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    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   BE   PL   IT   FR  
    Global end of trial date
    21 Apr 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Nov 2021
    First version publication date
    13 Nov 2017
    Other versions
    		 v1
    Version creation reason

    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
    Final
    Date of interim/final analysis
    21 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2021
    Was the trial ended prematurely?
    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
    United Kingdom: 14
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Poland: 7
    Worldwide total number of subjects
    44
    EEA total number of subjects
    30
    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

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    Recruitment
    Recruitment details
    		 Part C was conducted only to provide Advagraf to pediatric subjects without interruption until they withdrew from the study or reached age 18 years which ever occurred first as Advagraf is not yet approved for pediatric use. Only safety data was collected in Part C, efficacy evaluation was not performed as this was not a study objective.

    Pre-assignment
    Screening details
    		 Eligible pediatric subjects(<16 years of age) undergoing primary heart, kidney or liver transplantation(de novo allograft) were enrolled and were randomized to either tacrolimus/tacrolimus prolonged release on 1:1 basis stratified by organ and center. Study conducted in-France(Part A,B), and Czech Republic, Italy, Poland, UK(Part A, B, C).

    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
    		 Subjects 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
    Subjects 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
    		 Subjects 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
    Subjects 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 B)
    Arm description
    		 After Part A, subjects 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
    Subjects 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, subjects continued to receive tacrolimus prolonged release twice 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
    Subjects 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 B) Tacrolimus Prolonged Release (Part B)
    Started
    23
    20
    Treated with Study Drug
    23
    20
    Completed
    21
    20
    Not completed
    2
    0
         Adverse Event
    1
    -
         Noncompliance with scheduled visits
    1
    -
    Period 3
    Period 3 title
    Part C
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tacrolimus Prolonged Release (Part C)
    Arm description
    		 After Part B, eligible subjects continued to receive tacrolimus prolonged release capsule per investigator's opinion until tacrolimus prolonged release became available to the subjects for commercial use, or the subjects discontinued, or subjects reached to 18 years of age whichever was the earliest (up to 3 years 11 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Subjects 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 occurrence of adverse events and blood trough level ranges on plus/minus 30 days of clinical visits.

    Number of subjects in period 3 [1]
    		Tacrolimus Prolonged Release (Part C)
    Started
    12
    Completed
    6
    Not completed
    6
         Death
    1
         Miscellaneous
    3
         Withdrawal by Subject
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible subjects from Part B entered Part C.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus (Part A)
    Reporting group description
    		 Subjects 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
    		 Subjects 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

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    End points reporting groups
    Reporting group title
    Tacrolimus (Part A)
    Reporting group description
    		 Subjects 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
    		 Subjects 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 B)
    Reporting group description
    		 After Part A, subjects 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, subjects continued to receive tacrolimus prolonged release twice daily for up to 48 weeks in Part B of the study.
    Reporting group title
    Tacrolimus Prolonged Release (Part C)
    Reporting group description
    		 After Part B, eligible subjects continued to receive tacrolimus prolonged release capsule per investigator's opinion until tacrolimus prolonged release became available to the subjects for commercial use, or the subjects discontinued, or subjects reached to 18 years of age whichever was the earliest (up to 3 years 11 months).

    Subject analysis set title
    Tacrolimus (Part A+B)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects 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
    Subjects 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

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    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 subjects 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 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
    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

    Primary: Number of Subjects with Adverse Events

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    End point title
    		 Number of Subjects with Adverse Events [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 subjects 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), From first dose of study in Part C up to 7 days after last dose in Part C (up to 3 years 11 months)
    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: 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.
    End point values
    		 Tacrolimus Prolonged Release (Part C) Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    12
    24
    20
    Units: subjects
    number (not applicable)
        TEAEs
    10
    23
    19
        Drug-related AEs
    5
    15
    14
        Deaths
    1
    0
    0
        SAEs
    8
    15
    13
        Drug-related SAEs
    4
    9
    10
        Deaths Resulting from AEs
    0
    0
    0
        AEs Leading to Discontinuation of Study Drug
    0
    1
    0
        Drug-related AEs Leading to Discont. of Study Drug
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Tacrolimus

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    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 subjects received only one dose in the morning, and therefore is denoted as "99999." One subject 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 subjects 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

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    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 subjects received only one dose in the morning, and therefore is denoted as "99999." One subject 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 subjects for day 1=14.
    No statistical analyses for this end point

    Secondary: Trough Concentration (C12) for Tacrolimus

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    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: Combined outcome measure data is presented for tacrolimus and tacrolimus prolonged release by using subject analysis set for Parts A and B.
    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

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    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 subjects 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

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    End point title
    		 Correlation between AUC24 & C24
    End point description
    The analysis population was the PKAS. Only subjects 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 subjects for day 28=17.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Acute Rejections

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    End point title
    		 Number of Subjects 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 7 years 5 months
    End point values
    		 Tacrolimus Prolonged Release (Part C) Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    12
    24
    20
    Units: participants
    number (not applicable)
        1. Any Acute Rejections
    3
    7
    2
        1.a. Spontaneously Resolving Acute Rejection
    0
    1
    0
        1.b. Corticosteroid Sensitive Acute Rejection
    0
    6
    2
        1.c. Corticosteroid Resistant Acute Rejection
    0
    0
    0
        1.c.1 Resolved with further treatment
    3
    0
    0
        1.c.2 Unresolved with further treatment
    0
    0
    0
        1.c.3 Unresolved with no further treatment
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects 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: subjects
    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

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    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 subjects 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: subjects
    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

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    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 subjects 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

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    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 subjects 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

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    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 subject 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 subjects in the tacolimus group had efficacy failure due to an unknown outcome as these 3 subjects discontinued early from the study. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Up to 7 years 5 months
    End point values
    		 Tacrolimus Prolonged Release (Part C) Tacrolimus (Part A+B) Tacrolimus prolonged release (Part A+B)
    Number of subjects analysed
    12
    24
    20
    Units: subjects
    number (not applicable)
        Graft loss
    0
    0
    0
        BPAR
    0
    4
    1
        Death
    1
    0
    0
        Unknown
    0
    3
    0
    No statistical analyses for this end point

    Adverse events

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    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), From first dose of study in Part C up to 7 days after last dose in Part C (up to 3 years 11 months)
    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
    		 Subjects 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 C)
    Reporting group description
    		 After Part B, eligible subjects continued to receive tacrolimus prolonged release capsule per investigator's opinion until tacrolimus prolonged release became available to the subjects for commercial use, or the subjects discontinued, or subjects reached to age of 18 years, whichever was the earliest (up to 3 years 11 months).

    Reporting group title
    Tacrolimus prolonged release (Part A + B)
    Reporting group description
    		 Subjects 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 C) Tacrolimus prolonged release (Part A + B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 24 (62.50%)
    7 / 12 (58.33%)
    13 / 20 (65.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 12 (16.67%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 12 (25.00%)
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain scan abnormal
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endoscopic retrograde cholangiopancreatography
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Histology abnormal
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Device connection issue
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital ectodermal dysplasia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reversible posterior leukoencephalopathy syndrome
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary fistula
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Residual urine
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis bacterial
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis sapovirus
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    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 C) Tacrolimus prolonged release (Part A + B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 24 (91.67%)
    6 / 12 (50.00%)
    19 / 20 (95.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papilloma
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 24 (37.50%)
    0 / 12 (0.00%)
    6 / 20 (30.00%)
         occurrences all number
    9
    0
    6
    Peripheral coldness
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Surgical and medical procedures
    Post procedural drainage
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    4
    0
    1
    General disorders and administration site conditions
    Bloody discharge
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    Pain
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    2
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    4
    0
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Social circumstances
    Exposure to communicable disease
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 12 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    4
    0
    11
    Epistaxis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Interstitial lung disease
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    Pleural effusion
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    5
    0
    2
    Sneezing
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    3
    0
    4
    Blood iron decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Blood phosphorus decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    2
    Heart rate decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Immunosuppressant drug level decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    Urine output decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Injury, poisoning and procedural complications
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Drug dispensing error
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    2
    Expired drug administered
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Wrist fracture
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 12 (8.33%)
    4 / 20 (20.00%)
         occurrences all number
    2
    1
    4
    Paraesthesia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Reversible posterior leukoencephalopathy syndrome
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 12 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    6
    0
    5
    Leukopenia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    0
    1
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    4
    Abdominal pain lower
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    Aphthous stomatitis
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    4
    0
    1
    Constipation
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    11 / 24 (45.83%)
    0 / 12 (0.00%)
    11 / 20 (55.00%)
         occurrences all number
    12
    0
    19
    Gastritis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Lip oedema
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    4
    0
    4
    Peritoneal effusion
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    5 / 24 (20.83%)
    0 / 12 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    8
    0
    7
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    Biliary dilatation
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Cholestasis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Jaundice
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    0
    1
    2
    Night sweats
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Detrusor sphincter dyssynergia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    3
    Muscle spasms
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    Osteopenia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    2
    Bronchopneumonia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    1
    Epididymitis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Epstein-Barr viraemia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    Epstein-Barr virus infection
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 12 (8.33%)
    2 / 20 (10.00%)
         occurrences all number
    2
    1
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    Rhinitis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    3
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Rubella
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 12 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    4
    0
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    4
    0
    2
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Anorexia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 12 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 12 (8.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    2
    Hyponatraemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 12 (8.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    1

    More information

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    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.
    05 May 2020
    This amendment added for Part C to update the sponsor contact details, schedule of assessments. Country-specific amendments for Italy, Poland and the Czech Republic were also prepared.
    06 May 2020
    This amendment added for Part C to update the sponsor contact details, schedule of assessments. Country-specific amendment for UK was also prepared.

    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
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    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.

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