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    Clinical Trial Results:
    A PHASE II, OPEN LABEL, PARALLEL GROUP, MULTI-CENTER STUDY TO COMPARE THE PHARMACOKINETICS OF TACROLIMUS IN ADULT SUBJECTS UNDERGOING PRIMARY ALLOGRAFT TRANSPLANTATION RECEIVING AN ADVAGRAF OR PROGRAF BASED IMMUNOSUPPRESSIVE REGIMEN, INCLUDING A LONG-TERM FOLLOW-UP

    Summary
    EudraCT number
    2010-019859-21
    Trial protocol
    AT   GB   IT   BE  
    Global end of trial date
    15 Nov 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Mar 2016
    First version publication date
    28 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PMR-EC-1501
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01332201
    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
    Final
    Date of interim/final analysis
    15 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the systemic exposure (AUC0-24h) of tacrolimus for Advagraf versus Prograf after the first dose and following repeated administration in patients undergoing primary heart, lung, pancreas (including simultaneous pancreas kidney (SPK)) transplantation.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    The Investigational Medicinal Products (IMP) Advagraf and Prograf were provided by the Sponsor. Antibodies (Anti-thymocyte globulin (ATG) was recommended), Mycophenolate Mofetil (MMF) and corticosteroids were not considered IMP in this study and were not provided by the Sponsor, but were provided by the local hospital pharmacy. Antibody Induction: the first dose of antibody induction therapy was to be given intravenously (IV) within 24 hours after skin closure. The initial dose and any later dose adjustments followed the routine practice of the center. The recommended dosing regimen for MMF was as follows: a loading dose of 1g of MMF given pre-operatively. The first post-operative dose of MMF administered within 72 hours following reperfusion. The daily dose of 2g given orally and split into two doses (equals 1g twice daily) for the first 14 days. Thereafter the daily dose was reduced to 1g given in two doses (equals 0.5g twice daily). From day 42 the dose of MMF was in accordance with the routine practice of the center. Corticosteroids: day -3 (500mg or less i.v. bolus pre, intra or post-operatively), day -2 (125mg i.v. bolus) for heart transplantation recipients. Day -1 (500mg or less i.v. bolus pre, intra or post-operatively), day 1 (125mg i.v. bolus) for lung/pancreas/SPK recipients. Prednisolone or equivalent: day -1 to 14 (20mg/day), day 15 to 28 (15mg/day), day 29 to 42 (10mg/day), Day 43 to 407 (≥ 5mg/day) for heart transplantation recipients. Day 2 to 14 (20mg/day), day 15 to 28 (15mg/day), day 29 to 42 (10mg/day), Day 43 to 407 (≥ 5mg/day) for lung/pancreas/SPK recipients.
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Jul 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Taiwan: 5
    Worldwide total number of subjects
    17
    EEA total number of subjects
    12
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This multinational, multicenter study was conducted at 6 contracted sites in a total of 5 countries: Austria, France Italy (2 sites), Taiwan and United Kingdom. Due to poor recruitment the study was terminated early.

    Pre-assignment
    Screening details
    Eligibility took place baseline day -3 and day -2 prior to day 1/Visit 1 for heart transplant recipients and on day -1 for lung/pancreas/SPK recipients. Screening assessments: patient data, pregnancy test, donor/organ data, surgical details, physical examination (including body weight), vital signs and routine laboratory evaluations were performed.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable as this is an open label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Advagraf
    Arm description
    Advagraf in strengths of 0.5mg, 1mg, 3mg and 5mg capsules for once daily oral administration.
    Arm type
    Experimental

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    FK506E (MR4)
    Other name
    MR4, Tacrolimus, Tacrolimus modified release, Tacrolimus prolonged release formulation
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Advagraf® was defined as study drug, considered IMP and provided by the Sponsor, available as hard gelatin capsules with 0.5 mg, 1 mg, 3 mg and 5 mg of tacrolimus. Dosing of Advagraf: heart transplant recipients: initial dose was 0.075mg/kg/day given orally (one dose), administered at 3 days (72 hours) post skin closure (Day 1) in the morning. Lung transplant recipients: initial dose was 0.075mg/kg/day given orally in one dose, administered in the morning following skin closure. Pancreas/SPK transplant recipients: initial dose was 0.2 mg/kg/day orally (one dose), administered in the morning following skin closure. Subsequent doses were taken orally once a day only in the morning. Advagraf was taken on an empty stomach or at least one hour before or 2 to 3 hours after meal. Dose adjustments were based on clinical evidence of efficacy/occurrence of adverse events (AEs)/observing the following recommended Tacrolimus blood trough levels: Day 1-42 10-20 ng/ml, Day 43-407 5-15 ng/ml.

    Arm title
    Prograf
    Arm description
    Prograf in strengths of 0.5mg, 1mg and 5mg capsules for twice daily oral administration.
    Arm type
    Active comparator

    Investigational medicinal product name
    Prograf
    Investigational medicinal product code
    FK506
    Other name
    Tacrolimus, Tacrolimus immediate release formulation
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Prograf® was defined as study drug, considered to be IMP and provided by the Sponsor, available as hard gelatin capsules with 0.5 mg, 1 mg and 5 mg of tacrolimus. Dosing of Prograf: heart transplant and lung recipients: initial total daily dose was 0.075mg/kg/day given orally (two doses) (equals 0.0375mg/kg) in the morning and the evening, first dose was to be administered 3 days (72 hours) post skin closure in the morning. Pancreas/SPK transplant recipients: initial dose was 0.2mg/kg/day given orally in two doses (equals 0.1mg/kg), first dose was to be administered in the morning following skin closure. Subsequent doses were taken orally twice a day in the morning and evening. Prograf was taken on an empty stomach or at least one hour before or 2 to 3 hours after the meal. Dose adjustments were based on clinical evidence of efficacy/occurrence of AE’s/observing the following recommended Tacrolimus blood trough levels: Day 1-42 10-20 ng/ml, Day 43-407 5-15 ng/ml.

    Number of subjects in period 1
    Advagraf Prograf
    Started
    8
    9
    Completed
    6
    8
    Not completed
    2
    1
         Randomized but not treated
    1
    -
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Advagraf
    Reporting group description
    Advagraf in strengths of 0.5mg, 1mg, 3mg and 5mg capsules for once daily oral administration.

    Reporting group title
    Prograf
    Reporting group description
    Prograf in strengths of 0.5mg, 1mg and 5mg capsules for twice daily oral administration.

    Reporting group values
    Advagraf Prograf Total
    Number of subjects
    8 9 17
    Age categorical
    Age values provided are for the total randomized population.
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    8 9 17
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Gender values provided are for the Full Analysis Set (FAS) population. The FAS consisted of all patients transplanted and randomized who received at least one dose of study drug.
    Units: Subjects
        Female
    4 0 4
        Male
    3 9 12
        Not recorded
    1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Advagraf
    Reporting group description
    Advagraf in strengths of 0.5mg, 1mg, 3mg and 5mg capsules for once daily oral administration.

    Reporting group title
    Prograf
    Reporting group description
    Prograf in strengths of 0.5mg, 1mg and 5mg capsules for twice daily oral administration.

    Primary: Systemic exposure area under the plasma concentration – time curve (AUC)0-24h of tacrolimus after first dose and under steady state conditions

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    End point title
    Systemic exposure area under the plasma concentration – time curve (AUC)0-24h of tacrolimus after first dose and under steady state conditions [1]
    End point description
    FAS population. AUC0-24h was calculated using the trapezoidal rule. N equals number of patients with pharmacokinetic data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 3, Day 7 and Day 42. For Days 3, 7 and 42 profile was to be performed after a minimum of 3 days without a dose change.
    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: Since the enrollment for the study was terminated early due to poor recruitment, the data obtained are insufficient to make any meaningful comparison of systemic exposure of tacrolimus between the 2 treatment regimens.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: ng/mL.h
    arithmetic mean (standard deviation)
        Day 1 [N=7,8]
    244.97 ± 214.59
    339.91 ± 197.89
        Day 3 [N=7,9]
    439.55 ± 287.91
    412.62 ± 233.45
        Day 7 [N=6,5]
    437.34 ± 222.87
    231.47 ± 34.51
        Day 42 [N=5,6]
    335.52 ± 41.7
    334.03 ± 140.87
    No statistical analyses for this end point

    Primary: Safety as assessed by recording adverse events, laboratory assessments and vital signs

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    End point title
    Safety as assessed by recording adverse events, laboratory assessments and vital signs [2]
    End point description
    Treatment-emergent Adverse Events (TEAEs) were AEs observed at the same time as or after starting administration of the study drug, and before the start of another treatment, if any. A treatment-related TEAE was defined as a TEAE whose relationship to study drug was assessed as “possible” or “probable” by the investigator, or whose relationship to study drug is missing. FAS population. Only one death occurred after patient was discontinued from the study but during serious adverse event 30 day follow-up window.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug until end of study. Treatment was a total of 58 weeks.
    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: Since the enrollment for the study was terminated early due to poor recruitment, the data obtained are insufficient to make any meaningful comparison of systemic exposure of tacrolimus between the 2 treatment regimens.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: Participants
        Any TEAE
    7
    9
        Drug-related TEAEs
    5
    7
        Deaths
    0
    1
        Serious TEAEs
    2
    6
        Drug-related Serious TEAEs
    1
    2
        TEAEs Leading to Discontinuation
    0
    0
        Drug-related TEAEs Leading to Discontinuation
    0
    0
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax)

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    End point title
    Maximum Concentration (Cmax)
    End point description
    FAS population. N equals number of patients with pharmacokinetic data.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 7 and Day 42.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 [N=7,9]
    20.03 ± 15.77
    20.45 ± 13.17
        Day 3 [N=7,9]
    29.46 ± 13.35
    24.32 ± 13.67
        Day 7 [N=6,5]
    29.32 ± 15.41
    16.97 ± 6.56
        Day 42 [N=5,6]
    27.16 ± 5.85
    25.08 ± 11.25
    No statistical analyses for this end point

    Secondary: Time to Attain Maximum Concentration (Tmax)

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    End point title
    Time to Attain Maximum Concentration (Tmax)
    End point description
    FAS population. If Cmax occurred on more than one time point, the first time it occurred was considered for tmax. N equals number of patients with pharmacokinetic data.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 7 and Day 42.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: hours
    median (full range (min-max))
        Day 1 [N=7,9]
    4 (1 to 6)
    3 (0.5 to 4)
        Day 3 [N=7,9]
    2 (1 to 24)
    2 (1 to 4)
        Day 7 [N=6,5]
    2.5 (1 to 8)
    2 (1 to 3)
        Day 42 [N=5,6]
    2 (1 to 4)
    2 (1 to 4)
    No statistical analyses for this end point

    Secondary: Concentration prior to the morning dose C24 (24 hours after morning dose of once daily advagraf or 12 hours after evening dose of twice daily prograf)

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    End point title
    Concentration prior to the morning dose C24 (24 hours after morning dose of once daily advagraf or 12 hours after evening dose of twice daily prograf)
    End point description
    FAS population. N equals number of patients with pharmacokinetic data.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 7 and Day 42.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 [N=7,8]
    6.91 ± 5.82
    13.6 ± 7.61
        Day 3 [N=7,9]
    15.83 ± 13.09
    14.72 ± 8.61
        Day 7 [N=6,5]
    13.63 ± 8.38
    7.69 ± 1.64
        Day 42 [N=5,6]
    9.19 ± 1.8
    10.91 ± 4.56
    No statistical analyses for this end point

    Secondary: Rejection Episodes

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    End point title
    Rejection Episodes
    End point description
    FAS population.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: Participants
        Biopsy Confirmed Acute Rejection (BCAR)
    0
    2
        Clinical Signs of Acute Rejection
    1
    0
        Clinical Diagnosis of Acute Rejection
    0
    1
    No statistical analyses for this end point

    Secondary: Subject survival

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    End point title
    Subject survival
    End point description
    FAS population. Only one death occurred in the study.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: Participants
    7
    8
    No statistical analyses for this end point

    Secondary: Graft survival

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    End point title
    Graft survival
    End point description
    FAS population. Graft loss was defined as retransplantation, nephrectomy, death or dialysis ongoing at the End of Study or at discontinuation unless superseded by follow-up information.
    End point type
    Secondary
    End point timeframe
    Up to 58 weeks.
    End point values
    Advagraf Prograf
    Number of subjects analysed
    7
    9
    Units: Participants
    7
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until end of study. TEAEs were AEs observed at the same time as or after starting study drug, and before the start of another treatment, if any. Treatment was a total of 58 weeks.
    Adverse event reporting additional description
    An AE is defined as any untoward medical occurrence in a subject administered a study drug and which does not necessarily have a causal relationship with this treatment. FAS population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Advagraf
    Reporting group description
    Advagraf in strengths of 0.5mg, 1mg, 3mg and 5mg capsules for once daily oral administration.

    Reporting group title
    Prograf
    Reporting group description
    Prograf in strengths of 0.5mg, 1mg and 5mg capsules for twice daily oral administration.

    Serious adverse events
    Advagraf Prograf
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 9 (66.67%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Surgical procedure repeated
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Epstein-Barr virus associated lymphoproliferative disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         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
    Pleural effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Heart transplant rejection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreas transplant rejection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Candida sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Advagraf Prograf
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Circulatory collapse
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid neoplasm
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Prostatism
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Incisional hernia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Skin laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Wound dehiscence
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Drug level increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Electroencephalogram abnormal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Plasma cells increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Tumour marker increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchostenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 9 (33.33%)
         occurrences all number
    3
    3
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Lung disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Organising pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    Pneumothorax
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pulmonary hilum mass
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 9 (44.44%)
         occurrences all number
    5
    4
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 9 (22.22%)
         occurrences all number
    3
    3
    Lymphadenopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Thrombocythaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    Loss of consciousness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 9 (33.33%)
         occurrences all number
    4
    3
    Diarrhoea
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 9 (33.33%)
         occurrences all number
    3
    5
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    3
    Inguinal hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Melaena
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    3
    Stomach discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Oliguria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Renal failure chronic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Ureteric stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Hepatic cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hepatic lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Keratosis pilaris
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Osteolysis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 9 (22.22%)
         occurrences all number
    3
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Viral infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early due to poor recruitment. The data obtained are insufficient to draw firm conclusions from the results of this study.
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