participants continued to receive tacrolimus prolonged release once daily for up to 48 weeks in Part B of the study.

    Subject analysis set title
    Tacrolimus (Part A+B)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received tacrolimus twice daily starting from day 1 for 4 weeks for in Part A, and continued to receive tacrolimus twice daily up to end of Part B of the study.

    Subject analysis set title
    Tacrolimus prolonged release (Part A+B)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received tacrolimus prolonged release once daily starting from day 1 for 4 weeks for in Part A, and continued to receive tacrolimus prolonged release once daily up to end of Part B of the study.

    Primary: Area Under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours (AUC0-24h) for Tacrolimus

    Close Top of page
    End point title
    Area Under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours (AUC0-24h) for Tacrolimus
    End point description
    The analysis population was the Pharmacokinetic Set (PKAS), which included all participants who received at least one dose of study drug and who provided 3 complete pharmacokinetic (PK) profiles.
    End point type
    Primary
    End point timeframe
    Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    18
    15
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    224.1438 ± 55.4
    157.3656 ± 63.4
        Day 7
    295.4154 ± 35.9
    292.4430 ± 36.0
        Day 28
    260.0736 ± 38.4
    268.9836 ± 36.7
    Statistical analysis title
    AUC0-24h Comparison on Day 1
    Statistical analysis description
    The comparison of AUC0-24h between tacrolimus and tacrolmus prolonged release was assessed using an analysis of covariance (ANCOVA) model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus Prolonged Release (Part A) v Tacrolimus (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric least squares (LS) mean ratio
    Point estimate
    66.33
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    46.39
         upper limit
    94.84
    Statistical analysis title
    AUC0-24h Comparison on Day 7
    Statistical analysis description
    The comparison of AUC0-24h between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    92.48
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    71.22
         upper limit
    120.09
    Statistical analysis title
    AUC0-24h Comparison on Day 28
    Statistical analysis description
    The comparison of AUC0-24h between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    99.91
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    80.64
         upper limit
    123.78

    Primary: Number of Participants with Adverse Events (Part A + B)

    Close Top of page
    End point title
    Number of Participants with Adverse Events (Part A + B) [1]
    End point description
    Safety was assessed by adverse events (AEs), which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A serious AE (SAE) was an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, was life-threatening, required or prolonged hospitalization or was considered medically important. The analysis population was the Full Analysis Set (FAS), which consisted of all participants who received at least one dose of any of the study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 7 days after last dose of study drug in Part B (up to 53 weeks)
    Notes
    [1] - 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: There were no pre-determined hypothesis or other statistical analyses performed on the primary safety endpoint.
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    24
    20
    Units: participants
    number (not applicable)
        AEs
    23
    19
        Drug-related AEs
    15
    14
        Deaths
    0
    0
        SAEs
    15
    13
        Drug-related SAEs
    9
    10
        Deaths Resulting from AEs
    0
    0
        AEs Leading to Discontinuation of Study Drug
    1
    0
        Drug-related AEs Leading to Discont. of Study Drug
    1
    0
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Tacrolimus

    Close Top of page
    End point title
    Maximum Concentration (Cmax) of Tacrolimus
    End point description
    The analysis population was the PKAS. This PK parameter was not assessed in the evening for the tacrolimus prolonged release arm as the participants received only one dose in the morning, and therefore is denoted as "99999." One participant had an assessment in the evening of day 1, and data available are included below.
    End point type
    Secondary
    End point timeframe
    Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    18
    15 [2]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Morning
    14.7228 ± 68.7
    12.7344 ± 67.9
        Day 1: Evening
    17.3022 ± 67.0
    4.0000 ± 99999
        Day 7: Morning
    20.9616 ± 52.3
    26.7438 ± 50.9
        Day 7: Evening
    15.5052 ± 57.0
    99999 ± 99999
        Day 28: Morning
    22.9368 ± 54.9
    21.3462 ± 32.0
        Day 28: Evening
    12.6120 ± 34.2
    99999 ± 99999
    Notes
    [2] - The number of participants for day 1=14.
    Statistical analysis title
    Cmax Comparison on Day 1
    Statistical analysis description
    The comparison of Cmax between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    77.29
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    52.64
         upper limit
    113.49
    Statistical analysis title
    Cmax Comparison on Day 7
    Statistical analysis description
    The comparison of Cmax between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    120.33
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    87.32
         upper limit
    165.83
    Statistical analysis title
    Cmax Comparison on Day 28
    Statistical analysis description
    The comparison of Cmax between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    92.16
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    72.33
         upper limit
    117.42

    Secondary: Time to Attain Maximum Concentration (tmax) of Tacrolimus

    Close Top of page
    End point title
    Time to Attain Maximum Concentration (tmax) of Tacrolimus
    End point description
    The analysis population was the PKAS. This PK parameter was not assessed in the evening for the tacrolimus prolonged release arm as the participants received only one dose in the morning, and therefore is denoted as "99999." One participant had an assessment in the evening of day 1, and data available are included below.
    End point type
    Secondary
    End point timeframe
    Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    18
    15 [3]
    Units: hours
    median (full range (min-max))
        Day 1: Morning
    1.9998 (0.000 to 11.751)
    3.9498 (0.984 to 23.001)
        Day 1: Evening
    1.9998 (0.966 to 11.250)
    6.0000 (6.000 to 6.000)
        Day 7: Morning
    1.0086 (0.951 to 6.051)
    1.9998 (0.966 to 13.032)
        Day 7: Evening
    3.9582 (0.000 to 12.018)
    99999 (99999 to 999999)
        Day 28: Morning
    1.0002 (0.933 to 3.984)
    1.9500 (0.918 to 6.000)
        Day 28: Evening
    3.9414 (0.999 to 12.000)
    99999 (99999 to 99999)
    Notes
    [3] - The number of participants for day 1=14.
    No statistical analyses for this end point

    Secondary: Trough Concentration (C12) for Tacrolimus

    Close Top of page
    End point title
    Trough Concentration (C12) for Tacrolimus [4]
    End point description
    The analysis population was the PKAS.
    End point type
    Secondary
    End point timeframe
    Days 1, 7 and 28, 12 hours after dosing
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This PK parameter only applies to the tacrolimus group, due to the frequency of the study drug administration.
    End point values
    Tacrolimus (Part A)
    Number of subjects analysed
    18
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    5.2224 ± 61.8
        Day 7
    8.7840 ± 45.0
        Day 28
    7.4322 ± 37.4
    No statistical analyses for this end point

    Secondary: Trough Concentration (C24) for Tacrolimus

    Close Top of page
    End point title
    Trough Concentration (C24) for Tacrolimus
    End point description
    The analysis population was the PKAS.
    End point type
    Secondary
    End point timeframe
    Days 1, 7 and 28, 24 hours after dosing
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    18 [5]
    15
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    6.8154 ± 58.5
    5.0736 ± 63.9
        Day 7
    9.0744 ± 30.5
    7.7442 ± 46.3
        Day 28
    7.9188 ± 38.9
    7.0506 ± 45.6
    Notes
    [5] - The number of participants for day 28=17.
    Statistical analysis title
    C24 Comparison on Day 1
    Statistical analysis description
    The comparison of C24 between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    66.29
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    44.63
         upper limit
    98.46
    Statistical analysis title
    C24 Comparison on Day 7
    Statistical analysis description
    The comparison of C24 between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    82.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    63.36
         upper limit
    106.65
    Statistical analysis title
    C24 Comparison on Day 28
    Statistical analysis description
    The comparison of C24 between tacrolimus and tacrolmus prolonged release was assessed using an ANCOVA model on log-transformed pharmacokinetic parameters with treatment and organ transplant as fixed effects and age at baseline as continuous covariate. The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolmus prolonged release and its 90% CI are back-transformed to the raw scale and expressed as percentages.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    90.88
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    69.62
         upper limit
    118.64

    Secondary: Correlation between AUC24 & C24

    Close Top of page
    End point title
    Correlation between AUC24 & C24
    End point description
    The analysis population was the PKAS. Only participants with available C24 and AUC24 at each visit are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Days 1, 7 and 28 at predose, 1, 2, 4, 6, 12, 13, 14, 16, 18 and 24 hours postdose
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    18 [6]
    15
    Units: pearson correlation coefficient
    number (not applicable)
        Day 1
    0.82
    0.87
        Day 7
    0.87
    0.72
        Day 28
    0.88
    0.87
    Notes
    [6] - The number of participants for day 28=17.
    No statistical analyses for this end point

    Secondary: Number of Participants with Acute Rejections

    Close Top of page
    End point title
    Number of Participants with Acute Rejections
    End point description
    Rejection episodes/acute rejections were indicated by clinical and/or laboratory signs, and were classified according to their rejection specific treatment: •Spontaneously Resolving Acute Rejection: not treated with new or increased corticosteroid medication, antibodies or any other medication and resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Sensitive Acute Rejection: treated with new or increased corticosteroid medication only and which has resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Resistant Acute Rejection: did not resolve following treatment with corticosteroids; - Resolved with further treatment: any acute rejection with an end date AND a treatment other than corticosteroid used; - Unresolved with further treatment: any acute rejection with no end date AND a treatment other than corticosteroid used; - Unresolved with no further treatment: any acute rejection with no end date AND ONLY corticosteroid treatment was used. FAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    24
    20
    Units: participants
    number (not applicable)
        1. Any Acute Rejections
    7
    2
        1.a. Spontaneously Resolving Acute Rejection
    1
    0
        1.b. Corticosteroid Sensitive Acute Rejection
    6
    2
        1.c. Corticosteroid Resistant Acute Rejection
    0
    0
        1.c.1 Resolved with further treatment
    0
    0
        1.c.2 Unresolved with further treatment
    0
    0
        1.c.3 Unresolved with no further treatment
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Biopsy-proven Acute Rejection Episodes (BPARs)

    Close Top of page
    End point title
    Number of Participants with Biopsy-proven Acute Rejection Episodes (BPARs)
    End point description
    BPAR episodes were defined as acute rejection episodes confirmed by biopsy, and were classified according to their rejection specific treatment: •Spontaneously Resolving Acute Rejection: not treated with new or increased corticosteroid medication, antibodies or any other medication and resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Sensitive Acute Rejection: treated with new or increased corticosteroid medication only and which has resolved, irrespective of any tacrolimus dose changes; •Corticosteroid Resistant Acute Rejection: did not resolve following treatment with corticosteroids; - Resolved with further treatment: any acute rejection with an end date AND a treatment other than corticosteroid used; - Unresolved with further treatment: any acute rejection with no end date AND a treatment other than corticosteroid used; - Unresolved with no further treatment: any acute rejection with no end date AND ONLY corticosteroid treatment used. FAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    24
    20
    Units: participants
    number (not applicable)
        1. Biopsy proven acute rejections
    4
    1
        1.a. Spontaneously Resolving Acute Rejection
    1
    0
        1.b. Corticosteroid Sensitive Acute Rejection
    3
    1
        1.c. Corticosteroid Resistant Acute Rejection
    0
    0
        1.c.1 Resolved with further treatment
    0
    0
        1.c.2 Unresolved with further treatment
    0
    0
        1.c.3 Unresolved with no further treatment
    0
    0
    No statistical analyses for this end point

    Secondary: Severity of Biopsy Proven Acute Rejection Episodes

    Close Top of page
    End point title
    Severity of Biopsy Proven Acute Rejection Episodes
    End point description
    The severity of BPARs was categorized with specific criteria by organ: For kidney transplant participants, according to Banff ‘97 Diagnostic categories for renal allograft biopsies – Banff ’07 update (C4d deposition, Acute antibody-mediated rejection I, II, and III, Acute T cell mediated rejection IA, IB, IIA, IIB and III); for liver transplant participants, according to 1997 Banff Schema for Grading of Liver Allograft Rejection - Rejection Activity Index (mild, moderate, severe or indeterminate/borderline); for heart, according to Standardized Nomenclature of the International Society of Heart and Lung Transplantation - Standardised Cardiac Biopsy Grading: Acute Cellular Rejection 2004 (mild, moderate, severe). N is the number of participants analyzed by type of organ transplant in each arm. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    24
    20
    Units: participants
    number (not applicable)
        Kidney [N=12, 13]: C4d deposition
    0
    0
        Kidney [N=12, 13]: Antibody-mediated rejection I
    0
    0
        Kidney [N=12, 13]: Antibody-mediated rejection II
    0
    0
        Kidney [N=12, 13]: Antibody-mediated rejection III
    0
    0
        Kidney [N=12, 13]: T cell mediated rejection IA
    0
    0
        Kidney [N=12, 13]: T cell mediated rejection IB
    0
    0
        Kidney [N=12, 13]: T cell mediated rejection IIA
    0
    0
        Kidney [N=12, 13]: T cell mediated rejection IIB
    0
    0
        Kidney [N=12, 13]: T cell mediated rejection III
    0
    0
        Liver [N=8, 4]: Mild
    2
    1
        Liver [N=8, 4]: Moderate
    1
    0
        Liver [N=8, 4]: Severe
    1
    0
        Liver [N=8, 4]: Indeterminate or borderline
    0
    0
        Heart [N=4, 3]: Mild
    0
    0
        Heart [N=4, 3]: Moderate
    0
    0
        Heart [N=4, 3]: Severe
    0
    0
    No statistical analyses for this end point

    Secondary: Patient Survival

    Close Top of page
    End point title
    Patient Survival
    End point description
    Patient survival was defined as the time from first dose of study drug to the date of death from any cause. Since no participants died during the study, survival analysis was not conducted.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: days
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - There were no deaths.
    [8] - There were no deaths.
    No statistical analyses for this end point

    Secondary: Graft Survival

    Close Top of page
    End point title
    Graft Survival
    End point description
    Graft survival was defined as the time from the first dose of study drug to graft loss. Graft loss was defined as retransplantation, nephrectomy (in case of kidney transplantation), death or dialysis (in case of kidney transplantation) ongoing at end of study or at discontinuation, unless superseded by follow-up information. Since no participants experienced graft loss during the study, survival analysis was not conducted.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: days
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - There were no graft losses.
    [10] - There were no graft losses.
    No statistical analyses for this end point

    Secondary: Efficacy Failure

    Close Top of page
    End point title
    Efficacy Failure
    End point description
    Efficacy failure was defined as the composite of the following: death, graft loss, BPAR and unknown outcome. A participant was considered to have an unknown outcome if he/she did not have the event of interest (death, graft loss, BPAR) or did not have a study assessment prior to day 335. Three participants in the tacolimus group had efficacy failure due to an unknown outcome as these 3 participants discontinued early from the study. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    24
    20
    Units: participants
    number (not applicable)
        Graft loss
    0
    0
        BPAR
    4
    1
        Death
    0
    0
        Unknown
    3
    0
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 7 days after last dose of study drug in Part B (up to 53 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Tacrolimus (Part A + B)
    Reporting group description
    Participants received tacrolimus twice daily starting from day 1 for 4 weeks for in Part A, and continued to receive tacrolimus twice daily up to end of Part B of the study.

    Reporting group title
    Tacrolimus prolonged release (Part A + B)
    Reporting group description
    Participants received tacrolimus prolonged release once daily starting from day 1 for 4 weeks for in Part A, and continued to receive tacrolimus prolonged release once daily up to end of Part B of the study.

    Serious adverse events
    Tacrolimus (Part A + B) Tacrolimus prolonged release (Part A + B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 24 (62.50%)
    13 / 20 (65.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Device connection issue
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 24 (8.33%)
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    1 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain scan abnormal
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endoscopic retrograde cholangiopancreatography
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histology abnormal
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reversible posterior leukoencephalopathy syndrome
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Residual urine
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary fistula
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis bacterial
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis sapovirus
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tacrolimus (Part A + B) Tacrolimus prolonged release (Part A + B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 24 (91.67%)
    19 / 20 (95.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 24 (37.50%)
    6 / 20 (30.00%)
         occurrences all number
    9
    6
    Surgical and medical procedures
    Post procedural drainage
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papilloma
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Social circumstances
    Exposure to communicable disease
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Bloody discharge
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Pain
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
    3 / 20 (15.00%)
         occurrences all number
    4
    4
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Drug dispensing error
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Expired drug administered
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 20 (15.00%)
         occurrences all number
    3
    4
    Blood iron decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Blood phosphorus decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Blood urea increased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    2
    Body temperature increased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Heart rate decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Immunosuppressant drug level decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urine output decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pericardial effusion
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Tachycardia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 24 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    4
    11
    Epistaxis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Interstitial lung disease
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 20 (10.00%)
         occurrences all number
    5
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Sneezing
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 24 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    6
    5
    Leukopenia
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 24 (8.33%)
    4 / 20 (20.00%)
         occurrences all number
    2
    4
    Paraesthesia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Reversible posterior leukoencephalopathy syndrome
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Visual impairment
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 20 (10.00%)
         occurrences all number
    3
    4
    Abdominal pain lower
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Aphthous stomatitis
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    11 / 24 (45.83%)
    11 / 20 (55.00%)
         occurrences all number
    12
    19
    Dyspepsia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Lip oedema
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 24 (12.50%)
    4 / 20 (20.00%)
         occurrences all number
    4
    4
    Peritoneal effusion
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    5 / 24 (20.83%)
    5 / 20 (25.00%)
         occurrences all number
    8
    7
    Renal and urinary disorders
    Detrusor sphincter dyssynergia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cholestasis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Jaundice
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Night sweats
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Muscle spasms
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Osteopenia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Hyperuricaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Bronchopneumonia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Epstein-Barr viraemia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Epstein-Barr virus infection
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    2
    2
    Gastroenteritis viral
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    3
    3
    Rubella
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 24 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    4
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 20 (5.00%)
         occurrences all number
    4
    2

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2011
    This amendment was issued to change an inclusion criterion specific to heart transplant patients, to update the specifics regarding concomitant medications (antibody induction, mycophenolate mofetil [MMF], steroids) and prohibited concomitant medications, to change the emergency contact to clarify the safety reporting requirements.
    21 Oct 2013
    This amendment added the Part C extension to the study (particularly for Italy and Poland).
    13 May 2014
    This amendment added the Part C extension to the study (particularly for Czech Republic).
    28 Jun 2016
    This amendment added the Part C extension to the study for the United Kingdom.

    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA