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    Clinical Trial Results:
    A Multicentre, Open-label, Pharmacokinetic Study of Modigraf® (Tacrolimus Granules) in de Novo Paediatric Allograft Recipients

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2009-012258-19
    Trial protocol
    		 ES   GB   DE   BE   FR  
    Global end of trial date
    03 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2016
    First version publication date
    29 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F506-CL-0403
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01371331
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: OPTION
    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
    03 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the pharmacokinetics (PK) of tacrolimus following oral administration of Modigraf, after the first oral dose and at steady state in pediatric participants undergoing de novo allograft 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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    17
    Children (2-11 years)
    34
    Adolescents (12-17 years)
    1
    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
    		 This multicenter study was conducted at 10 contracted sites in a total of 6 countries including United Kingdom (UK) (1 site), Spain (3 sites), Germany (2 sites), Belgium (1 site), Poland (1 site) and France (2 sites).

    Pre-assignment
    Screening details
    		 Eligibility was determined through screening assessments; medical history, vital signs, body weight, physical examination, and clinical laboratory tests.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was an open-label study, blinding was not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Heart Transplant
    Arm description
    		 This arm consisted of heart transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Modigraf®
    Investigational medicinal product code
    FK506
    Other name
    tacrolimus granules
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Total initial daily dose of 0.3 mg/kg/day (0.15 mg/kg twice daily (BID) oral suspension) for all transplant recipients for treatment duration of 14 days (+-3 days). The first dose of 0.15 mg/kg of tacrolimus was to be administered within 24 hours (h) after reperfusion (this period may have been extended up to 5 days for heart transplant recipients. Subsequent oral tacrolimus doses were adjusted based on clinical evidence of efficacy and occurrence of adverse events (AEs), and observing the following recommended whole blood trough level range of 5 to 20 ng/mL.

    Arm title
    		 Liver Transplant
    Arm description
    		 This arm consisted of liver transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Modigraf®
    Investigational medicinal product code
    FK506
    Other name
    tacrolimus granules
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Total initial daily dose of 0.3 mg/kg/day (0.15 mg/kg twice daily (BID) oral suspension) for all transplant recipients for treatment duration of 14 days (+-3 days). The first dose of 0.15 mg/kg of tacrolimus was to be administered within 24 hours (h) after reperfusion (this period may have been extended up to 5 days for heart transplant recipients. Subsequent oral tacrolimus doses were adjusted based on clinical evidence of efficacy and occurrence of adverse events (AEs), and observing the following recommended whole blood trough level range of 5 to 20 ng/mL.

    Arm title
    		 Kidney Transplant
    Arm description
    		 This arm consisted of kidney transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Modigraf®
    Investigational medicinal product code
    FK506
    Other name
    tacrolimus granules
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Total initial daily dose of 0.3 mg/kg/day (0.15 mg/kg twice daily (BID) oral suspension) for all transplant recipients for treatment duration of 14 days (+-3 days). The first dose of 0.15 mg/kg of tacrolimus was to be administered within 24 hours (h) after reperfusion (this period may have been extended up to 5 days for heart transplant recipients. Subsequent oral tacrolimus doses were adjusted based on clinical evidence of efficacy and occurrence of adverse events (AEs), and observing the following recommended whole blood trough level range of 5 to 20 ng/mL.

    Number of subjects in period 1
    		Heart Transplant Liver Transplant Kidney Transplant
    Started
    17
    20
    15
    Completed
    17
    17
    12
    Not completed
    0
    3
    3
         Withdrawal of Consent
    -
    -
    2
         Medication Therapy
    -
    1
    -
         Pharmacokinetic (PK) profile 1 not completed
    -
    -
    1
         Took prohibited medication in the trial
    -
    1
    -
         Intolerable Adverse Event (AE)
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Heart Transplant
    Reporting group description
    		 This arm consisted of heart transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Liver Transplant
    Reporting group description
    		 This arm consisted of liver transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Kidney Transplant
    Reporting group description
    		 This arm consisted of kidney transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group values
    		 Heart Transplant Liver Transplant Kidney Transplant Total
    Number of subjects
    		 17 20 15
    Age categorical
    Units: Subjects
    Age continuous
    Age values were based on the Safety Analysis Set (SAF). The SAF consisted of all enrolled participants who took at least 1 dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 5.2 ± 4.2 2.6 ± 3.2 5.4 ± 3 -
    Gender categorical
    Gender values were based on the SAF.
    Units:
        Male
    		 13 10 12 35
        Female
    		 4 10 3 17

    End points

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    End points reporting groups
    Reporting group title
    Heart Transplant
    Reporting group description
    		 This arm consisted of heart transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Liver Transplant
    Reporting group description
    		 This arm consisted of liver transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Kidney Transplant
    Reporting group description
    		 This arm consisted of kidney transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Subject analysis set title
    Overall Participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All trial participants (heart, liver, kidney transplant recipients).

    Primary: Area under the plasma concentration-time curve for a dosing interval (AUCtau) of tacrolimus

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    End point title
    		 Area under the plasma concentration-time curve for a dosing interval (AUCtau) of tacrolimus [1]
    End point description
    The study analysis population for this endpoint consisted of the pharmacokinetic (PK) analysis set (PKAS). The PKAS included all participants from the Safety Analysis Set (SAF) population who provided two complete PK profiles (on Day 1, after the first dose of tacrolimus after transplantation and at Day 7). The SAF consisted of all participants who took at least 1 dose of study medication. AUCtau was calculated using the trapezoidal rule. All analyses were performed by type of organ transplant (liver, kidney and heart transplant) and overall. In the case of a combined liver and kidney transplant the participant was counted in the liver transplant group only.
    End point type
    Primary
    End point timeframe
    Day 1 post transplant (blood samples were collected before dosing at (0 hours) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing) and Day 7 (before dosing (0h) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing.) (+/- 7 days).
    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: Statistical analysis not applicable, only descriptive statistics available for this primary endpoint.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant Overall Participants
    Number of subjects analysed
    12
    14
    12
    38
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1
    224.13 ± 114.3
    210.56 ± 84.01
    97.4 ± 36.77
    179.11 ± 99.81
        Day 7
    165.17 ± 39.12
    195.08 ± 94.63
    208.32 ± 68.75
    189.81 ± 72.97
    No statistical analyses for this end point

    Primary: Maximum concentration (Cmax) of tacrolimus

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    End point title
    		 Maximum concentration (Cmax) of tacrolimus [2]
    End point description
    The study analysis population for this endpoint consisted of the PKAS. All analyses were performed by type of organ transplant (liver, kidney and heart transplant) and overall. In the case of a combined liver and kidney transplant the participant was counted in the liver transplant group only.
    End point type
    Primary
    End point timeframe
    Day 1 post transplant (blood samples were collected before dosing at (0 hours) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing) and Day 7 (before dosing (0h) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing.) (+/- 7 days).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis not applicable, only descriptive statistics available for this primary endpoint.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant Overall Participants
    Number of subjects analysed
    12
    14
    12
    38
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    45.61 ± 19.55
    25.11 ± 10.78
    18.04 ± 8.1
    29.35 ± 17.55
        Day 7
    32.69 ± 9.78
    30.52 ± 19.35
    36.63 ± 13.97
    33.14 ± 14.99
    No statistical analyses for this end point

    Primary: Time to attain Cmax (Tmax) of tacrolimus

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    End point title
    		 Time to attain Cmax (Tmax) of tacrolimus [3]
    End point description
    The study analysis population for this endpoint consisted of the PKAS. All analyses were performed by type of organ transplant (liver, kidney and heart transplant) and overall. In the case of a combined liver and kidney transplant the participant was counted in the liver transplant group only.
    End point type
    Primary
    End point timeframe
    Day 1 post transplant (blood samples were collected before dosing at (0 hours) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing) and Day 7 (before dosing (0h) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing.) (+/- 7 days).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis not applicable, only descriptive statistics available for this primary endpoint.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant Overall Participants
    Number of subjects analysed
    12
    14
    12
    38
    Units: hours (h)
    median (full range (min-max))
        Day 1
    1 (0.5 to 12)
    2.017 (0.98 to 8.1)
    1.992 (0.97 to 4.03)
    2 (0.5 to 12)
        Day 7
    0.775 (0.5 to 2)
    1.5 (0.5 to 4)
    1 (0.48 to 2.08)
    1 (0.48 to 4)
    No statistical analyses for this end point

    Primary: Plasma concentration at the end of a dosing interval (Ctrough) of tacrolimus

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    End point title
    		 Plasma concentration at the end of a dosing interval (Ctrough) of tacrolimus [4]
    End point description
    The study analysis population for this endpoint consisted of the PKAS. All analyses were performed by type of organ transplant (liver, kidney and heart transplant) and overall. In the case of a combined liver and kidney transplant the participant was counted in the liver transplant group only.
    End point type
    Primary
    End point timeframe
    Day 1 post transplant (blood samples were collected before dosing at (0 hours) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing) and Day 7 (before dosing (0h) and at 0.5h, 1h, 2h, 4h, 8h and 12h after dosing.) (+/- 7 days).
    Notes
    [4] - 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: Statistical analysis not applicable, only descriptive statistics available for this primary endpoint.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant Overall Participants
    Number of subjects analysed
    12
    14
    12
    38
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    12.6 ± 13.4
    13.41 ± 7.11
    3.54 ± 1.45
    10.04 ± 9.59
        Day 7
    7.57 ± 1.8
    9.71 ± 4.03
    8.92 ± 3.59
    8.78 ± 3.36
    No statistical analyses for this end point

    Secondary: Number of participants with rejection episodes

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    End point title
    		 Number of participants with rejection episodes
    End point description
    Analysis population consisted of the SAF. A BPAR episode was defined as any acute rejection episode confirmed by biopsy. SRAR: rejection episode that was not treated with new/increased corticosteroid medication, antibodies/any other medication and resolved, irrespective of dose changes. CSAR: rejection episode treated with new/increased corticosteroid medication only and resolved, irrespective of dose changes. CRAR: rejection episode that did not resolve following treatment with corticosteroids (included rejection episodes not treated with corticosteroids first, only with antibodies). AR and BPAR episodes that resolved with further treatment, were unresolved with further treatment and were unresolved with no further treatment were classified under CRARs. Other: rejection episode that cannot be classified into any of the above.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1 (within 24 hours prior to treatment)) and up to Day 14 post treatment.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant
    Number of subjects analysed
    17
    20
    15
    Units: Participants with rejection episodes
        All Rejections
    2
    3
    0
        Biopsy-proven acute rejections (BPARs)
    1
    3
    0
        Non-Biopsy-proven acute rejections (nonBPARs)
    1
    0
    0
        Any Acute Rejections (ARs)
    2
    3
    0
        Spontaneously resolving Acute Rejections (SRAR)
    1
    1
    0
        Corticosteroid Sensitive Acute Rejections (CSAR)
    1
    2
    0
        Corticosteroid Resistant Acute Rejections (CRAR)
    0
    0
    0
        Any AR - Resolved with further treatment
    0
    0
    0
        Any AR - Unresolved with further treatment
    0
    0
    0
        Any AR - Unresolved with no further treatment
    0
    0
    0
        BPAR - Spontaneously resolving Acute Rejections
    1
    1
    0
        BPAR - Corticosteroid Sensitive Acute Rejections
    0
    2
    0
        BPAR - Corticosteroid Resistant Acute Rejections
    0
    0
    0
        BPAR - Resolved with further treatment
    0
    0
    0
        BPAR - Unresolved with further treatment
    0
    0
    0
        BPAR - Unresolved with no further treatment
    0
    0
    0
        Other acute rejections
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Severity of BPAR

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    End point title
    		 Severity of BPAR
    End point description
    Analysis population consisted of the safety analysis set (SAF). The histological evaluation of the biopsy (to grade BPARs) was performed by the local histopathologist following the Histological Grading of Liver Biopsies for Rejection, the Banff 97 diagnostic categories for renal allograft biopsies – Banff ’07 update or the standardised nomenclature of the International Society of Heart and Lung Transplantation (ISHLT). The Rejection Activity Index (RAI) Represents the Sum of Grades (0-3) for portal Inflammation, bile duct inflammation and venular inflammation as collected in the eCRF. The Liver RAI ranges from 0-9. “9999” will be used in place of “N/A” when a category is not applicable to a specific arm/population due to the EudraCT system limitation of only allowing for numerical values.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1 (within 24 hours prior to treatment)) and up to Day 14 post treatment.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant
    Number of subjects analysed
    17
    20
    15
    Units: Participants with rejection episodes
        Heart - Mild (Grade 1 Rejection (R))
    1
    9999
    9999
        Heart - Moderate (Grade 2 R)
    0
    9999
    9999
        Heart - Severe (Grade 3 R)
    0
    9999
    9999
        Liver RAI score - 0-2 (No Rejection)
    9999
    0
    9999
        Liver RAI score - 3 (Borderline Rejection)
    9999
    0
    9999
        Liver RAI score - 4-5 (Mild Rejection)
    9999
    1
    9999
        Liver RAI score - 6-7 (Moderate Rejection)
    9999
    2
    9999
        Liver RAI score - 8-9 (Severe Rejection)
    9999
    0
    9999
        Kidney - C4d deposition
    9999
    9999
    0
        Kidney - antibody-mediated rejection I
    9999
    9999
    0
        Kidney - antibody-mediated rejection II
    9999
    9999
    0
        Kidney - antibody-mediated rejection III
    9999
    9999
    0
        Kidney - T cell mediated rejection IA
    9999
    9999
    0
        Kidney - T cell mediated rejection IB
    9999
    9999
    0
        Kidney - T cell mediated rejection IIA
    9999
    9999
    0
        Kidney - T cell mediated rejection IIB
    9999
    9999
    0
        Kidney - T cell mediated rejection III
    9999
    9999
    0
    No statistical analyses for this end point

    Secondary: Patient survival

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    End point title
    		 Patient survival
    End point description
    The study analysis population for this endpoint consisted of the SAF. Patient survival was defined as any participant known to be alive at Study Week 2.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1 (within 24 hours prior to treatment)) and up to Day 14 post treatment.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant
    Number of subjects analysed
    17
    20
    15
    Units: Participants
        Deaths
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Graft survival

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    End point title
    		 Graft survival
    End point description
    The study analysis population for this endpoint consisted of the SAF. Graft survival was defined as any participant who did not experience graft failure during the study. Graft failure was defined as re-transplantation, nephrectomy, requiring ongoing dialysis, or death. The date of graft failure was the earliest date of any of these events. Kidney transplanted participants who underwent a nephrectomy or who required ongoing dialysis were counted as participants with graft failure with the date of nephrectomy or the date of started dialysis as date of event.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1 (within 24 hours prior to treatment)) and up to Day 14 post treatment.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant
    Number of subjects analysed
    17
    20
    15
    Units: Participants
        Graft loss
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events (AEs)

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    End point title
    		 Number of participants with adverse events (AEs)
    End point description
    The study analysis population for this endpoint consisted of the SAF. An AE was defined as any untoward medical occurrence in a subject administered a study drug and which did not necessarily have a causal relationship with treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug. A treatment emergent adverse event (TEAE) was defined as an AE observed after investigational drug administration.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after the final intake of study medication.
    End point values
    		 Heart Transplant Liver Transplant Kidney Transplant
    Number of subjects analysed
    17
    20
    15
    Units: Participants
        Any TEAE
    14
    20
    12
        Drug-related TEAEs
    10
    18
    6
        Deaths
    0
    0
    0
        Serious TEAEs
    4
    9
    4
        Drug-related Serious TEAEs
    1
    5
    2
        Deaths Resulting from AEs
    0
    0
    0
        TEAEs Leading to Discontinuation of Study Drug
    0
    1
    0
        Drug-related TEAEs Leading to Disc. of Study Drug
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after the final intake of study medication.
    Adverse event reporting additional description
    A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death, is life threatening, results in persistent or significant disability/incapacity, Results in congenital anomaly, or birth defect, requires inpatient hospitalisation or leads to prolongation of hospitalisation, or other medically important events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Heart Transplant
    Reporting group description
    		 This arm consisted of heart transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Liver Transplant
    Reporting group description
    		 This arm consisted of liver transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Reporting group title
    Kidney Transplant
    Reporting group description
    		 This arm consisted of kidney transplant recipients that received Modigraf® (tacrolimus granules) based immunosuppressive treatment regimen post-operatively. Participants received daily dose of oral Modigraf® 0.3 mg/kg/day (given in two doses, 0.15 mg/kg twice daily).

    Serious adverse events
    		 Heart Transplant Liver Transplant Kidney Transplant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
    9 / 20 (45.00%)
    4 / 15 (26.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural bile leak
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Toxicity to various agents
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (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
    Intra-abdominal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Mechanical ileus
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Hepatobiliary disorders
    Hepatic artery occlusion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Hepatic artery thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Portal vein thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Respiratory, thoracic and mediastinal disorders
    Diaphragmatic paralysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (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
    Pneumothorax
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (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
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Renal impairment
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Heart Transplant Liver Transplant Kidney Transplant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 17 (82.35%)
    20 / 20 (100.00%)
    12 / 15 (80.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 17 (11.76%)
    9 / 20 (45.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    10
    2
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Device occlusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Face oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Irritability
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    4
    Reproductive system and breast disorders
    Penile discharge
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Penile erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Penile pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Scrotal oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Bronchospasm
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Diaphragmatic paralysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypopnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory distress
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Delirium tremens
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Withdrawal syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Antithrombin III decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Drug level below therapeutic
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Prothrombin time shortened
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Urine output decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    Complications of transplanted liver
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    Contusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Overdose
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Post procedural bile leak
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Procedural hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural site reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Scrotal haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Toxicity to various agents
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Transplant failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Wound dehiscence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Convulsion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 20 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    3
    Coombs positive haemolytic anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Splenic infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    3
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Ascites
         subjects affected / exposed
    0 / 17 (0.00%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 20 (10.00%)
    5 / 15 (33.33%)
         occurrences all number
    2
    2
    5
    Gastric haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    Haematemesis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Lip dry
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    3
    6
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic artery stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Portal vein stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Skin lesion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Nephropathy
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Oliguria
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Polyuria
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure acute
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Renal impairment
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Renal injury
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Bacterial infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Fungaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Infectious peritonitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Skin bacterial infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Wound infection pseudomonas
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 20 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    4
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 20 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    2
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 20 (5.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    1
    2
    Hyponatraemia
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 20 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Hypophagia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Metabolic acidosis
         subjects affected / exposed
    0 / 17 (0.00%)
    6 / 20 (30.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    6
    0
    Metabolic alkalosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2011
    The substantial Amendment 1.0 was issued to update contact details of the qualified person for pharmacovigilance and to update the list of excluded concomitant medication by allowing amlodipine as concomitant medication. In addition, it was specified that excluded concomitant medication was prohibited throughout the 2-week study and 7 days prior to the first dose of Modigraf and not prior to study. This substantial amendment had no consequences for the evaluation of data, for patients already included in the study and for the patient information and informed consent (IC).

    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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