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    Clinical Trial Results:
    A Phase II, Open-label, Multi-center Study to Compare the Pharmacokinetics of Tacrolimus in Stable Pediatric Allograft Recipients Converted from a Prograf® Based Immunosuppressive Regimen to a Tacrolimus Prolonged Release, Advagraf® Based Immunosuppressive Regimen, Including a Long-term Follow-up

    Summary
    EudraCT number
    2010-020925-42
    Trial protocol
    AT   FR   DE   BE   PL   CZ   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    19 May 2017
    First version publication date
    19 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PMR-EC-1206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01294020
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe, Ltd
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey Surrey, 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?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    28 Oct 2016
    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
    To compare the steady state area under the plasma concentration-time curve from time 0 to time 24 hours (AUC0-24h) of tacrolimus for tacrolimus prolonged release (Advagraf) with that of tacrolimus (Prograf) in stable pediatric allograft recipients after 1:1 (mg:mg) conversion from Prograf to Advagraf.
    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 fed ral, 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). After enrollment, participants entered a 30-day screening period in Part A of the study during which time they were maintained on their routine twice daily tacrolimus (commercial Prograf) based immunosuppressive regimen, as determined by the Investigator and as supplied by the local hospital pharmacy.
    Evidence for comparator
    -
    Actual start date of recruitment
    25 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    35
    Adolescents (12-17 years)
    46
    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
    Children aged 5 years to 16 years of age were enrolled in sites in 7 countries: Belgium, Czech Republic, Germany, 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
    Stable pediatric allograft recipients (children who previously received a single organ liver, kidney, heart, lung or intestinal transplantation [≥ 6 months post-transplant]) being treated with a tacrolimus based immunosuppressive regimen (≤ 3 months) who consented to enter this study and fulfilled all the eligibility criteria were enrolled.

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

    Arms
    Arm title
    Tacrolimus Prolonged Release (Part A)
    Arm description
    Participants converted from their routine tacrolimus based immunosuppressive regimen to tacrolimus as a study medication twice daily on day 1 and continued to receive treatment up to day 7. On day 8, participants switched to tacrolimus prolonged release once daily and received treatment up to day 14 in Part A of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus prolonged release
    Investigational medicinal product code
    FK506E
    Other name
    Advagraf, Astagraf XL, Graceptor, Prograf XL
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tacrolimus prolonged release (strengths of 0.5 mg, 1 mg, 3 mg, 5 mg) with the same daily dose (1:1, mg:mg) after being coverted from tacrolimus on day 8, with the dose maintained up to day 14 in Part A of the study. Tacrolimus prolonged release capsules were taken orally once daily only in the morning, on an empty stomach, or at least 1 hour before or 2 to 3 hours after a meal.

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    FK506
    Other name
    Prograf
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tacrolimus (strengths of 0.5 mg, 1 mg, 5 mg) with the same daily dose (1:1, mg:mg) as received during the 30-day screening period in Part A of the study. Tacrolimus capsules were taken orally twice daily, morning and evening, on an empty stomach or at least 1 hour before, or 2 to 3 hours after any meal.

    Number of subjects in period 1
    Tacrolimus Prolonged Release (Part A)
    Started
    81
    Treated with study drug
    81
    Completed
    78
    Not completed
    3
         Withdrawal of consent
    1
         Site staff could not cover the overnight visit
    1
         Adverse Event
    1
    Period 2
    Period 2 title
    Part B: Long-Term Follow-up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Tacrolimus Prolonged Release (Part B)
    Arm description
    After Part A, participants continued to receive tacrolimus prolonged release once daily from day 15 up to the end of Part B of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus prolonged release
    Investigational medicinal product code
    FK506E
    Other name
    Advagraf, Astagraf XL, Graceptor, Prograf XL
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continued to receive tacrolimus prolonged release (strengths of 0.5 mg, 1 mg, 3 mg, 5 mg) with the same daily dose (1:1, mg:mg) from day 15 up to the end of Part B of the study but could be adjusted on the basis of trough drug measurement results. Tacrolimus prolonged release capsules were taken orally once daily only in the morning, on an empty stomach, or at least 1 hour before or 2 to 3 hours after a meal.

    Number of subjects in period 2
    Tacrolimus Prolonged Release (Part B)
    Started
    78
    Completed
    76
    Not completed
    2
         Adverse Event
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus Prolonged Release (Part A)
    Reporting group description
    Participants converted from their routine tacrolimus based immunosuppressive regimen to tacrolimus as a study medication twice daily on day 1 and continued to receive treatment up to day 7. On day 8, participants switched to tacrolimus prolonged release once daily and received treatment up to day 14 in Part A of the study.

    Reporting group values
    Tacrolimus Prolonged Release (Part A) Total
    Number of subjects
    81 81
    Age categorical
    Units: Subjects
        5-7 years
    11 11
        8-10 years
    17 17
        11-13 years
    31 31
        14-16 years
    22 22
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.5 ± 2.87 -
    Gender categorical
    Units:
        Male
    47 47
        Female
    34 34
    Type of Organ Transplant
    Units: Subjects
        Kidney
    48 48
        Liver
    31 31
        Heart
    2 2
        Other (Lung, Intestine)
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus Prolonged Release (Part A)
    Reporting group description
    Participants converted from their routine tacrolimus based immunosuppressive regimen to tacrolimus as a study medication twice daily on day 1 and continued to receive treatment up to day 7. On day 8, participants switched to tacrolimus prolonged release once daily and received treatment up to day 14 in Part A 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 from day 15 up to the end of Part B of the study.

    Subject analysis set title
    Tacrolimus (Part A)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in the pharmacokinetic analysis set who received tacrolimus twice daily on day 1 up to day 7 in Part A of the study.

    Subject analysis set title
    Tacrolimus Prolonged Release (Part A)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in the pharmacokinetic analysis set who received tacrolimus prolonged release once daily from day 8 up to day 14 in Part A of the study.

    Subject analysis set title
    Tacrolimus Prolonged Release (Part A + B)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received tacrolimus prolonged release once daily from day 8 up to day 14 in Part A, and once daily from day 15 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 and Tacrolimus Prolonged Release

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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 and Tacrolimus Prolonged Release
    End point description
    The analysis population was the Pharmacokinetics Analysis Set (PKAS), which consisted of all participants who received at least 1 dose of study drug and who provided 2 complete pharmacokinetic profiles.
    End point type
    Primary
    End point timeframe
    Day 7 (for tacrolimus) and day 14 (for tacrolimus prolonged release) at predose and 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
    74
    74
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    159.133 ± 32.7
    153.8194 ± 29.3
    Statistical analysis title
    AUC24 (steady-state systemic exposure) Comparison
    Statistical analysis description
    The comparison of pharmacokinetic (PK) parameter AUC24 between tacrolimus and tacrolimus prolonged release was assessed with a mixed effects model on log-transformed PK parameters with treatment, organ transplant and age (continuous variable) at baseline as fixed effects and patient as random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=74.
    Comparison groups
    Tacrolimus Prolonged Release (Part A) v Tacrolimus (Part A)
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Geometric least squares (LS) mean ratio
    Point estimate
    96.66
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    92.31
         upper limit
    101.22
    Notes
    [1] - The difference of LS means of log-transformed PK parameters between tacrolimus and tacrolimus prolonged release and its 90% CI are back-transformed to the raw scale and are expressed as percentages.

    Secondary: Maximum Concentration (Cmax) of Tacrolimus and Tacrolimus Prolonged Release

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    End point title
    Maximum Concentration (Cmax) of Tacrolimus and Tacrolimus Prolonged Release
    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 prespecified in the protocol and is denoted as "99999."
    End point type
    Secondary
    End point timeframe
    Day 7 (for tacrolimus) and day 14 (for tacrolimus prolonged release) at predose and 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
    74
    74
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Morning
    11.792 ± 44.1
    11.048 ± 38.9
        Evening
    8.198 ± 40
    99999 ± 99999
    Statistical analysis title
    Cmax Comparison
    Statistical analysis description
    The comparison of pharmacokinetic parameter Cmax between tacrolimus and tacrolimus prolonged release was assessed with a mixed effects model on log-transformed PK parameters with treatment, organ transplant and age (continuous variable) at baseline as fixed effects and patient as random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=74.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    93.69
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    87.07
         upper limit
    100.81
    Notes
    [2] - The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolimus prolonged release and its 90% CI are back-transformed to the raw scale and are expressed as percentages. Morning Cmax in tacrolimus group was used for comparison with Cmax for participants in tacrolimus prolonged release group.

    Secondary: Trough Concentration (C12) for Tacrolimus

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    End point title
    Trough Concentration (C12) for Tacrolimus
    End point description
    The analysis population was the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 7, 12 hours after dosing
    End point values
    Tacrolimus (Part A)
    Number of subjects analysed
    69
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4.753 ± 36.2
    No statistical analyses for this end point

    Secondary: Trough Concentration (C24) for Tacrolimus and Tacrolimus Prolonged Release

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    End point title
    Trough Concentration (C24) for Tacrolimus and Tacrolimus Prolonged Release
    End point description
    The analysis population was the PKAS.
    End point type
    Secondary
    End point timeframe
    Days 7 and 14, 24 hours after dosing
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    74
    74
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4.955 ± 37.6
    4.479 ± 31.7
    Statistical analysis title
    C24 Comparison
    Statistical analysis description
    The comparison of pharmacokinetic parameter C24 between tacrolimus and tacrolimus prolonged release was assessed with a mixed effects model on log-transformed PK parameters with treatment, organ transplant and age (continuous variable) at baseline as fixed effects and patient as random effect. The number of participants analyzed is calculated by the system and cannot be changed; actual N=74.
    Comparison groups
    Tacrolimus (Part A) v Tacrolimus Prolonged Release (Part A)
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Geometric LS mean ratio
    Point estimate
    90.39
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    85
         upper limit
    96.13
    Notes
    [3] - The difference of LS means of log-transformed pharmacokinetic parameters between tacrolimus and tacrolimus prolonged release and its 90% CI are back-transformed to the raw scale and are expressed as percentages.

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

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    End point title
    Time to Attain Maximum Concentration (tmax) of Tacrolimus and Tacrolimus Prolonged Release
    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 prespecified in the protocol and is denoted as "99999."
    End point type
    Secondary
    End point timeframe
    Day 7 (for tacrolimus) and day 14 (for tacrolimus prolonged release) at predose and 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
    74
    74
    Units: hours
    median (full range (min-max))
        Morning
    1.0584 (0.9 to 6)
    1.9833 (0.917 to 24)
        Evening
    3.9667 (0 to 12)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Correlation between AUC24 and C24

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    End point title
    Correlation between AUC24 and 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
    Day 7 (for tacrolimus) and day 14 (for tacrolimus prolonged release) at predose and 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
    74
    74
    Units: Pearson correlation coefficient
        number (not applicable)
    0.84
    0.89
    No statistical analyses for this end point

    Secondary: Number of Participants with Acute Rejections

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    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. mFAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    79
    Units: participants
        1. Any Acute Rejections
    2
        1.a. Spontaneously Resolving Acute Rejection
    0
        1.b. Corticosteroid Sensitive Acute Rejection
    1
        1.c. Corticosteroid Resistant Acute Rejection
    1
        1.c.1 Resolved with further treatment
    1
        1.c.2 Unresolved with further treatment
    0
        1.c.3 Unresolved with no further treatment
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Biopsy Proven Acute Rejections (BPARs)

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    End point title
    Number of Participants with Biopsy Proven Acute Rejections (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. mFAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    79
    Units: participants
        1. Biopsy proven acute rejections
    1
        1.a. Spontaneously Resolving Acute Rejection
    0
        1.b. Corticosteroid Sensitive Acute Rejection
    0
        1.c. Corticosteroid Resistant Acute Rejection
    1
        1.c.1 Resolved with further treatment
    1
        1.c.2 Unresolved with further treatment
    0
        1.c.3 Unresolved with no further treatment
    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 (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 (mild, moderate, severe or indeterminate/borderline); for heart, according to Standardized Nomenclature of the International Society of Heart and Lung Transplantation (mild, moderate, severe). The analysis population was the modified Full Analysis Set (mFAS), which consisted of all participants who received at least 1 dose of tacrolimus prolonged release study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    79
    Units: participants
        Kidney: Antibody-mediated rejection I
    0
        Kidney: Antibody-mediated rejection II
    1
        Kidney:Antibody-mediated rejection III
    0
        Kidney:T cell mediated rejection IA
    0
        Kidney:T cell mediated rejection IB
    1
        Kidney:T cell mediated rejection IIA
    0
        Kidney:T cell mediated rejection IIB
    0
        Kidney:T cell mediated rejection III
    0
        Liver: Mild
    0
        Liver: Moderate
    0
        Liver: Severe
    0
        Liver: Indeterminate or borderline
    0
        Heart: Mild
    0
        Heart: Moderate
    0
        Heart: Severe
    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 tacrolimus as 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 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    0 [4]
    Units: days
        number (confidence interval 95%)
    ( to )
    Notes
    [4] - 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 tacrolimus as 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 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    0 [5]
    Units: days
        number (confidence interval 95%)
    ( to )
    Notes
    [5] - 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 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. The analysis population was the mFAS.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    79
    Units: participants
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (Part A)

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    End point title
    Number of Participants with Adverse Events (Part A)
    End point description
    Safety as 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 1 dose of any of the study drug (tacrolimus/tacrolimus prolonged release).
    End point type
    Secondary
    End point timeframe
    From first dose of tacrolimus up to 7 days after last dose of tacrolimus prolonged release in Part A (up to 21 days)
    End point values
    Tacrolimus (Part A) Tacrolimus Prolonged Release (Part A)
    Number of subjects analysed
    81
    79
    Units: participants
        AEs
    8
    14
        Drug-related AEs
    1
    2
        Deaths
    0
    0
        SAEs
    0
    0
        Drug-related SAEs
    0
    0
        Deaths Resulting from AEs
    0
    0
        AEs Leading to Permanent Discontinuation
    0
    0
        Drug-related AEs Leading to Permanent Discont.
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (Part B)

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    End point title
    Number of Participants with Adverse Events (Part B)
    End point description
    Safety as 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 mFAS.
    End point type
    Secondary
    End point timeframe
    From first dose of tacrolimus prolonged release in Part A up to 7 days after last dose of tacrolimus prolonged release in Part B (up to 55 weeks)
    End point values
    Tacrolimus Prolonged Release (Part A + B)
    Number of subjects analysed
    79
    Units: participants
        AEs
    67
        Drug-related AEs
    28
        Deaths
    0
        SAEs
    19
        Drug-related SAEs
    10
        Deaths Resulting from AEs
    0
        AEs Leading to Permanent Discontinuation
    1
        Drug-related AEs Leading to Permanent Discont.
    1
    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 (tacrolimus/tacrolimus prolonged release) in Part A up to last dose of study drug (tacrolimus prolonged release) in Part B of the study
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Tacrolimus
    Reporting group description
    Participants converted from their routine tacrolimus based immunosuppressive regimen to tacrolimus as a study medication twice daily on day 1 and continued to receive treatment up to day 7 in Part A of the study.

    Reporting group title
    Tacrolimus prolonged release
    Reporting group description
    Participants switched to tacrolimus prolonged release once daily on day 8 and received treatment up to day 14 in Part A and continued to receive tacrolimus prolonged release once daily from day 15 up to the end of Part B of the study.

    Serious adverse events
    Tacrolimus Tacrolimus prolonged release
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 81 (0.00%)
    19 / 79 (24.05%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Expired drug administered
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar haemorrhage
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Benign intracranial hypertension
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug interaction
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tacrolimus Tacrolimus prolonged release
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 81 (9.88%)
    66 / 79 (83.54%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Vena cava thrombosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Dermabrasion
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Skin papilloma
         subjects affected / exposed
    0 / 81 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Enanthema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 81 (0.00%)
    6 / 79 (7.59%)
         occurrences all number
    0
    8
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Agitation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Mood altered
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Chronic allograft nephropathy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    Contusion
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Drug dispensing error
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Drug dose omission
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Expired drug administered
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Joint sprain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 81 (0.00%)
    6 / 79 (7.59%)
         occurrences all number
    0
    6
    Blood iron decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Blood pressure increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Immunosuppressant drug level decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    0 / 81 (0.00%)
    9 / 79 (11.39%)
         occurrences all number
    0
    9
    Oropharyngeal pain
         subjects affected / exposed
    0 / 81 (0.00%)
    5 / 79 (6.33%)
         occurrences all number
    0
    5
    Pharyngeal oedema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Leukocytosis
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Leukopenia
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Lymphadenitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 79 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Nervous system disorders
    Clonus
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Epilepsy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 81 (2.47%)
    11 / 79 (13.92%)
         occurrences all number
    2
    14
    Loss of consciousness
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Syncope vasovagal
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Eye disorders
    Chorioretinal atrophy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Macular degeneration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Papilloedema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 81 (1.23%)
    5 / 79 (6.33%)
         occurrences all number
    1
    7
    Aphthous stomatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    0 / 81 (0.00%)
    11 / 79 (13.92%)
         occurrences all number
    0
    17
    Gastritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Odynophagia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 81 (1.23%)
    8 / 79 (10.13%)
         occurrences all number
    1
    10
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Liver disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Cold sweat
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 79 (1.27%)
         occurrences all number
    1
    1
    Eczema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Ephelides
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Intertrigo
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Photodermatosis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Pityriasis rosea
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Scar pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 79 (1.27%)
         occurrences all number
    1
    1
    Subcutaneous nodule
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 79 (2.53%)
         occurrences all number
    1
    3
    Sever's disease
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Tendinous contracture
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Hyperlipidaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Bronchitis
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    4
    Cystitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 81 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    4
    Gastroenteritis viral
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 81 (0.00%)
    6 / 79 (7.59%)
         occurrences all number
    0
    11
    Oral fungal infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 81 (1.23%)
    4 / 79 (5.06%)
         occurrences all number
    1
    4
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    2 / 81 (2.47%)
    8 / 79 (10.13%)
         occurrences all number
    2
    12
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Purulent discharge
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Rhinitis
         subjects affected / exposed
    1 / 81 (1.23%)
    5 / 79 (6.33%)
         occurrences all number
    1
    5
    Rotavirus infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Scarlet fever
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 81 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    5
    Tracheitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Tracheobronchitis mycoplasmal
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    5 / 79 (6.33%)
         occurrences all number
    1
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2013
    This amendment added trough levels of tacrolimus as an inclusion factor, and updated details of study administration.
    04 Nov 2013
    This amendment added the Part C extension to the study (particularly for Italy and Poland).
    23 Apr 2014
    This amendment added the Part C extension to the study (particularly for Germany and Czech Republic).
    01 Dec 2014
    The protocol was reissued to combine all the individual country-specific amendments into 1 combined Country Protocol Amendment for Italy, Poland, German and Czech Republic.
    28 Jun 2016
    This amendment added UK sites to Part C of the study to comply with a UK-specific requirement.

    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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